Comparison of the binding affinities of some proteins with metal ions.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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In recent year, many monoclonal antibody drugs have been developed, and some of them are practically used in therapy [1, 2, 3]. With respect to catalytic antibodies, they have extensively been developed [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14] for the last two decades from the viewpoint of both basic research and the application, where it has been proved that there are many catalytic antibodies being effective against anti-rabies virus [15], anti-influenza virus [16], anti-Helicobacter pylori [17], anti-HIV [7, 8, 10], anti-Alzheimer’s disease [14, 18], etc. Interestingly, some of them have been advanced to the stage tested in vivo in this decade [15, 16, 17, 18, 19]. In the case of catalytic antibodies, some of them play the role as a whole structure of IgG [5, 9, 11, 13], IgA [20], or IgM [21, 22, 23]. On the other hand, in some cases, their subunits (light chain or heavy chain) exhibit unique functions [1, 2, 3, 4, 6, 7, 8, 12]. Once the antibody subunits are separated, the structure of the light or heavy chain becomes flexible and has a tendency to possess structural diversity (or molecular heterogeneity). Regarding structural heterogeneity, it was found about 20 years ago that a whole antibody possesses the structural heterogeneity. These studies were extensively studied by Harris et al. [24] and
We have also reported about the molecular heterogeneity caused by different electrical charges and different molecular size in mouse monoclonal antibody [28]. This phenomenon is not good for the preparation efficacy, high reproducibility, and practical application. In addition, the structural diversity leads us to ask what structure plays the most important role in exhibiting the catalytic antibody functions. It also provides us with another subject of how we can best make a significant structure with high reproducibility and productivity.
\nWe have recently found a crucial method to solve the heterogeneity problem by using copper ion, which can convert the multi-molecular forms into mono-molecular forms for many recombinant human antibody light chains. In addition, the constant region domain of the light chain (CL) plays an important role in generating a mono-molecular form.
\nIn this review, we will describe a novel method for preparing a single and defined mono-form structure in detail.
\nWe have found an interesting phenomenon in 2D-gel electrophoresis for mouse type monoclonal antibodies (mAbs), which were prepared against the hemagglutinin molecule of influenza virus [29]. In the experiment, these monoclonal antibodies showed many different spots at the same molecular size [28]. Figure 1a shows the results using InfA-9 mAb. In the case, the whole antibody and the subunits, heavy and light chains separated and purified from the parent whole antibody, were analyzed by 2D-gel electrophoresis. In Figure 1a, many spots in the whole antibody of InfA-9 are shown. The clear four spots (pI = 6.0, 6.1, 6.2 and 6.5) in the heavy chain and three spots (pI = 5.9, 6.1 and 6.5) in the light chain were detected. Except these spots, many faint spots were observed in the same molecular size (the spots observed over the heavy chain were unknown). Then, the heavy and light chains were separated from the whole antibody of InfA-9, highly purified, and submitted to 2D-gel electrophoresis. The results exhibited the similar phenomena. In the heavy chain, similar spots are seen, and clear five spots (pI = 6.1, 6.3, 6.5, 6.7 and 6.9) were detected in this case. The pI positions of the spots were a little bit different compared to the whole antibody. For the case of the light chain, clear six spots (pI = 5.7, 5.9, 6.0, 6.1, 6.2 and 6.7) were detected. The number of spots increased compared with those of the whole antibody. These phenomena are not exceptional, but general. The mAb, InfA-15, exhibited similar results. Figure 1b shows 2D-gel electrophoresis using InfA-15 mAb. In the results of the whole antibody and the heavy chain and the light chain, the pattern of spots were a little different from those of InfA-9 mAb, but several different pI spots were observed in all cases. Namely, different pI spots are present at the same molecular size in any mAb. Note that structural diversity (molecular heterogeneity) should be existing even in the monoclonal antibody and the subunits, while they are a single protein. In our case, it is considered that the various electrical charges of the molecule may be one of the causes.
\n2D electrophoresis for mouse type monoclonal antibodies against hemagglutinin molecule of influenza virus. SDS-PAGE; Running gel 12.5%. Strip; pH 3–10 nonlinear 7 cm. Sample; whole antibody 3.2 μg, heavy and light chain: 1.6 μg. Staining; deep purple (GE Healthcare). (a) InfA-9 monoclonal antibody. Whole antibody: many spots are seen in the whole antibody of InfA-9. The clear four spots (pI = 6.0, 6.1, 6.2 and 6.5) in the heavy chain and three spots (pI = 5.9, 6.1 and 6.5) in the light chain were detected. Heavy chain (H): clear five spots (pI = 6.1, 6.3, 6.5, 6.7 and 6.9) were detected. The pI positions of the spots were a little bit different compared to the whole antibody. Light chain (L): clear six spots (pI = 5.7, 5.9, 6.0, 6.1, 6.2 and 6.7) were detected. The number of spots increased compared with those of the whole antibody. (b) InfA-15 monoclonal antibody. For the whole antibody and the heavy and light chain, similar results showing many spots at different pI for the same molecular sizes were observed, suggesting that the molecular heterogeneity of antibodies are generally occurring events.
The structural diversity of antibodies has been found about 20 years ago [26, 27], suggesting that an antibody has some different structures (not a mono-form structure) caused by the various electrical charges. Regarding the charge heterogeneity, Harris et al. [24] and Nebija et al. [25, 30] have extensively studied this phenomenon with recombinant antibodies using capillary isoelectric focusing and 2D-gel electrophoresis.
\nThe former paper [24] pointed out a deamidation of Asn residues in the protein.
\nThe latter papers showed multiple spots of pI spreading at heavy and light chains, caused by generation of charge-related isoforms. The pI spreading pattern in 2D-gel electrophoresis [30] is similar to our cases. The effects of sugar chains are also taken into account for molecular heterogeneity.
\nAs it is well known that an antibody light chain has no sugar chain, this can be excluded for this subunit. Thus, in our case, it is thought that the structural diversity is mostly due to the heterogeneity of the different electrical charges. In addition, the possibility of deamidation is excluded because it is hardly considered that the addition of a copper ion causes a reverse reaction of the deamidation and the heterogeneity is lost.
\nIn this section, we will describe the phenomena of structural diversity using full-length light chains of human antibodies. Figure 2a shows the amino acid sequences of human antibody kappa light chains of C51, #4 and #7. The proteins were expressed in Escherichia coli in accordance with the protocol described in the section of Materials and Methods in Refs. [19, 31, 32]. Methionine was adducted at the N-terminus and confirmed by amino acid sequence analysis after cloning the cDNA of the light chain into the Nco I site of the pET-20b vector. Leu and Glu residues were inserted by employing the Xho I site before a histidine–tag (His × 6) included in the vector for purification.
\nC51 light chain. (a) Amino acid sequences of human light chains (kappa type). (b) First-step purification of C51 light chain. (b-1) Steps from E. coli culture to Ni-NTA column chromatography. (b-2) Ni-NTA column chromatogram for C51 light chain. (b-3) Results of SDS-PAGE of fraction 28–45. C51 light chain was mainly the monomer form with a slight contamination of dimer forms at approximately 45 kDa. (c) Cation exchange chromatography as the second-step purification without copper ion. Several peaks were observed from 15 to 27 min. The peaks 1, 2, and 3 were the monomer, the mixture of monomer and dimer, and the dimer, respectively. (d) Cation exchange chromatography as the second-step purification with addition of 0.5 eq. copper ion in cell suspension. A main peak (peak 4) was observed at the retention time of 26 min but other peaks (1–3) were small. The SDS-PAGE gave a dimer for peak 4. (e) Cation exchange chromatography as the second-step purification with addition of 0.5 eq. copper ion in the Ni-NTA eluent. Only a main peak (peak 3) was observed at the retention time of 26 min but other peaks (1 and 2) were scarcely detected. The SDS-PAGE gave a dimer for peak 3. The addition of Cu2+ led to formation of dimers.
After the transformed E. coli cells were recovered by centrifugation, they were sonicated. Then, the soluble fraction was subjected to purification using Ni-NTA affinity chromatography. The result of a Ni-NTA affinity chromatography for the C51 light chain is shown in Figure 2b. The C51 light chain was eluted from fraction 28 (Fr.28) to Fr.44. Fr.35 showed the maximum absorbance. Fr.35 was collected and analyzed by SDS-PAGE with CBB staining, where the C51 light chain was mainly the monomer form with a slight contamination of dimer forms.
\nThe eluted fractions from Fr.30 to Fr.40 were collected and subjected to a cation exchange chromatography. Figure 2c shows the chromatogram, where several peaks were observed. The SDS-PAGEs of the peaks were shown in the figure on the right side. The peaks 1, 2, and 3 were the monomer, the mixture of monomer and dimer, and the dimer, respectively.
\nTwenty μM of CuCl2 (Cu2+) was added to either the cell suspension after recovery of the cells (cell-suspension) or the eluent of Ni-NTA chromatography (Ni-NTA eluent). By the addition of Cu2+ to the cell suspension, the chromatogram changed to that shown in Figure 2d, where a main peak (peak 4) was observed at the retention time of 26 min but other peaks (1, 2 and 3) were small. The SDS-PAGE gave a dimer for peak 4. In Figure 2e, 20 μM of Cu2+ (0.5 equivalent to the light chain) was added to the Ni-NTA eluent. In this case, only a main peak (peak 3) was observed at the retention time of 26 min but other peaks (1 and 2) were scarcely detected. The SDS-PAGE gave a dimer for peak 3. The addition of Cu2+ led to dimer formation.
\nMass spectroscopic (MS) analysis was performed for the main peaks observed above (data not shown). Briefly, a monomeric light chain was detected at 25,000 m/z and a dimer at 49,000 m/z. A small trimer and tetramer were also detected at 74,000 and 98,000 m/z, respectively. By the addition of Cu2+ to the cell suspension or the Ni-NTA eluent, the signal for the monomer was substantially reduced. Conclusively, the addition of Cu2+ was effective for the formation of the dimer.
\nIn order to examine the pI of the light chain, 2D-gel electrophoresis was performed with and without the addition of Cu2+. The results are shown in Figure 3a and b. In the case without Cu2+, many spots at different pIs were observed with the same molecular size of 31 kDa (Figure 3a). The pI spots were widely located from 6.12 to 10.0. The strong spot was observed at pI = 6.45–6.73. In contrast, in the case with the addition of Cu2+, the spots were gathered on the strongest spot at pI = 6.57, while two faint spots were detected at around pI = 6.32 and 6.90 (Figure 3b). It is evident that the electrical charges of the molecule became mono-form by the effect of Cu2+.
\n2D-gel electrophoresis for C51 light chain. (a) Without copper ion. The pI spots were widely located from 6.12 to 10.0. (b) With copper ion. The spots were gathered on the strongest spot at pI = 6.57, although two faint spots were detected at around pI = 6.32 and 6.90.
It must be invested whether or not the changes from multi-molecular forms to mono-molecular forms by the addition of copper ions is a general phenomenon. The following experiments were carried out.
\nFor the purpose of confirmation of the observed phenomena on the structural diversity, other antibody light chains such as #4 and #7 were examined. As stated above, the chromatogram in Ni-NTA purification is similar for many light chains. Thus, the following is focused on the results of cation exchange chromatography, which were very different in each light chain used. The effect of copper ions on the diversity issue will be discussed.
\nThe cation chromatograms for #4 light chain are shown in the cases without and with Cu2+ as presented in Figure 4a and b, respectively. In the case without Cu2+, there were several peaks. The results of SDS-PAGE (non-reduced condition) corresponding to three peaks are also shown. The observed peaks were a mixture of monomers and dimers. Namely, several structurally different light chains caused by different electrical charges are coexisting in the solution. However, when 20 μM of Cu2+ (0.5 equivalent to the light chain) was added to the Ni-NTA eluent, the several peaks in Figure 4a surprisingly became a single peak (Figure 4b), which was mainly the dimer.
