Expressional alterations in myelin-specific transcripts in human vastus lateralis muscle after endurance exercise.
\r\n\tDNA is responsible for carrying all the information an organism needs to survive, grow and reproduce. However, during its lifetime an each organism experiences a wide range of cases with DNA damages; therefore the DNA repair ability of a cell is vital to the integrity of its genome and thus to the normal functionality of that organism. Mutagenesis is known as an important factor which may lead to different disorders, disabilities and diseases. Any defect in DNA repair system may lead to the death of the organism.
\r\n\r\n\t
\r\n\tRecognition of these items in different organisms drives us to know more about the characteristics of DNA repair systems in different types of organisms. Hopefully, this book will offer an interesting read by introducing, explaining and comparing these diversities.
Charcot-Marie-Tooth disease (CMT) is the most common inherited neurologic disorder. Reportedly 10-28 cases exist per 100,000 in Western societies. CMT patients suffer from a variable degree of motor dysfunction which adversely affects locomotion and balance. These deficits explain by a slowing of impulse conduction in motor and sensory nerves. This affects the recruitment of muscle fibres for contraction whereby slow motor units are preferentially affected (Gale et al., 1982; Roy et al., 1996). This results in muscle weakness and wasting in the extremities of the body.
\n\t\t\tThe inefficient propagation of excitatory signals in moto neurons towards peripheral muscle in CMT disease is caused by a myelination defect which has a genetic origin. Some 20 genes for axon proteins and myelin have been implicated in CMT, and allow the classification into specific subtypes of the disease. Frequently affected of these genes are peripheral myelin protein 22 (pmp22) and myelin protein zero (MPZ) which are mutated in a majority of cases (Braathen et al., 2011). CMT subtype 1A (CMT1A) is the most predominant disease type being associated with a duplication of the pmp22 gene (Wise et al., 1993; Magyar et al. 1996). The pmp22 gene encodes for a factor that is incorporated into the myelin sheet of neurons and is thought to control myelin thickness. The pathology on the CMT1A disease types is explained by slowed saltatory transduction in moto neurons due to the aberrant nerve insulation (Sereda & Griffiths, 1996).
\n\t\t\tCurrently there is no cure for CMT. There are however a number of occupational interventions that can be used to effectively manage its symptoms (
Gene transfer therapy is a promising route for future cures of muscular disorders. However major limitations appear regarding the treatment of neurological diseases such as CMT. In this case one would normally expect that the therapy must directly target moto neurons to initiate a compensatory mechanism that can correct the missing myelination. This is currently not feasible. In this regard the important positive influence of exercise on motor performance in CMT patients demands consideration as this may offers an indirect means to improve neuromuscular function. This relates to the well established feed forward control of the muscle phenotype by muscle use (Fluck & Hoppeler, 2003). It has been pointed out that the effects of increased muscle recruitment with exercise involve the promotion of the slow-oxidative expression program (Schmutz et al., 2010; Baumann et al., 1987). Recently, has been established that electrically imposed muscle recruitment can re-establish muscle functionality in denervated muscle of tetraplegic patients through the remodelling of the contractile and metabolic makeup (Boncompagni et al., 2007). The positive influence of exercise in CMT patients suggests that the use-dependent pathway importantly affects neuro-muscular function.
\n\t\t\tWe reasoned that altered muscle use combined with gene therapy for focal adhesion kinase (FAK), an enzyme that regulates recruitment dependent slow oxidative gene expression, would be a suitable venue to promote pmp22 expression in skeletal muscle. Towards this end we investigated the use dependence of pmp22 expression in human skeletal muscle and assessed the nature of contractile defects in muscles of a mouse model for CMT at the molecular, cellular and functional level. Subsequently we tested whether overexpression of FAK can enhance pmp22 expression in skeletal muscle (Durieux et al., 2009).
\n\t\t\n\t\t\t\tResponse to exercise in human muscle - A resting biopsy was collected with a conchotome from the non-exercising leg after an overnight fast and prior to exercise. Thereafter, each participant performed an acute single-legged endurance exercise bout at 60% of their Pmax on an Ergoline bicycle ergometer (Jaeger). There was an incremental warm-up period to reach their 60% Pmax, and after 20 minutes of cycling at 80 rpm, the resistance was increased by 5 W every 10 seconds until volitional exhaustion. A biopsy was collected with the ACECUT needle system (UK Surgical Ltd) from the exercised leg 8 hours after the bout of exercise. Biopsy position was standardized based on an ultra-sound measurement at 50% of femur length. This study was performed at Manchester Metropolitan University (United Kingdom) with permission of the institutional ethics Committee, in compliance with the Helsinki Convention for research on human subjects.