\nCation exchange chromatography for #4 light chain. (a) Without copper ion. There were mainly three peaks, which were a mixture of monomers and dimers. Namely, several structurally different light chains caused by different electrical charges are coexisting in the solution. (b) With copper ion of 0.5 eq. When 0.5 equivalent to the light chain was added to the Ni-NTA eluent, the several peaks became a single peak of mainly the dimer.
In the case of the chromatography for #7 light chain, huge three peaks were observed in the case without Cu2+ as shown in Figure 5a. The peak of the retention time at 9 min was the monomer. The peak at 13 min was a mixture of monomer and dimer. The peak at 22 min was also a mixture. Note that light chains possess different molecular sizes and electrical charges in solution.
\nCation exchange chromatography for #7 light chain. (a) Without copper ion. Huge three peaks were observed. The peak of the retention time at 9 min was the monomer, peak at 13 min was the mixture of monomers and dimers, and peak at 22 min was a mixture. In this case, the light chains possess different molecular sizes and electrical charges in solution. (b) With copper ion of 0.38 eq. Two peaks at 12 min and 23 min retention time were observed and both peak A and peak B were dimers. (c) With copper ion of 1.0 eq. Only peak C, which corresponds to peak A in (b), was observed at 12 min as the dimer form.
When 15 μM of Cu2+ (0.38 eq.) was added to the Ni-NTA eluent, two peaks at 12 min and 23 min of retention time were observed in the chromatography. The results of SDS-PAGE analysis (Figure 5b) indicated that both peak A and peak B were dimers. It is interesting that two kinds of dimers with different electrical charges were coexisting. When 40 μM of Cu2+ (1.0 eq.) was added to the same eluent, only peak C, which corresponds to peak A in Figure 5b, was observed at 12 min and peak B was not detected (Figure 5c). It is thought that peak B moved to peak A in Figure 5b. Conclusively, the dimeric light chains possessing two kinds of electrical charges became one kind of state possessing a unique electrical charge by the addition of 40 μM of Cu2+.
\nA chemical analysis of Cu2+ gave interesting results. The ratio of Cu to light chain (Cu/light chain) is 0.48, 0.03, and 0.64 for peaks A, B and C, respectively. When the ratio of Cu/light chain was 0.48 in Figure 5b and 0.64 in Figure5c, the dimer was eluted at 12 min. In contrast, at a ratio of 0.03, the retention time was 23 min. These results suggest that whenever enough Cu2+ is present in the solution, an electrically homogeneous light chain could be observed at a retention time of 12 min.
\nUV/VIS spectroscopy for these peaks was also conducted. The results are shown in Figure 6. We could see the absorbance around 560 nm, which is assigned to the absorbance of the interaction of cupper with the amino acids for peak A and peak C, but not for peak B, whose spectrum was very similar without copper ion.
\nUV/VIS spectroscopy. The absorbance around 560 nm, which is assigned to the absorbance of the interaction of a copper ion with the amino acids, was observed for peak A and peak C, but not for peak B. It is obvious that peak B has no copper ion.
In order to investigate the morphology of antibody light chains, we conducted atomic force microscopy (AFM) analysis. The peaks of A, B, and C were collected and subjected to AFM analysis as shown in Figure 7a–c. Figure7a shows the AFM image for peak A. The images for peak B and C are shown in Figure 7b and c, respectively. The red circle represents the clear image of the dimeric light chain. The size of the dimer was roughly estimated at an approximate length of 20 nm, the width of 10 nm, and the height of 4 nm. The lateral and height length are comparable with the AFM image of IgG by Querghi et al. [33]. We could not identify the position of the copper ion residing in the light chain from this AFM analysis.
\nAFM analysis. The peaks of A, B, and C were collected and subjected to AFM analysis. The red circle represents the clear image of the dimeric light chain. (a) Peak A included Cu2+ with the ratio of Cu/#7 light chain = 0.48. (b) Peak B did not include Cu2+ (Cu/#7 light chain = 0.03). (c) Peak C included Cu2+ with the ratio of Cu/#7 light chain = 0.64. The size of the dimer was roughly estimated at an approximate length of 20 nm, the width of 10 nm, and the height of 4 nm.
In the previous section, we focused on a full-length light chain, which is consisted of the variable and the constant domain. It is noteworthy to study which domain, the former or latter, causes the structural diversity problem. Although there are many studies on the role of the constant domains (especially for a Fc region) of the heavy chain of the antibody, the reports on the role of the constant region domain of the light chain are scarcely seen. From this point of view, we investigated the role of the constant domain as described in the following.
\nFigure 8 shows the amino acid sequence of the recombinant constant region domain (kappa type) of a human antibody light chain employed in this study. Methionine (M) and alanine (A) at position nos. 1 and 2 of the aa sequence have been inserted by cloning using the restriction enzyme Nco I. Underlined is the sequence of the constant region domain. Arginine (R) at position no. 3 is the first amino acid residue of the constant region. Leucine (L) and glutamic acid (E) before His × 6 were also inserted by using the restriction enzyme (Xho I).
\nAmino acid sequence of the constant region domain of a human antibody light chain (kappa type). Underlined is the aa sequence of the constant region domain of the kappa light chain. Methionine (M) and alanine (A) of the aa sequence at the first and second position were inserted by cloning using the restriction enzyme Nco I. Arginine (R) at the third position is the first amino acid residue of the constant region. Leucine (L) and glutamic acid (E) before His × 6 were also inserted by cloning using the restriction enzyme Xho I.
The expression and purification of the kappa type constant domain were similarly conducted as made in the full-length light chain. Ni-NTA chromatography was also performed to purify the recovered constant region domain. The result was also similar with that obtained in the case of full-length light chain except for the molecular size. The SDS-PAGE analysis for the collected fraction in the Ni-NTA chromatography is shown in Figure 9. Under non-reduced condition, a strong band was detected in the monomeric form at 15 kDa as well as a weak band in the dimeric form at 30 kDa. Under reduced condition, only the monomeric form was observed and the purity was over 95%. This sample was applied to cation exchange chromatography. The results are shown in Figure 10 along with the SDS-PAGE analysis under non-reduced condition. Several peaks were observed at retention times from 5 to 25 min while it was a single material of the constant domain. In Figure 10, peak 1 appearing at the retention time of 7.5 min is a monomer, and peaks 2, 3, and 4 appearing at 14–17 min contain mainly monomers. The dimers or/and trimer were detected for peaks 2 and 4. Peaks 5 and 6 appearing at 21–23 min are the dimer. These results mean that differently charged molecules of the constant region domain as well as differently sized molecules coexisted in solution at the same time. It is obvious that a constant region molecule shows molecular heterogeneity (structural diversity) from the viewpoint of both electrical charge and molecular size, which are very similar with those observed in the full-length light chain.
\nSDS-PAGE of the constant region domain after Ni-NTA chromatography. Under non-reduced condition, a strong band was detected in the monomeric form at 15 kDa as well as a weak band in the dimeric form at 30 kDa. Under reduced condition, only the monomeric form was observed and the purity was over 95%.
Cation exchange chromatography for the constant region domain molecule of the light chain (CL). Peak 1 appearing at the retention time of 7.5 min is a monomer and peaks 2, 3, and 4 appeared at 14–17 min contain mainly monomers. The dimers or/and trimer were detected for peaks 2 and 4. Peaks 5 and 6 appearing at 21–23 min are the dimer. These results mean that differently charged molecules of the constant region domain as well as differently sized molecules coexisted in solution at the same time. This result was very similar with that observed with the full-length light chain.
As stated previously, copper ion (Cu2+) hugely influenced the structural diversity of the full-length light chain. The same experiment was performed with the constant region domain molecule. The results are summarized in Figure 11a–f. In the case of 0.1 eq. addition of Cu2+ for the constant region domain molecule, we observed a small peak 7 and one main peak 8, which were eluted at the retention time around 16 and 22 min, respectively (Figure 11a). Peak 8 was the dimer by the SDS-PAGE analysis under non-reduced condition (peak 7 was not analyzed because of the small peak). In the case of 0.2 eq. addition of copper, mainly two peaks (9 and 10) were obtained (Figure 11b). The elution times of peaks 9 and 10 were identical with those of peaks 7 and 8, respectively. Peak 9 included mainly the dimer with a very slight amount of the monomer. Peak 10 was the dimer. For these two peaks, UV/VIS spectroscopy was performed. The results are presented in Figure 12. Peak 9 showed an absorbance of around 580 nm, which was based on the interaction of Cu2+ and amino acids of the constant region domain molecule. On the other hand, no absorbance was detected for peak 10. Namely, protein of peak 9 bound to Cu2+ but peak 10 did not. Though the peaks are dimeric forms of the constant region domain, they were separated by the cation exchange column chromatography whether or not the peak contains Cu2+. For the case of 0.3 eq. addition, the main peak was peak 11 observed at the retention time of 16 min, which included the dimer along with a slight monomer and trimer forms (Figure 11c). In the case of 0.4 eq. addition, a clear single peak of the dimer form was detected at the retention time of 16 min (Figure 11d). In Figure 11e and f, peaks 13 and 14 were observed as single peak at the retention time of 16 min. And they were the dimer. It seems that enough content of added copper ion was 0.4 eq. to induce mono-form formation from the multi-forms of the constant region domain molecule.
\nEffect of copper ions. (a) 0.1 eq. addition of Cu2+: a small peak 7 and one main peak 8 were observed at the retention time around 16 and 22 min, respectively. Peak 8 was the dimer. (b) 0.2 eq. addition of Cu2+: the eluted times of peaks 9 and 10 were identical with those of peaks 7 and 8, respectively. Peak 9 included mainly the dimer with a very slight contamination of the monomer. Peak 10 was the dimer. (c) 0.3 eq. addition of Cu2+: peak 11 was observed as the main peak at the retention time of 16 min. (d) 0.4 eq. addition of Cu2+: A clear single peak of the dimer form was detected at the retention time of 16 min. (e) 1.0 eq. addition of Cu2+: only peak 13 was observed at the retention time of 16 min. It was the dimer. (f) 10.0 eq. addition of Cu2+: only peak 14 was observed at the retention time of 16 min. It was also the dimer. It seems that the amount of 0.4 eq. added copper ions is sufficient to induce the mono-molecular form from the multi-molecular forms of the constant region domain molecule.
UV/VIS spectra. Peak 9 showed the absorbance of around 580 nm, which was based on the interaction of Cu2+ and amino acids of the constant region domain molecule. On the other hand, no absorbance was detected for peak 10.
The amount of Cu2+ bound to the constant region domain molecule was also quantified using a commercially available copper detection kit (Copper, Low Concentration, Assay Kit, AKJ, CU21M, Metallogenics Co., Ltd., Chiba, Japan). For the peak appearing at the retention time of 16 min and containing Cu2+, the ratio of Cu2+: constant region domain was around 0.55. This result agreed with those of the UV/VIS spectroscopy, suggesting that two constant region domain molecules bind one copper ion.
\nThe UV/VIS spectrum changed as different concentrations of Cu2+ was added to the Ni-NTA elution after the samples were dialyzed against PBS. The results are presented in Figure 13. The absorbance of 580 nm became larger along with an increase in the amount of added Cu2+, as showing a slight red shift. In Figure 14, the values for the concentration of added Cu2+ were plotted vs. the maximum absorbance, which is the absorption isotherm curve for Cu2+ binding to constant region domain molecules. The Langmuir plot is shown in the inset of Figure 14, indicating a good linear relationship. The binding constant was estimated to be 48.0 μM−1.
\nSpectrum changes with the concentration of added Cu2+. Along with an increase of the concentration of added Cu2+, the absorbance at around 580 nm became larger.
Kinetic analysis. The values for the concentration of added Cu2+ were plotted vs. the absorbance at 580 nm, which is the isothermal curve for copper binding to the CL protein. The Langmuir plot is presented in the inset of the graph, indicating a good linear relationship. The binding constant was estimated to be 48.0 μM−1.
The binding affinity from several proteins incorporating divalent metal ions was investigated. The values (K) are presented in Table 1. Hemocyanin and metallothionein have very strong affinity to bind Cu2+. Carbonic anhydrase-binding Zn2+ shows a strong affinity. Aminopeptidase III binding Co2+ possesses a weak affinity. In the case of CL, the value (48.0 μM−1) seems to be intermediate among those metalloproteins.
\nProteins (metal ion) | \nK (M−1) | \nAffinity | \n
---|---|---|
Hemocyanin (Cu2+) | \n1017–1019 | \nVery strong | \n
Metallothionein (Cu2+) | \n1017–1019 | \nVery strong | \n
Carbonic anhydrase (Zn2+) | \n~1012 | \nStrong | \n
Aminopeptidase III (Co2+) | \n2 × 104 | \nWeak | \n
CL (Cu2+) | \n4.8 × 107 | \nMedium | \n
Comparison of the binding affinities of some proteins with metal ions.
In order to further investigate the molecular heterogeneity of the constant region domain molecule, two-dimensional (2D) electrophoresis was performed using samples with or without Cu2+. Figure 15a and b shows the results for the cases without and with the addition of Cu2+under non-reduced conditions, respectively. In the former case, many spots were observed: two spots at pI = 6.9 for the dimer and three spots at pI = 6.2, 6.5, and 6.9 for the monomer. In contrast, one strong spot was observed at pI = 6.9 for the dimer in the case with the addition of Cu2+, while very faint spots were detected in the positions of the monomer. Note that Cu2+ can facilitate changes from the multimeric form to the monomeric form as well as from different electrical charges to a single electrical charge.
\n2D electrophoresis for the constant region domain (CL). (a) Without Cu2+: two spots at pI = 6.9 for the dimer and three spots at pI = 6.2, 6.5, and 6.9 for the monomer were found. (b) With Cu2+: one strong spot was observed at pI = 6.9 for the dimer. It is revealed that copper ion accelerates both dimerization and generation of a mono-molecular form of the light chain.
About 1.0 eq. of a metal ion such as Ca2+, Mg2+, Ni2+, and Zn2+was added in each Ni-NTA elution and incubated overnight. Figure 16 shows the results of the cation exchange chromatography and SDS-PAGE (non-reduced) for peaks P3 and P5. For the cases of Ca2+, Mg2+, and Ni2+ (Figure 16a–c, respectively), a large peak P3 was observed at 17 min along with a small peak P5 at 23 min. Interestingly, a large peak P3 was observed and peak P5 became very small in the case of Zn2+ (Figure 16d). The chromatogram resembled the case of Cu2+ (Figure 16e). From the results of the SDS-PAGE, the peak P3 was mostly in a monomeric form for all the cases of Ca2+, Mg2+, Ni2+, and Zn2+. On the other hand, P3 of Cu2+ was the dimer. The molecular form (size) of P3 in the case of Ca2+, Mg2+, Ni2+, and Zn2+ was quite different from that of Cu2+. It must be considered that the Zn2+ could not accelerate the dimerization of the constant region domain molecule, while the ion decreased the peak P5 and showed a large peak P3. Zn2+ could have some ability to unify the structural diversity, but the effect is different from that of copper.
\nOther metal ions. In all cases, 1.0 eq. metal ion was added. Cation exchange chromatograms are presented with the results of SDS-PAGE (under non-reduced condition). m: monomer; di: dimer. (a) Addition of Ca2+. (b) Addition of Mg2+. (c) Addition of Ni2+. (d) Addition of Zn2+. (e) Addition of Cu2+. Peak P3 was mostly in a monomeric form for all the cases of Ca2+, Mg2+, Ni2+ and Zn2+. In the cases of addition of Ca2+, Mg2+, and Ni2+ (Figure 16a–c, respectively), a large peak, P3, was observed at 17 min along with a small peak, P5, at 23 min. In the case of Zn2+ (Figure 16d), a large peak P3 was observed and peak P5 became very small. The chromatogram seemed to be like the case of Cu2+.
Zn2+ did not accelerate the dimerization of the constant region domain molecule but has some functions that may contribute to solve the heterogeneity problem. Out of the several metals analyzed, Zn2+ exhibited an interesting behavior, which must be a characteristic feature of Zn2+. Although there are several reports on the relationship between metal ions and the enzymatic activity of catalytic antibodies, details of the contributions of metal ions to the molecular structure of catalytic antibodies are unclear at present [20, 34]. Paul et al. reported an interesting function regarding Zn2+, which was essential for exhibiting the catalytic function of the antibody light chain to cleave beta-amyloid peptides, while the ion will not affect the catalytic site [14].
\nFor the reason why the addition of copper hugely effects the formation of a mono-form structure of the constant light chain domain, we postulated one of the situations from the viewpoint of potential energy and the wall height as illustrated in Figure 17. It is likely that the energy potential of each molecular form is at a comparable level after the preparation of the molecule (CL) without Cu2+, as shown in Figure 17a. In this case, transfer of the potential well A to B (or C) is easy because the walls of the potential energies of the wells are low (Figure 17b). However, the energy potential is drastically changed when copper ions are added. The multi-molecular forms of the constant region domain, which are sitting in each potential well, drop in one deep potential energy level, as shown in Figure 17c, resulting in the formation of a mono-molecular form from the multi-molecular forms. Once the molecule dropped into the deep potential well, the form would be no longer able to transfer to other forms. As a consequence, the monomolecular form of the constant region domain molecule became stable. This situation can be achieved by the presence of copper ion in a ratio of more than 0.5 eq. of Cu2+ to the constant region domain molecule.
\nConsideration about conversion of unstable forms to a stable form of CL. (a) State A (corresponding to peak 1 in Figure 10), State B (corresponding to peaks 2, 3, and 4 in Figure 10), and State C (corresponding to peaks 5 and 6 in Figure 10) may stay in a chemical equilibrium. (b) Assumed situation in potential energy for the case without Cu2+: each potential energy level for the case without Cu2+ may be comparable in wells of A, B, and C. The walls among the potential energy wells are not high. (c) Assumed situation of potential energy for the case with Cu2+: when Cu2+ is incorporated, a deep potential level can be generated, and all molecules showing a different heterogeneity may drop into the well and exist as a stable form.
In order to clarify the copper-binding site, two mutants were prepared from the C51 light chain, because the light chain has no histidine residues in the variable region compared to the sequence of the constant region domain comprising 2 His residues (Figure 8). Both histidine and cysteine residues are considered as the most plausible candidates for the binding site. Therefore, the residues of His195, His204, and Cys220 present in the constant region domain of the C51 light chain were mutated to Ala. As the consequence, two mutants were made. One is Cys220Ala (C220A: mono-mutant) and another is His195Ala, His204Ala, and Cys220Ala (H195A/H204A/C220A: triple-mutant; Figure 18a). The locations of the mutated residues are shown in Figure 18b.
\nC51 mutants and locations of His and Cys residues. There are no histidine residues in the variable region of the C51 light chain. (a) Location of Cys220, His195 and His204 in wild type. The mutated positions, C220A and H195A/H204A/C220A, are also indicated with green colored character. (b) Three-dimensional structure of the C51 light chain. Light blue is sheet structure and red is helix structure.
These mutants were similarly expressed and purified as stated in the previous experiments. Fifty μM of Cu2+ (1.25 eq.) was added to both the cell suspension and the Ni-NTA eluent, where all light chains gave a single peak in the cation exchange chromatography. The copper uptake by the wild type and each mutant was chemically analyzed and the results are presented in Table 2. The wild type possessed 0.75 atoms of Cu2+ per one C51 light chain of full length. That of the C220A and H195A/H204A/C220A mutant was 0.54 and 0.25, respectively.
\n\n | \n
Copper uptake by each light chain and constant region domain (CL).
As stated in the above section, the value in the case of the constant region domain was 0.55. Taking together this finding and the full-length cases into account, it is considered that the variable region domain uptakes 0.20 atom (0.75–0.55 = 0.20). Therefore, the mono-mutant C220A is supposed to bind with 0.34 atom-Cu (0.54–0.20 = 0.34) and the triple-mutant H195A/H204A/C220A 0.05 atom-Cu (0.25–0.20 = 0.05). These facts are strongly implying that histidine residues at positions 195th and 204th as well as cysteine at position 220th are responsible for the copper-binding site.
\nIt is not well known that there is a zinc finger-like motif in the constant region of the antibody light chain. Interestingly, Radulescu pointed out that the motif is a type of Cys-X3-His [35]. The sequence Cys-X3-His-X15-Cys-X3-His is a complete motif of a zinc finger. The aa sequence of the constant region domain used in this article is presented in Figure 8. The sequence from positions 190th–224th of the constant region domain is CEVTHQGLSSPVTKSFNRGECLEHH. The sequence of LEHH was adducted as a His-tag was introduced. The underlined amino acids agree with those of the zinc finger motif, Cys-X3-His-X15-Cys-X3-His, in which His224 is a part of the His-tag. This motif can uptake a metal ion such as Zn2+, which is a divalent metal ion. As Cu2+ is also a divalent metal ion, it can bound to the motif. Based on the results of the chemical analysis of copper ions in mutants, those histidine and cysteine residues must be responsible to uptake the copper ion. It is plausible that a copper ion is able to bind to the zinc finger motif instead of a zinc ion. As seen in the investigation of divalent metal ions on the structural diversity, zinc ions showed some effect. This maybe ascribed to the presence of a zinc finger motif in the constant domain in the light chain (note that the zinc finger motif is conserved in both human and mouse antibody light chain (kappa type)). In addition, the similar motif composed of the same amino acids exists in the CH1 domain of the heavy chain.
\nAs well known, a zinc finger can function as a transcription factor influencing gene regulation and protein expression. Few studies on the relationship between antibody and zinc finger have been made so far. From the viewpoint that one protein can have dual or multi-functions in case, the chemical and biochemical functions of each domain of an antibody should be investigated in detail.
\nTaking those facts mentioned above and discussed, the binding site of copper is assumed as illustrated in Figure 19. Cu2+ must be coordinated with histidine and cysteine residues of dimeric CL molecules. In this situation, the copper ion mediates the CL molecule placing the lowest potential energy level.
\nAssumed binding site for copper ion. A zinc finger motif, Cys-X3-His-X15-Cys-X3-His, from positions 190th to 224th (His224 is a part of a His-tag) is existing in the constant region domain of the light chain (CL). As Cu2+ is also a divalent metal ion, it can be bound with the motif instead of a zinc ion, unless the ion is present in the solution. By the addition of copper ions, the CL is easily becoming the dimer form. Considering the chemical analysis of copper ions, one copper atom binds with two CL molecules (CL1 and CL2) via His and Cys residues.
AFM analysis was performed using the #4 light chain as shown in Figure 20a–g. Figure 20a, c, and e demonstrates the wild type of the #4 light chain. The results obtained with the mutant (C220A) of the #4 light chain are shown in Figure 20f and g. The red circles in the figures represent the clear image of the AFM.
\nAFM analysis for #4 light chains. These AFM images were taken under the same condition as in Figure 7. (a) #4 wild type (cis form). (b) Molecular modeling for cis form. (c) #4 wild type (trans form). (d) Molecular modeling for trans form. (e) Mixture of cis and trans forms. In the case of the #4 wild type, two kinds of forms were observed. One is the dimer circled with #1 red color (a). This seems to be a cis form, whose molecular conformation corresponds to that of (b). A variable region faces to another variable region. The dimer circled with #2 red color (c) seems to be a trans form, whose molecular conformation corresponds to that of (d). Figure 20e was another view, where cis and trans forms were observed. (f) #4 mutant (C220A). (g) #4 mutant (C220A) (another spot). For #4 mutant (C220A), one simple form was observed. In any views, only monomeric forms were observed.
In the case of the #4 wild type, two kinds of form were observed. One is the dimer circled with #1 red color (Figure 20a). This seems to be a cis form, whose molecular conformation corresponds to that of Figure 20b. A variable region faces to another variable region. On the other hand, the dimer circled with #2 red color (Figure 20c) seems trans form, whose molecular conformation corresponds to that of Figure 20d. Figure 20e was another spot, where cis and trans forms were observed. In contrast, a very simple form was observed in the case of #4 mutant C220A, as shown in Figure 20f and g. In any spots, only monomeric forms were observed.
\nIf copper ion is incorporated into the zinc finger motif residing in the constant region domain, the dimeric form observed in the #4 wild type is easily formed. On the other hand, the mutant C220A exists as the monomeric form, which indicates that the cysteine locating at position 220th is a crucial amino acid to bind to a copper ion.
\nWe are trying to determine the detailed steric conformation of a catalytic light chain. At present, the structure of the main chain of the #4 mutant C220A was clarified as a preliminary experiment. Figure 21a shows a single crystal of the #4 mutant C220A formed in the experiment. By using the single crystal, X-ray diffraction analysis was performed. The result is presented in Figure 21b, where a 3.1 Å resolution was attained. Interestingly, there are eight molecules of the #4 mutant in one lattice mediated by hydrophobic interaction.
\nX-ray diffraction analysis for #4 C220A. (a) crystallization: a single crystal (like a small pillar) of the #4 mutant C220A is seen in a red dotted circle. (b) Conformation of the main chain: As the preliminary experiment, the conformation of the main chain for the #4 mutant 220A was determined. Each #4 mutant molecule is indicated with each color such as red, yellow, green, blue, etc. Eight molecules of the mutant were packed in one lattice, indicating that the mutant molecules may interact with each other by hydrophobic interaction.
In the case of the AFM analysis, the #4 mutant C220A was a monomer. This is ascribed that the mica as the supporting material firmly interacts with the #4 mutant molecule. In solution, the #4 mutant may interact with each other with a strong Van der Waals force.
\nAs stated in the abstract and introduction, the issue of structural diversity (heterogeneity) of antibodies has become a big subject along with the development of antibody drugs and catalytic antibodies. This subject has not been solved for a long period, because many difficult and complex problems were existing. For this long-period unsolved problem, copper ion showed a drastic effect and gave one of the answers for solving the structural diversity issue. Note that the antibody and/or the subunits must have a defined structure for practical use.
\nIn recent years, many possibilities of the development of antibody drugs and catalytic antibodies have been reported by research groups throughout the world. This article offers huge insights into the development of catalytic antibodies, maybe, as well as antibody drugs. Because the preparation can be standardized, many scientists and engineers will easily be able to produce the defined structure and the same functional antibody under any circumstances and anywhere in the world.
\nThis study was supported by the Japan Science and Technology Agency (CREST/“Establishment of Innovative Manufacturing Technology Based on Nanoscience”); “Super Highway”: the accelerated research to bridge university IPs and practical use; and Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (24350085 and 16H02282). The authors thank Oxford Instruments KK (Dr. H. Sugasawa), Dr. Y. Nishikawa (High Energy Accelerator Research Organization), Dr. H. Makio (High Energy Accelerator Research Organization), and Ms. Y. Akiyoshi (Oita University) for the assistance with this study.
\nMuscle mass and strength have been linked to overall health and mortality [1, 2], and improvements in skeletal muscle properties and the prevention of muscle wasting with disuse/atrophy are essential for all individuals, particularly inactive older adults [3]. Sarcopenia is characterized by the loss of skeletal muscle mass and physical function (muscle strength or physical performance) with advancing age [4–6]. It is associated with physical disability, poor quality of life, and increased mortality in older adults [5]. Although the loss of muscle mass and physical function is associated with aging, rates of decline vary across the population [7]. Therefore, modifiable behavioral factors, such as diet, may influence the development of sarcopenia. Since a poor diet and nutritional status are common among the elderly [8–10], improvements in these factors may contribute to the prevention and treatment of sarcopenia, thereby promoting better health in later life for this population [11].
\nThe term diet quality describes how well an individual’s diet conforms to dietary recommendations using a principal component or factor analysis [12, 13]. In older adults, a higher quality diet leads to several positive health outcomes, including a reduced risk of common age-related diseases and greater longevity. For example, a high quality diet is associated with a significantly reduced risk of all-cause mortality, cardiovascular disease, cancer, type 2 diabetes, and neurodegenerative disease, as well as reduced mortality in cancer survivors [14–17].
\nWhile there is growing evidence linking healthier diets with greater muscle strength and better physical performance outcomes in older adults, limited information is currently available on how diet quality influences sarcopenia in older adults [11, 18]. A recent systematic review concluded that the number of longitudinal studies was too small to reach concrete conclusions; however, there is growing evidence for the benefits of adhering to a Mediterranean diet [19–21]. The next section summarizes current epidemiological evidence for the relationship between diet quality and sarcopenia in older adults.
\nThe world’s population is getting older [22]. Based on a 2017 report, the number of adults aged 60 years and older will increase worldwide, from 962 million (or one in eight individuals) in 2017 to 2.1 billion (one in five) by the middle of the 21st century [23]. Several environmental and lifestyle factors may modify the aging process [24], including physical activity [25, 26] and diet [27–29].
\nA large number of observational and intervention studies have used a single-nutrient approach to investigate the relationship between diet and muscle health in aging. However, difficulties are associated with isolating the influence of one dietary component on health outcomes from other components as well as obtaining a clearer understanding of how dietary components interact within a whole diet to affect health outcomes. Previous studies using a whole-diet approach were conducted to clarify the role diet quality plays in muscle health with aging [30–33].
\nTwo main methods of defining diet quality—a priori (hypothesis-driven) and a posteriori (data driven)—have been used to investigate the relationships between diet quality and muscle health in epidemiological studies on muscle aging. The a priori method defines diet quality as adherence to predefined dietary scores or indices based on current knowledge on what constitutes a healthy diet for a particular health condition (e.g., cardiovascular disease or diabetes). In this method, higher scores reflect the greater consumption of beneficial foods (e.g., fruits, vegetables, lean meat, fish, nuts, and low-fat foods) and lower consumption of nutrient-poor foods (e.g., sweets, processed meat, refined grains, and trans-fats) [34–36]. In contrast, the a posteriori method is exploratory, using all available dietary data to define diet quality. This method may be used to describe a population’s normal diet, which may or may not be related to particular health outcomes. In this method, multivariate statistical tools (e.g., a factor principal component analysis [PCA] and cluster analysis) may be used to assess diet quality. While these two tools follow markedly different procedures, they may be used in tandem to improve the interpretability of the data obtained from each method [37].
\nWe reviewed nutritional epidemiology studies on the role of diet quality in muscle health and function in older adults (Table 1). Only eight studies reported a relationship between diet quality (i.e., the amount of nutrients consumed and/or the uptake of specific nutrients from foods) and sarcopenia components [38–45]. Five of these studies were cross-sectional, while three were longitudinal. Study sample sizes ranged between 156 and 2983 participants. The majority of studies were conducted in a community setting (e.g., a nursing home or care facility) and with participants whose mean age ranged between 65 and 75 years.
\nReference | \nPopulation | \nStudy design | \nDiet quality (DQ) | \nPhysical function | \n|
---|---|---|---|---|---|
Robinson et al. (2008) [38] | \nn = 2983 community-dwelling men (n = 1569) and women (n = 1414), 65.7 ± 2.9 years (men) 66.6 ± 2.7 years (women) | \nCross-sectional | \nAdministered FFQ based on EPIC Questionnaire 18, pertaining to the 3-month period preceding the interview. | \nMen and women with high prudent diet scores had stronger grip strengths. | \n|
Martin et al. (2011) [39] | \nn = 628 community-dwelling men (n = 348) and women (n = 280), 67.8 ± 2.5 years (men) 68.1 ± 2.5 years (women) | \nCross-sectional | \nAdministered FFQ pertaining to the 3-month period preceding the interview Data-driven: PCA. A “prudent” dietary pattern was identified. | \nIn women, a higher prudent diet score was associated with a shorter 3-m walk time, shorter chair-rise time, and better balance. | \n|
Bollwein et al. (2013) [40] | \nn = 192 community-dwelling men and women, 83 ± 4 years | \nCross-sectional | \nAdministered FFQ of the German part of the EPIC study. Dietary indices: Adherence to a Mediterranean dietary pattern was assessed using the MED score | \nA relationship was observed between a high MED score and lower risk of a slow walking speed. | \n|
Rahi et al. (2014) [41] | \nn = 156 community-dwelling men (n = 94) and women (n = 62) with type 2 diabetes, 74.3 ± 4.2 years (men) 75.0 ± 4.2 years (women) | \nLongitudinal | \nThree non-consecutive 24-h dietary recalls. Dietary indices; DQ was evaluated at recruitment using the Canadian Healthy Eating Index (C-HEI). | \nGood DQ was combined with stable or increased physical activity, and muscle strength losses were minimal in diabetic older males. | \n|
Hashemi et al. (2015) [42] | \nn = 300 elderly men and women (55 years old and older), 66.8 ± 7.2 years | \nCross-sectional | \nThree major dietary patterns (DP) were identified. a. DP1, Mediterranean b. DP2, Western c. DP3, Mixed | \nParticipants in the highest tertile of DP1 had a lower odds ratio for sarcopenia than those in the lowest tertile. | \n|
Granic et al. (2016) [43] | \nn = 791 men (n = 302) and women (n = 489), living either at home or in a care facility, 68.7 ± 0.3 years | \nLongitudinal | \nThree dietary patterns were identified. a. DP1, High Red Meat b. DP2, Low Meat c. DP3, High Butter | \nMen in DP1 had worse overall hand grip strength and slower timed up and go than those in DP2. Women in DP3 had slower timed up and go than those in DP2. Men in DP3 had a steeper decline in hand grip strength than those in DP1. | \n|
Perälä et al. (2016) [44] | \nn = 1072 participants, elderly men and women, 61.3 ± 0.2 years | \nLongitudinal | \nDietary indices: The a priori-defined Nordic diet score (NDS) was calculated as a measure of a healthy Nordic diet. | \nWomen in the highest fourth of the NDS had a 5-point higher Senior Fitness Test score on average than those in the lowest fourth. | \n|
Suthutvoravut et al. (2020) [45] | \nn = 1241 community-dwelling men (n = 646) and women (n = 595), 74.6 ± 5.5 years | \nCross-sectional | \nThree dietary patterns were identified. a. DP1, high factor loading for fish, tofu, vegetables, and fruits b DP2, high factor loading for fish, rice, and miso soup c. DP3, high factor loading for noodles | \nMen with the lowest tertile of the DP1 score had a higher likelihood of being sarcopenic. Women with the lowest tertile of the DP2 score had a moderate likelihood of being sarcopenic. | \n
Summary of diet quality and physical function in older adults.
Robinson et al. examined the relationship between diet quality and grip strength in older men and women [38]. A food frequency questionnaire (FFQ) based on the European Prospective Investigation of Cancer (EPIC) questionnaire was used to assess the subject’s diet. They used the FFQ that contained 129 foods and food groups and assessed the average frequency of the consumption of the listed foods over the three months preceding the interview. Nutrient intake for each food item consumed was calculated by multiplying the nutrient content listed in the UK national food composition database or manufacturer composition data. The 129 foods listed in the FFQ were divided into 54 food groups based on similarity and nutrient compositions. The PCA of the reported weekly consumption frequencies of these food groups was used to define diet patterns. The prudent diet was characterized by the high consumption of fruit, vegetables, whole grain cereals, and fatty fish and by the low consumption of white bread, chips, sugar, and full-fat dairy products. Participants with higher prudent diet scores had stronger grip strengths. In addition, an increase was observed in grip strength of 0.43 kg in men and 0.48 kg in women for each additional fatty fish portion consumed per week.
\nMartin et al. investigated the relationship between diet and physical performance (measured using a short physical performance battery) in a group of men and women living in West Hertfordshire who were part of the Hertfordshire Cohort Study [39]. Nutrient intake for each food item consumed was calculated by multiplying the nutrient content listed in the UK national food composition database or manufacturer composition data. Higher prudent diet scores were related to shorter three-meter walk times and shorter chair-rise times in women. Additionally, inverse relationships were observed between physical function and the consumption of vegetables, whitefish, shellfish, and oily fish. These findings indicate that a relationship exists between diet variations in community-dwelling older women and differences in physical performance. However, further studies are needed to clarify the role of diet variations in physical performance, particularly in men.
\nBollwein et al. examined whether the risk of frailty was significantly reduced in participants who scored in the highest quartile for Mediterranean diet consumption (MED) [40]. This scoring is an alternative to the MED scoring used by Fung et al. [46], who adapted the original MED score used by Trichopoulou et al. [47] for a non-Mediterranean population. They combined FFQ foods into nine nutritional characteristics, classified as either beneficial (vegetables, legumes, fruits, unrefined cereals, nuts, fish, high monounsaturated fatty acid [MUFA]/saturated fatty acid [SFA] foods, and moderate alcohol consumption) or detrimental (red and processed meats) to health, to calculate the score, and found an inverse correlation between a low walking speed and MED scores. Moreover, a relationship was observed between high diet quality (high MED score) and slow walking speed in older men and women.
\nRahi et al. investigated the relationship between diet quality and muscle strength changes over three years in diabetic participants aged 67 to 84 years [41]. Diet quality was evaluated at recruitment using the validated Diet Quality Index-Canada and nine-item Canadian Healthy Eating Index (C-HEI) [48]. Diet quality was calculated using data from the mean of three, non-consecutive, 24-hour dietary recalls collected using the five-step, multiple-pass method [49]. The C-HEI has nine components. The first four components evaluate the extent to which respondents meet age and gender-based recommendations for the number of portions eaten from each of the four groups of Canada’s Food Guide (grain products, vegetables and fruits, milk and alternatives, and meat and alternatives). The next four items reflect Canadian nutritional recommendations for moderation: the daily percentage of energy from total fat, the daily percentage of energy from saturated fat, cholesterol intake (mg), and sodium intake (mg). The final component, dietary variety (adapted from the Dietary Diversity Score), was assessed as the daily consumption of at least one food from each food group. The findings obtained indicated that the combination of a high diet quality with stable or increased physical activity minimized muscle strength losses in diabetic older males over the three-year follow-up period.
\nHashemi et al. investigated whether adherence to a particular dietary pattern was associated with sarcopenia among elderly adults in a district of Teheran, Iran [42]. A semiquantitative FFQ was used to survey the dietary intake of 300 randomly-selected older men and women. They evaluated the dietary patterns of participants using PCA. Participants in the highest tertile of the Mediterranean dietary pattern had a lower odds ratio for developing sarcopenia than those in the lowest tertile. In contrast, adherence to the Western dietary pattern (characterized by the high consumption of sugar, soy, and fast foods) and mixed dietary pattern (characterized by the high consumption of animal proteins, potatoes, and refined grains) did not affect the odds of developing sarcopenia. These findings suggested that Mediterranean diet adherence was associated with a lower odds ratio for the development of sarcopenia among older Iranian individuals.
\nGranic et al. examined the relationship between previously established dietary patterns and declines in muscle strength and physical performance among older adults [43]. In total, 791 participants were followed for five years to detect changes in grip strength and timed up and go test (TUG) scores. Trained research nurses kept a detailed record of food intake on the previous day for each participant on two different days of the week, at least one week apart. Each food had a unique food code (>2000), and intakes were entered into a Microsoft Access-based dietary data system, then further grouped into 118 food groups based on McCance and Widdowson’s composition of foods [50, 51]. These 118 groups were combined into 33 food groups based on food/nutrient composition similarities and then classified as either absent or present in each participant’s food intake. Participants were divided into three groups: dietary pattern 1 (DP1; high red meat); dietary pattern 2 (DP2; low meat); and dietary pattern 3 (DP3; high butter). The findings obtained showed that men in DP1 had worse overall grip strength, whereas those in DP3 had steeper grip strength declines than those in DP2. Additionally, TUG scores were significantly longer for men in DP1 and women in DP3 than those in DP2. Therefore, diets high in red meats, potatoes, gravy, and butter appear to adversely affect muscle strength and physical performance in later life.
\nPerälä et al. researched whether the consumption of a healthy Nordic diet for 10 years was associated with improved physical performance measures [44]. After the diets of 1072 participants (mean age 67 years) had been examined using a validated 128-item FFQ, the a priori Nordic diet score was calculated. The diet items checked included Nordic fruits and berries, vegetables, cereals, low-fat milk, fish, red and processed meat, alcohol, polyunsaturated omega-3 fatty acids (PUFA)/SFA and trans-fatty acids ratios, and total fat. Since participants had a mean age of 71 years, their physical performance was measured using the Senior Fitness Test (SFT), and an overall SFT score was calculated. The findings obtained revealed that women with the highest diet scores had 17% better in that of walk, 16% better in that of arm curl, and 20% better in that of chair-stand than women with the lowest diet scores. These findings indicated that women who consumed a healthy Nordic diet had better physical performance (i.e., better aerobic endurance and upper and lower body strength) 10 years later.
\nSuthutvoravut et al. investigated the relationship between dietary patterns and sarcopenia in a sample of older community-dwelling Japanese adults [45]. The sample included 1241 older adults aged 65 years and older who were not eligible for long-term care. Dietary intake by participants was assessed using the brief self-administered diet history questionnaire. Dietary patterns were identified using both PCA and Japanese diet scores (soybeans and soybean products, fish, vegetables, pickles, mushrooms, seaweeds, and fruits). Participants were classified into three groups: dietary pattern 1 (DP1; high factor loading for the consumption of fish, tofu, vegetables, and fruits found in typical Japanese side dishes); dietary pattern 2 (DP2; high factor loading for fish, rice, and miso soup found in typical Japanese main dishes); and dietary pattern 3 (DP3; high factor loading for noodles). The findings obtained showed that men with the lowest tertile DP1 score had a higher likelihood of being sarcopenic, while women with the lowest tertile DP2 score had a moderate likelihood of being sarcopenic. Additionally, low adherence to Japanese dietary patterns increased with the prevalence of sarcopenia in both genders.
\nMany traditional regional diets may have similar benefits to those described here. We then focused on diets with demonstrated effects on muscle mass, reported by randomized controlled trials that investigated diet quality using precise parameters. For example, the traditional diets of Korea and China may be beneficial for preventing sarcopenia in the populations of these countries. Healthier diets are higher in plant-based food and lower in animal-based foods than Western diets. Further epidemiological studies are needed to investigate the relationship between healthy diets and development of sarcopenia throughout the world, particularly in developing countries.
\nSkeletal muscle is a dynamic, plastic tissue with a mass that is regulated by the balance between the rates of muscle protein synthesis and breakdown. Adopting an appropriate dietary strategy is crucial for facilitating an anabolic response that may prevent muscle wasting with atrophy by suppressing the breakdown of muscle protein. An adequate nutrient intake is essential for maintaining and improving muscle properties. Many supplements have been proposed to enhance muscle mass and strength. More than 50% of adults in the United States take some form of dietary supplement to improve their health or well-being [52]. However, there is no scientific evidence for the effectiveness of many of these supplements. In some cases, their use has been linked to serious adverse side effects. This section summarizes the effects of several popular nutritional supplements when administered under strict dietary controls, either alone or in combination with other supplements.
\nIn a randomized study, Tieland et al. examined the effects of 24 weeks of dietary protein supplementation on muscle mass, strength, and physical performance in a sample of frail older adults [53]. This study included 65 frail participants who were allocated to either the daily protein supplementation group (15 g protein consumed at breakfast and lunch) or placebo group (0 g protein at breakfast and lunch). Participants recorded their food intake for three days with the help of trained dieticians. Dietary intake data were coded (the type of food, time of intake, and amount), and energy and macronutrient intakes were calculated using a food-calculation system from the 2006 Dutch food composition database. The findings obtained indicated that skeletal muscle mass did not change in either the protein or placebo group following the 24-week intervention. However, leg extension strength increased more in the protein group than in the placebo group. Furthermore, physical performance significantly improved (from 8.9 to 10.0 points) in the protein group, but not in the placebo group. Therefore, while dietary protein supplementation appeared to improve physical performance in frail older adults, it did not increase their skeletal muscle mass.
\nKim et al. investigated whether protein-energy supplementation prevented functional declines in frail older adults with a low socioeconomic status [54]. In that study, 84 frail elderly participants were assigned to either an intervention or control group. The intervention group received two 200-ml cans of commercial liquid formula (an additional 400 kcal of energy, 25 g of protein, 9.4 g of essential amino acids, and 400 ml of water) each day for 12 weeks, while the control group did not. Dietary intake was assessed in three, non-consecutive 24-hour recall sessions (one face-to-face and two by telephone; weekday and weekend ratio of 2:1) to show the nutritional status. The same research dietitian coded dietary data, and a nutrient analysis was performed using CAN-Pro 3.0. No significant changes were observed in grip strength in either group; however, physical functioning, usual gait speed, and TUG scores were significantly better in the protein group than in the control group. Therefore, protein-energy supplementation administered to frail older adults with a low socioeconomic status appeared to reduce the progression of functional decline.
\nVeronese et al. investigated whether 12 weeks of oral magnesium supplementation improved physical performance in healthy older women [55]. In that study, 124 participants were grouped into either a treatment group (300 mg of magnesium/day) or control group (no treatment). A dietary assessment was examined by a modified method including an estimated three-day record and a questionnaire about the frequency that participants generally ate certain foods. They used the data from the previous month as a reference and calculated the macronutrients and micronutrients of usual food intake by a national food composition table. After 12 weeks of supplementation with magnesium, the treatment group had significantly higher total short physical performance battery scores, chair-stand times, and four-minute walking speeds than the control group. These findings indicated that magnesium supplementation prevented or delayed age-related physical performance declines.
\nRoma et al. examined the effects of PUFA supplementation on the parameters of body composition, muscle strength, and physical performance in the elderly [56]. Fifty participants were randomly assigned to a PUFA-treated group (receiving 1.3 g of PUFA and 10 mg of vitamin E) or control group (receiving 11 mg of vitamin E). Participants were assessed using the mini nutritional assessment (composed of six questions related to decreased food intake in the three months before the test) and a 12-question survey on diet (number of meals consumed and consumption of protein, fruits, vegetables, and liquids) and the ability to feed themselves. No significant between-group differences were observed in muscle mass, grip strength, or TUG scores. Therefore, the 12-week PUFA supplementation did not appear to affect the parameters evaluated in elderly individuals with a decreased muscle mass.
\nBauer et al. sought to test the hypothesis that a specific oral nutritional supplement may improve selected sarcopenia measures [57]. The active group (n = 184) consumed a vitamin D and leucine-enriched whey protein nutritional supplement twice daily for 13 weeks. The control group (n = 196) consumed an iso-caloric control product twice daily for 13 weeks. A dietary assessment was completed at baseline and week 13 using three-day prospective diet records for two weekdays and one weekend day. Additional energy and protein intakes from both supplements were added to habitual three-day intakes to assess total intake. The active group gained more appendicular muscle mass and performed better in the chair-stand test than the control group. These findings demonstrated that specific nutritional supplementation alone may benefit geriatric patients, particularly those unable to exercise.
\nPorter et al. investigated whether participants following an enhanced protein regimen have greater functional status improvements and better lean muscle mass preservation than control group participants [58]. In that study, 67 obese older adults were randomly assigned to either a traditional weight loss regimen (control group) or one with a higher protein intake at each meal (protein group). Control group participants were prescribed a 500-kcal deficit diet (15% protein, 30% fat, and 55% carbohydrate), which met the recommended dietary allowance (RDA) for protein intake (0.8 g/kg of body weight). Protein group participants were also prescribed a 500-kcal deficit, but with a macronutrient distribution of 30% protein, 30% fat, and 40% carbohydrate, for a total prescribed protein intake of 1.2 g/kg. Both groups exhibited significant weight loss at the six-month endpoint. However, while both groups had improved muscle function, the Short Physical Performance Battery response was greater in the protein group than in the control group. These findings indicated that functionally limited obese adults undergoing a six-month weight loss intervention that included a meal-based protein enhancement lost similar amounts of weight, but had better functional improvements than the control group.
\nOnly one of the studies used an iso-caloric control supplement to investigate the efficacy of a vitamin D and leucine-enriched whey protein nutritional supplement (not combined with exercise) for attenuating sarcopenia. To produce the most useful data, future studies that investigate whether a simple nutrient supplement contributes to the prevention of sarcopenia will need to use dietary control in a sample of more than 100 elderly participants. Evidence from two in vivo studies showed that calorie restriction or fasting may help to prevent reductions in muscle mass or strength [59, 60]. Future human studies need to focus on the effects of the removal of some nutrients from the diet, instead of solely assessing the effects of their addition, in order to obtain more useful data (Table 2).
\nReference | \nPopulation | \nDiets | \nNutritional intervention | \nChanges in muscle mass and strength | \nPhysical function | \n
---|---|---|---|---|---|
Tieland et al. (2012) [53] | \nn = 65 frail elderly subjects | \n1935 kcal/day, 49% CHO, 35% fat, 16% protein (1.0 g protein/kg/day) | \n15 g protein × twice/day for 24 wks vs. non protein × twice/day for 24 wks | \nNo change in muscle mass in both groups Significant increase in muscle strength in both groups. | \nSignificantly improved physical performance in the protein group, but not in the control group | \n
Kim et al. (2013) [54] | \nn = 84 frail elderly subjects, 78.7 ± 5.8 years | \n896 kcal/day (0.7 g protein/kg/day) | \n400 kcal (25 g protein, 9.4 g amino acids, 56 g carbohydrate, 9 g lipids, micronutrients)/day for 12 wks vs. non-supplemental control | \nNo change in hand grip strength in both groups | \nSignificantly improved physical functioning, usual gait speed, and timed up-and-go in the protein group, but not in the control group | \n
Veronese et al. (2014) [55] | \nn = 124 elderly women, 71.5 ± 5.2 years | \n1490 kcal/day (383 mg magnesium/day) | \n300 mg magnesium/day for 12 wks vs. non-supplemental control | \nNo change in hand grip strength in both groups | \nSignificantly improved Short Physical Performance Battery score, chair-stand times, and 4-m walking speeds in the magnesium group, but not in the control group | \n
Roma et al. (2015) [56] | \nn = 50 elderly subjects, 74.9 ± 7.9 years | \nMini Nutritional Assessment score 24.1 ± 3.1 points | \n1.3 g omega-3 fatty acids/day for 12 wks vs. non-supplemental control | \nNo differences in muscle mass or hand grip in both groups | \nNo differences in timed up-and-go in both groups | \n
Bauer et al. (2015) [57] | \nn = 380 sarcopenic primarily independent-living older adults, 77.7 ± 6.9 years | \n1612 kcal/day (1.0 g protein/kg/day) | \n800 IU vitamin D + 20 g whey protein +3 g leucine twice/day for 13 wks (active) vs. iso-caloric control | \nSignificantly higher appendicular muscle mass in the active group than in the control | \nSignificantly improved chair-stand test in the active group from those in the control group | \n
Porter et al. (2016) [58] | \nn = 67 obese older adults with a Short Physical Performance Battery (SPPB) score of 4–10, 68.2 ± 5.6 years | \n1458 kcal/day, 55% CHO, 30% fat, 15% protein (0.8 g protein/kg/day) | \n30 g protein × 3 times/day for 6 mo vs. non-supplemental control | \nNo differences in lean body mass or hand grip in both groups | \nSignificantly improved total and chair-stand scores in the protein group from those in the control group | \n
Summary of effects of nutrient supplementation for attenuating sarcopenia.
A number of conditions, such as recovery from injury or illness or space flight, require prolonged periods of muscle disuse (i.e., unloading) in otherwise healthy individuals, resulting in the progressive loss of skeletal muscle mass that impairs functional strength, reduces the basal metabolic rate, and increases body fat mass. Therefore, prolonged muscle disuse is a significant health concern, particularly in aging populations. While nutrition is an important factor regulating muscle mass, the development of effective nutritional strategies that attenuate muscle loss during periods of muscle disuse warrants further efforts. Table 3 shows an overview of studies that have assessed the efficacy of nutritional interventions for attenuating muscle disuse atrophy under controlled diet quality.
\nReference | \nPopulation | \nDiets | \nNutritional intervention | \nChanges in muscle mass | \nLoss of strength | \n
---|---|---|---|---|---|
Paddon-Jones et al. (2004) [61] | \nn=13 young males, Bed rest (28 days) | \n2487 kcal/day, 59% CHO, 27% fat, 14% protein (1.0 g protein/kg/day) | \n30 g carbohydrate +16.5 g EAA vs. non-supplemental control | \nLeg lean mass maintained in EAA, but lost in the control | \nSignificantly lower decrease of 11% in EAA than in the control (23% down) | \n
Trappe et al. (2007) [62] | \nn = 24 young women, Bed rest (60 days) | \n1557 kcal/day, 56% CHO, 30% fat, 14% protein (1.0 g protein/kg/day) | \n1.0 (low), 1.6 (high) g/kg body mass/day dietary protein | \nGreater loss of quadriceps femoris muscle volume in high protein (24%) vs. low protein (21%) | \n19 ~ 33% decreased for the supine square in both groups | \n
Ferrando et al. (2010) [63] | \nn = 21 elderly, Bed rest (10 days) | \n(0.8 g protein/kg/day) | \n15 g × 3 times/day EAA vs. the non-supplemental control | \n~6% decrease in leg lean mass in both groups | \nBetter functional capacity in EAA than in control | \n
Deutz et al. (2013) [64] | \nn=19 older adults, Bed rest (10 days) | \n1900 kcal/day (0.8 g protein/kg/day) | \n3 g/day HMB vs. non-supplemental control, 5 days prior to bed rest | \nLeg lean mass maintained in HMB, but lost in control | \nNo difference in the knee extensor in both groups | \n
Dirks et al. (2014) [65] | \nn = 23 elderly men, One-legged immobilization (5 days) | \n2150 kcal/day, 51% CHO, 33% fat, 16% protein (1.1 g protein/kg/day) | \n9.3 g carbohydrate +20.7 g protein +3.0 g fat twice/day vs. the non-supplemental control | \n1.5 ~ 2.0% decrease in quadriceps CSA in both groups | \n8.3 ~ 9.3% decrease in maximal muscle strength in both groups | \n
English et al. (2016) [66] | \nn=19 middle-aged adults, Bed rest (10 days) | \n2111 kcal/day, 55% CHO, 30% fat, 15% protein (1.1 g protein/kg/day) | \n4.5 g × 3 times/day leucine vs. 4.5 g × 3 times/day alanine | \n5.3 ~ 6.9% reduction in leg lean mass in both groups | \nSignificantly smaller decrease of 7% in leucine than in alanine (15% down) with knee extensor peak torque | \n
Holloway et al. (2019) [67] | \nn = 20 young men, One-legged immobilization (8 days) | \n2521 kcal/day (1.0 g protein/kg/day) | \n23.7 g × 3 times/day amino acids vs. 23.7 g × 3 times/day maltodextrin (iso-caloric control) | \nSignificantly lower decrease of 3.1% in amino acids than in control (2.4% down) in quadriceps muscle volume | \nNo difference in both groups in peak leg isometric torque | \n
Summary of effects of nutritional interventions on muscle mass and strength during a period of muscle disuse.
Paddon-Jones et al. examined whether supplementation with essential amino acids and carbohydrates offset the catabolic response to 28 days of bed rest [61]. Thirteen healthy male participants were randomly assigned to either the experimental or control groups. The control group consumed nutritionally mixed meals three times a day. The experimental group consumed the same meals plus 30 g of carbohydrate and 16.5 g of essential amino acids three times a day. The Harris-Benedict equation was used to estimate daily caloric requirements, according to the following formula: daily energy requirement (kcal) = [66 + (13.7 × kg) + (5 × cm) – (6.8 × yr)] × 1.3 (activity factor for bed rest). Participants were placed on a three-day rotating diet with daily nutrient intake evenly distributed between the three meals. The findings obtained revealed that the experimental group maintained lean leg mass throughout bed rest (+0.2 kg), whereas the control group lost mass (−0.4 kg). In addition, strength loss was more pronounced in the control group (exp group, −8.8 kg; cont group, −17.8 kg). Therefore, supplementation with essential amino acids and carbohydrates during bed rest appeared to provide an anabolic stimulus that ameliorated lean muscle mass loss in an otherwise catabolic environment. However, it currently remains unclear whether additional energy intake contributed to these findings.
\nTrappe et al. investigated whether nutritional countermeasures, consisting of additional protein and free leucine, reduced volume and strength losses in lower-limb skeletal muscle during 60 days of simulated weightlessness [62]. Young women were assigned to either the bed rest group (control) or the bedrest plus a nutrition countermeasure group (intervention). Dietary staff prepared all meals for both groups. These meals contained controlled amounts of total energy and macronutrients. The findings obtained demonstrated that thigh muscle (quadriceps femoris) volume decreased in both the control (−21%) and intervention groups (−24%). Moreover, both groups exhibited similar large decreases in isometric and dynamic (centric force, eccentric force, power, and work) muscle strength for the supine squat (−19% to −33%). Therefore, the nutrition countermeasure did not appear to be effective at offsetting volume or strength losses in lower-limb muscles. Furthermore, exercise countermeasures may need to be modified to protect the calf muscles of participants.
\nFerrando et al. examined the effects of an increasing protein intake (through essential amino acid supplementation) in older individuals subjected to 10 days of bed rest on their lean body mass and muscle function [63]. Participants received either a placebo or 15 g of essential amino acids, three times a day throughout 10 days of bed rest. The placebo was a non-caloric diet soda. During diet stabilization and bed rest, subjects consumed a lacto-ovo vegetarian diet providing the RDA for protein (0.8 g/kg of protein per day). The diet consisted of a three-day rotation based on the Harris-Benedict equation designed to maintain body weight throughout the study. An activity factor of 1.3 was used to estimate daily energy requirements during bed rest. The findings obtained indicated that essential amino acids did not affect the maintenance of total or leg lean muscle mass. However, stair ascent power and standing plantar flexion appeared to be maintained with essential amino acid supplementation. Therefore, increasing protein intake above the RDA may preserve muscle function in elderly individuals during compulsory inactivity. However, this protocol may need to be operated under iso-caloric nutritional interventions.
\nDeutz et al. attempted to clarify whether beta-hydroxy-beta-methylbutyrate (HMB), a leucine metabolite, was capable of attenuating muscle decline in healthy older adults during 10 days of bed rest [64]. Healthy older adults were randomly assigned to a control group or HMB group (Ca-HMB, 1.5 g twice daily, total 3 g/day). Participants were fed a metabolically controlled diet for diet stabilization, providing the RDA for protein intake (0.8 g protein/kg of body weight per day). Total calorie needs were estimated using the Harris–Benedict equation for resting energy expenditure. An activity factor of 1.35 was used to estimate daily energy requirements during bedrest. The study protocol significantly decreased total lean body mass in the control group. In contrast, the treatment with HMB prevented these declines in all but one participant in the HMB group. However, differences in functional parameters were not observed between the two groups. These findings indicated that HMB supplementation contributed to the preservation of muscle mass during 10 days of bed rest. Further studies using larger samples and iso-calorie conditions for nutritional interventions are needed to clarify the preventative effects of HMB on the acute decline in muscle mass.
\nDirks et al. investigated whether protein supplementation preserved muscle mass during a short period of limb immobilization [65]. Healthy older men were subjected to five days of one-legged knee immobilization using a full-leg cast with or without the twice-daily administration of a dietary protein supplement (20.7 g of protein, 9.3 g of carbohydrate, and 3.0 g of fat). Weighted dietary intake records were completed by participants for the five-day immobilization period and on a separate consecutive five-day occasion, either before or after the immobilization period. Immobilization decreased the quadricep cross-sectional area by 1.5 and 2.0%, and muscle strength by 8.3 and 9.3% in the control and protein groups, respectively. These findings indicated that dietary protein supplementation (~20 g twice daily) did not attenuate muscle loss during short-term muscle disuse in healthy older men.
\nEnglish et al. investigated whether leucine protects skeletal muscle health during bed rest [66]. In that study, a group of middle-aged adults were randomly assigned to a leucine group (4.5 g leucine × 3 times/day) or alanine group (4.5 g alanine × 3 times/day). Participants were fed controlled isoenergetic diets with protein intake evenly distributed across three daily meals for diet stabilization. Daily energy requirements were estimated using the Harris-Benedict equation. An activity factor of 1.3 was used during the bedrest period. The findings obtained indicated that while leg lean mass significantly decreased in both groups, leucine supplementation protected knee extensor peak torque more than in the alanine group. Therefore, leucine supplementation appeared to protect muscle health during relatively brief periods of physical inactivity. The parameters of this study allowed for the strict control of diets and nutritional supplementation under energy-matched conditions; therefore, leucine supplementation may help protect muscle function in muscle disuse atrophy.
\nHolloway et al. examined the safety, tolerability, and atrophy-mitigating effects of a novel amino acid composition (containing essential amino acids and arginine, glutamine, and N-acetylcysteine) during single-limb immobilization [67]. Twenty young men were randomly assigned to receive either the amino acid mixture or an energy-matched, non-amino acid-containing placebo three times a day (two hours after breakfast, lunch, and dinner) for consecutive days. Diets were designed to achieve an energy balance, and meal plans included protein derived from dairy sources held constant at 1.0 g/kg/day. The reduction in the cross-sectional area of the quadriceps muscle was significantly lower in the amino acid group than in the placebo group. However, immobilization resulted in similar relative declines in peak torque in both groups. These findings indicated that the daily consumption of an amino acid mixture (three times a day for 28 days) attenuated muscle atrophy, and are bolstered by the use of well-controlled diets and nutritional supplementation with energy-matched conditions.
\nA number of human studies examined the effects of nutritional interventions on muscle mass and strength during a period of muscle disuse [68, 69]. Due to insufficient dietary control, these studies were not sufficient to clarify the nutritional value of such supplements. Despite these deficits, many studies have reported the efficacy of nutritional supplementation for preventing the loss of muscle mass and strength during a period of muscle disuse in vivo [70–72]. Future studies are needed to clarify whether these candidates for nutritional supplementation preserve muscle mass during disuse. These studies must control diet quality and modify the nutritional intervention period (e.g., expand the duration of nutritional administration before muscle disuse) to provide sufficient evidence.
\nIn this chapter, we (a) summarized nutritional epidemiology evidence related to sarcopenia from recent systematic reviews; (b) reviewed the role nutrient supplementation plays in attenuating sarcopenia through dietary control; (c) provided evidence for the efficacy of nutrient supplementation for treating disuse muscle atrophy under controlled diet quality conditions.
Dietary patterns of adequate quality for older adults (i.e., ensuring a sufficient intake of beneficial foods, such as fruits, vegetables, whole grain products, fish, nuts, and low-fat foods) are useful for preventing sarcopenia. While the Mediterranean diet has been touted as a healthy diet, other diets (healthy Nordic or traditional Asian diets) also help prevent sarcopenia in older adults.
Vitamin D and leucine-enriched whey protein supplement may be useful for attenuating sarcopenia in geriatric patients, particularly in those unable to exercise.
Further studies are needed to clarify the effects of protein and amino acid supplementation on muscle mass and strength.
Based on the strong evidence linking nutrition to muscle mass and function, nutrition plays a crucial role in both the prevention and management of sarcopenia. Further high quality studies, particularly those using large sample sizes, controlled diet quality, and iso-caloric placebo supplementation, are needed to provide a clear understanding of the dose and duration effects of nutrients on muscle atrophy.
\nThe authors declare no conflict of interest.
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",metaTitle:"Conflicts of Interest Policy",metaDescription:"As an Open Access publisher, IntechOpen is dedicated to maintaining the highest ethical standards and principles in publishing. In addition, IntechOpen promotes the highest standards of integrity and ethical behavior in scientific research and peer-review.",metaKeywords:null,canonicalURL:"/page/conflicts-of-interest-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"In each instance of a possible Conflict of Interest, IntechOpen aims to disclose the situation in as transparent a way as possible in order to allow readers to judge whether a particular potential Conflict of Interest has influenced the Work of any individual Author, Editor, or Reviewer. IntechOpen takes all possible Conflicts of Interest into account during the review process and ensures maximum transparency in implementing its policies.
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\n\nA Conflict of Interest is a situation in which a person's professional judgment may be influenced by a range of factors, including financial gain, material interest, or some other personal or professional interest. For IntechOpen as a publisher, it is essential that all possible Conflicts of Interest are avoided. Each contributor, whether an Author, Editor, or Reviewer, who suspects they may have a Conflict of Interest, is obliged to declare that concern in order to make the publisher and the readership aware of any potential influence on the work being undertaken.
\n\nA Conflict of Interest can be identified at different phases of the publishing process.
\n\nIntechOpen requires:
\n\nCONFLICT OF INTEREST - AUTHOR
\n\nAll Authors are obliged to declare every existing or potential Conflict of Interest, including financial or personal factors, as well as any relationship which could influence their scientific work. Authors must declare Conflicts of Interest at the time of manuscript submission, although they may exceptionally do so at any point during manuscript review. For jointly prepared manuscripts, the corresponding Author is obliged to declare potential Conflicts of Interest of any other Authors who have contributed to the manuscript.
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\n\nEditors can also have Conflicts of Interest. Editors are expected to maintain the highest standards of conduct, which are outlined in our Best Practice Guidelines (templates for Best Practice Guidelines). Among other obligations, it is essential that Editors make transparent declarations of any possible Conflicts of Interest that they might have.
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She performed (inter)national tasks as vice-president of the Concilium Anaesthesia and related committees. \nShe performed research in several fields, with over 100 publications in (inter)national journals and numerous papers on scientific conferences. \nShe received several awards and is a member of Honour of the Dutch Society of Anaesthesia.",institutionString:null,institution:{name:"Albert Schweitzer Hospital",country:{name:"Gabon"}}},{id:"83089",title:"Prof.",name:"Aaron",middleName:null,surname:"Ojule",slug:"aaron-ojule",fullName:"Aaron Ojule",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Port Harcourt",country:{name:"Nigeria"}}},{id:"295748",title:"Mr.",name:"Abayomi",middleName:null,surname:"Modupe",slug:"abayomi-modupe",fullName:"Abayomi Modupe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:null,institutionString:null,institution:{name:"Landmark University",country:{name:"Nigeria"}}},{id:"94191",title:"Prof.",name:"Abbas",middleName:null,surname:"Moustafa",slug:"abbas-moustafa",fullName:"Abbas Moustafa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94191/images/96_n.jpg",biography:"Prof. Moustafa got his doctoral degree in earthquake engineering and structural safety from Indian Institute of Science in 2002. He is currently an associate professor at Department of Civil Engineering, Minia University, Egypt and the chairman of Department of Civil Engineering, High Institute of Engineering and Technology, Giza, Egypt. He is also a consultant engineer and head of structural group at Hamza Associates, Giza, Egypt. Dr. Moustafa was a senior research associate at Vanderbilt University and a JSPS fellow at Kyoto and Nagasaki Universities. He has more than 40 research papers published in international journals and conferences. He acts as an editorial board member and a reviewer for several regional and international journals. His research interest includes earthquake engineering, seismic design, nonlinear dynamics, random vibration, structural reliability, structural health monitoring and uncertainty modeling.",institutionString:null,institution:{name:"Minia University",country:{name:"Egypt"}}},{id:"84562",title:"Dr.",name:"Abbyssinia",middleName:null,surname:"Mushunje",slug:"abbyssinia-mushunje",fullName:"Abbyssinia Mushunje",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Fort Hare",country:{name:"South Africa"}}},{id:"202206",title:"Associate Prof.",name:"Abd Elmoniem",middleName:"Ahmed",surname:"Elzain",slug:"abd-elmoniem-elzain",fullName:"Abd Elmoniem Elzain",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Kassala University",country:{name:"Sudan"}}},{id:"98127",title:"Dr.",name:"Abdallah",middleName:null,surname:"Handoura",slug:"abdallah-handoura",fullName:"Abdallah Handoura",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Supérieure des Télécommunications",country:{name:"Morocco"}}},{id:"91404",title:"Prof.",name:"Abdecharif",middleName:null,surname:"Boumaza",slug:"abdecharif-boumaza",fullName:"Abdecharif Boumaza",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Abbès Laghrour University of Khenchela",country:{name:"Algeria"}}},{id:"105795",title:"Prof.",name:"Abdel Ghani",middleName:null,surname:"Aissaoui",slug:"abdel-ghani-aissaoui",fullName:"Abdel Ghani Aissaoui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/105795/images/system/105795.jpeg",biography:"Abdel Ghani AISSAOUI is a Full Professor of electrical engineering at University of Bechar (ALGERIA). He was born in 1969 in Naama, Algeria. He received his BS degree in 1993, the MS degree in 1997, the PhD degree in 2007 from the Electrical Engineering Institute of Djilali Liabes University of Sidi Bel Abbes (ALGERIA). He is an active member of IRECOM (Interaction Réseaux Electriques - COnvertisseurs Machines) Laboratory and IEEE senior member. He is an editor member for many international journals (IJET, RSE, MER, IJECE, etc.), he serves as a reviewer in international journals (IJAC, ECPS, COMPEL, etc.). He serves as member in technical committee (TPC) and reviewer in international conferences (CHUSER 2011, SHUSER 2012, PECON 2012, SAI 2013, SCSE2013, SDM2014, SEB2014, PEMC2014, PEAM2014, SEB (2014, 2015), ICRERA (2015, 2016, 2017, 2018,-2019), etc.). His current research interest includes power electronics, control of electrical machines, artificial intelligence and Renewable energies.",institutionString:"University of Béchar",institution:{name:"University of Béchar",country:{name:"Algeria"}}},{id:"99749",title:"Dr.",name:"Abdel Hafid",middleName:null,surname:"Essadki",slug:"abdel-hafid-essadki",fullName:"Abdel Hafid Essadki",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Nationale Supérieure de Technologie",country:{name:"Algeria"}}},{id:"101208",title:"Prof.",name:"Abdel Karim",middleName:"Mohamad",surname:"El Hemaly",slug:"abdel-karim-el-hemaly",fullName:"Abdel Karim El Hemaly",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/101208/images/733_n.jpg",biography:"OBGYN.net Editorial Advisor Urogynecology.\nAbdel Karim M. A. El-Hemaly, MRCOG, FRCS � Egypt.\n \nAbdel Karim M. A. El-Hemaly\nProfessor OB/GYN & Urogynecology\nFaculty of medicine, Al-Azhar University \nPersonal Information: \nMarried with two children\nWife: Professor Laila A. Moussa MD.\nSons: Mohamad A. M. El-Hemaly Jr. MD. Died March 25-2007\nMostafa A. M. El-Hemaly, Computer Scientist working at Microsoft Seatle, USA. \nQualifications: \n1.\tM.B.-Bch Cairo Univ. June 1963. \n2.\tDiploma Ob./Gyn. Cairo Univ. April 1966. \n3.\tDiploma Surgery Cairo Univ. Oct. 1966. \n4.\tMRCOG London Feb. 1975. \n5.\tF.R.C.S. Glasgow June 1976. \n6.\tPopulation Study Johns Hopkins 1981. \n7.\tGyn. Oncology Johns Hopkins 1983. \n8.\tAdvanced Laparoscopic Surgery, with Prof. Paulson, Alexandria, Virginia USA 1993. \nSocieties & Associations: \n1.\t Member of the Royal College of Ob./Gyn. London. \n2.\tFellow of the Royal College of Surgeons Glasgow UK. \n3.\tMember of the advisory board on urogyn. FIGO. \n4.\tMember of the New York Academy of Sciences. \n5.\tMember of the American Association for the Advancement of Science. \n6.\tFeatured in �Who is Who in the World� from the 16th edition to the 20th edition. \n7.\tFeatured in �Who is Who in Science and Engineering� in the 7th edition. \n8.\tMember of the Egyptian Fertility & Sterility Society. \n9.\tMember of the Egyptian Society of Ob./Gyn. \n10.\tMember of the Egyptian Society of Urogyn. \n\nScientific Publications & Communications:\n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Asim Kurjak, Ahmad G. Serour, Laila A. S. Mousa, Amr M. Zaied, Khalid Z. El Sheikha. \nImaging the Internal Urethral Sphincter and the Vagina in Normal Women and Women Suffering from Stress Urinary Incontinence and Vaginal Prolapse. Gynaecologia Et Perinatologia, Vol18, No 4; 169-286 October-December 2009.\n2- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nFecal Incontinence, A Novel Concept: The Role of the internal Anal sphincter (IAS) in defecation and fecal incontinence. Gynaecologia Et Perinatologia, Vol19, No 2; 79-85 April -June 2010.\n3- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nSurgical Treatment of Stress Urinary Incontinence, Fecal Incontinence and Vaginal Prolapse By A Novel Operation \n"Urethro-Ano-Vaginoplasty"\n Gynaecologia Et Perinatologia, Vol19, No 3; 129-188 July-September 2010.\n4- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n5- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n6- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n7-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n8-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n9-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n10-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n11-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n12- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n13-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n14- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Mohamad A. Rizk and Mohamad A.K.M.El Hemaly.\n Urethro-plasty, a Novel Operation based on a New Concept, for the Treatment of Stress Urinary Incontinence, S.U.I., Detrusor Instability, D.I., and Mixed-type of Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/urethro-plasty_01\n\n15-Ibrahim M. Kandil, Abdel Karim M. El Hemaly, Mohamad M. Radwan: Ultrasonic Assessment of the Internal Urethral Sphincter in Stress Urinary Incontinence. The Internet Journal of Gynecology and Obstetrics. 2003. Volume 2 Number 1. \n\n\n16-Abdel Karim M. El Hemaly. Nocturnal Enureses: A Novel Concept on its pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecolgy/?page=articles/nocturnal_enuresis\n\n17- Abdel Karim M. El Hemaly. Nocturnal Enureses: An Update on the pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecology/?page=/ENHLIDH/PUBD/FEATURES/\nPresentations/ Nocturnal_Enuresis/nocturnal_enuresis\n\n18-Maternal Mortality in Egypt, a cry for help and attention. The Second International Conference of the African Society of Organization & Gestosis, 1998, 3rd Annual International Conference of Ob/Gyn Department � Sohag Faculty of Medicine University. Feb. 11-13. Luxor, Egypt. \n19-Postmenopausal Osteprosis. The 2nd annual conference of Health Insurance Organization on Family Planning and its role in primary health care. Zagaziz, Egypt, February 26-27, 1997, Center of Complementary Services for Maternity and childhood care. \n20-Laparoscopic Assisted vaginal hysterectomy. 10th International Annual Congress Modern Trends in Reproductive Techniques 23-24 March 1995. Alexandria, Egypt. \n21-Immunological Studies in Pre-eclamptic Toxaemia. Proceedings of 10th Annual Ain Shams Medical Congress. Cairo, Egypt, March 6-10, 1987. \n22-Socio-demographic factorse affecting acceptability of the long-acting contraceptive injections in a rural Egyptian community. Journal of Biosocial Science 29:305, 1987. \n23-Plasma fibronectin levels hypertension during pregnancy. The Journal of the Egypt. Soc. of Ob./Gyn. 13:1, 17-21, Jan. 1987. \n24-Effect of smoking on pregnancy. Journal of Egypt. Soc. of Ob./Gyn. 12:3, 111-121, Sept 1986. \n25-Socio-demographic aspects of nausea and vomiting in early pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 35-42, Sept. 1986. \n26-Effect of intrapartum oxygen inhalation on maternofetal blood gases and pH. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 57-64, Sept. 1986. \n27-The effect of severe pre-eclampsia on serum transaminases. The Egypt. J. Med. Sci. 7(2): 479-485, 1986. \n28-A study of placental immunoreceptors in pre-eclampsia. The Egypt. J. Med. Sci. 7(2): 211-216, 1986. \n29-Serum human placental lactogen (hpl) in normal, toxaemic and diabetic pregnant women, during pregnancy and its relation to the outcome of pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:2, 11-23, May 1986. \n30-Pregnancy specific B1 Glycoprotein and free estriol in the serum of normal, toxaemic and diabetic pregnant women during pregnancy and after delivery. Journal of the Egypt. Soc. of Ob./Gyn. 12:1, 63-70, Jan. 1986. Also was accepted and presented at Xith World Congress of Gynecology and Obstetrics, Berlin (West), September 15-20, 1985. \n31-Pregnancy and labor in women over the age of forty years. Accepted and presented at Al-Azhar International Medical Conference, Cairo 28-31 Dec. 1985. \n32-Effect of Copper T intra-uterine device on cervico-vaginal flora. Int. J. Gynaecol. Obstet. 23:2, 153-156, April 1985. \n33-Factors affecting the occurrence of post-Caesarean section febrile morbidity. Population Sciences, 6, 139-149, 1985. \n34-Pre-eclamptic toxaemia and its relation to H.L.A. system. Population Sciences, 6, 131-139, 1985. \n35-The menstrual pattern and occurrence of pregnancy one year after discontinuation of Depo-medroxy progesterone acetate as a postpartum contraceptive. Population Sciences, 6, 105-111, 1985. \n36-The menstrual pattern and side effects of Depo-medroxy progesterone acetate as postpartum contraceptive. Population Sciences, 6, 97-105, 1985. \n37-Actinomyces in the vaginas of women with and without intrauterine contraceptive devices. Population Sciences, 6, 77-85, 1985. \n38-Comparative efficacy of ibuprofen and etamsylate in the treatment of I.U.D. menorrhagia. Population Sciences, 6, 63-77, 1985. \n39-Changes in cervical mucus copper and zinc in women using I.U.D.�s. Population Sciences, 6, 35-41, 1985. \n40-Histochemical study of the endometrium of infertile women. Egypt. J. Histol. 8(1) 63-66, 1985. \n41-Genital flora in pre- and post-menopausal women. Egypt. J. Med. Sci. 4(2), 165-172, 1983. \n42-Evaluation of the vaginal rugae and thickness in 8 different groups. Journal of the Egypt. Soc. of Ob./Gyn. 9:2, 101-114, May 1983. \n43-The effect of menopausal status and conjugated oestrogen therapy on serum cholesterol, triglycerides and electrophoretic lipoprotein patterns. Al-Azhar Medical Journal, 12:2, 113-119, April 1983. \n44-Laparoscopic ventrosuspension: A New Technique. Int. J. Gynaecol. Obstet., 20, 129-31, 1982. \n45-The laparoscope: A useful diagnostic tool in general surgery. Al-Azhar Medical Journal, 11:4, 397-401, Oct. 1982. \n46-The value of the laparoscope in the diagnosis of polycystic ovary. Al-Azhar Medical Journal, 11:2, 153-159, April 1982. \n47-An anaesthetic approach to the management of eclampsia. Ain Shams Medical Journal, accepted for publication 1981. \n48-Laparoscopy on patients with previous lower abdominal surgery. Fertility management edited by E. Osman and M. Wahba 1981. \n49-Heart diseases with pregnancy. Population Sciences, 11, 121-130, 1981. \n50-A study of the biosocial factors affecting perinatal mortality in an Egyptian maternity hospital. Population Sciences, 6, 71-90, 1981. \n51-Pregnancy Wastage. Journal of the Egypt. Soc. of Ob./Gyn. 11:3, 57-67, Sept. 1980. \n52-Analysis of maternal deaths in Egyptian maternity hospitals. Population Sciences, 1, 59-65, 1979. \nArticles published on OBGYN.net: \n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n2- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n3- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n4-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n5-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n6-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n7-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n8-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n9- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n10-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n11- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Mohamad A. Rizk and Mohamad A.K.M.El Hemaly.\n Urethro-plasty, a Novel Operation based on a New Concept, for the Treatment of Stress Urinary Incontinence, S.U.I., Detrusor Instability, D.I., and Mixed-type of Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/urethro-plasty_01\n\n12-Ibrahim M. Kandil, Abdel Karim M. El Hemaly, Mohamad M. Radwan: Ultrasonic Assessment of the Internal Urethral Sphincter in Stress Urinary Incontinence. The Internet Journal of Gynecology and Obstetrics. 2003. Volume 2 Number 1. \n\n13-Abdel Karim M. El Hemaly. Nocturnal Enureses: A Novel Concept on its pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecolgy/?page=articles/nocturnal_enuresis\n\n14- Abdel Karim M. El Hemaly. 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