\n\t\t\t\n\t\t\t\tModel of altered muscle activity – Hindlimb suspension of rats was performed for 7 days as previously described (Fluck et al., 2005) at the Université Lyon 1 (France) and started 2 days after transfection. Subsequent reloading was provoked by allowing the animals to return to normal cage activity for 1 or 5 days.
\n\t\t\tHindlimb suspension of mice was performed for 3 days as previously described at the University of Berne (Switzerland) (Dapp et al., 2004). This was achieved by attaching the tail via a swivel hook to a movable X-Y system; thereby preventing the mouse from touching the ground with its hindlimbs while permitting free movement within the entire cage. Soleus muscles were extracted from anesthetized animals (5% isoflurane).
\n\t\t\t\n\t\t\t\tAnimal model of CMT - Pmp22-tg mouse (pmp22tg) as CMT model (strain C3Hb6) were bred at the University of Fribourg. The original strain was a gift of U. Suter (University of Zurich). The pmp22-tg mice carry approximately 16 and 30 copies of the pmp22 gene and display a severe congenital hypomyelinating neuropathy due to the accumulation of overexpressed pmp22 in the Golgi compartment, and the concomitant interference with myelin assembly during Schwann cell differentiation (Niemann et al., 2000). This is characterized by an almost complete lack of myelin and marked slowing of nerve conductions (Magyar al., 1996). The animals entering the study were between 1.5- and 3-month of age.
\n\t\t\t\n\t\t\t\tSomatic transgenesis for FAK - Gene transfer of pCMV-FAK into soleus muscle of 3-month old male Wistar rats was essentially carried out as previously described (Durieux et al., 2009). In brief, soleus muscles of anaesthetized rats (60 mg of sodium pentobarbital per kg body) were surgically exposed. 70 microgram per 70 microliter of endotoxin-free plasmid in Tris-EDTA buffer (plasmidfactory, Bielefeld, Germany, www.plasmidfactory.de) was injected in the belly portion of the soleus muscle and three trains of 80-pulses of 100 microseconds duration, each at 100 mA, were delivered using needle electrodes with the GET42generator (Electronique et Informatique du Pilat, Jonzieux, France). The wound was closed with sutures and animals transferred to single cages. Right soleus muscles were injected with cytomegalovirus promoter-driven plasmids for the constitutive overexpression of chicken FAK (pCMV-FAK). The plasmid was a gift from Tony Parsons (University of Virginia, Charlottesville, USA). The (left) soleus muscles of the contralateral leg were injected with empty pCMV plasmid.
\n\t\t\tThe experiments were performed at the Universities of Berne (Switzerland) and Lyon (France) with the permission of the local Animal Care Committee of the Canton of Berne (Switzerland) and following the recommendations provided by the European Convention for the protection of Vertebrate Animals used for Experimental and Scientific purposes (Strasbourg, 18.III.1986).
\n\t\t\t\n\t\t\t\tMuscle sampling – Collected muscles were frozen in nitrogen cooled isopentane and stored in sealed cryotubes at -80°C until use.
\n\t\t\t\n\t\t\t\tTranscript profiling – Transcript levels were assessed with microarray in total RNA. In brief, 25 micrometer cross-sections were prepared for 10 mm3 of muscle volume and total RNA extracted with the RNeasy mini-protocol (Qiagen, Basel, Switzerland) for skeletal muscle as described (Fluck, Schmutz et al. 2005). Integrity of the RNA was checked with denaturing agarose gel electrophoresis, and the concentration was quantified against ribosomal standard using the RiboGreen RNA quantification kit (Molecular Probes, Eugene, OR).
\n\t\t\tSubsequently RNA was labelled during reverse-transcription and hybridized to different platforms dependent on the species:
\n\t\t\tFor human samples this involved the use of a full human genome Affimetrix platform through a commercial provider (DNA vision, Gosselies, Belgium). For statistical analysis raw signals were normalized to total mRNA signal on the array and assessed with statistical analysis of microarrays between pre and 8-hours post samples with T-tests (SAM).
\n\t\t\tFor studies with rat and mouse soleus muscle, 3 micrograms of total RNA were reverse transcribed with SuperScript II (Life Technologies, Basel, Switzerland) using [α-32P]dATP and gene-specific primers. Radio-labelled target cDNA was hybridised in ExpressHyb solution overnight at 68°C to nylon membranes which spotted cDNA probes (BD Biosciences, Allschwil, Switzerland). The membranes were washed (four times for 1 h in 2x SSC (0.3 M sodium chloride, 0.03 M sodium citrate), 1% SDS and once for 30 min in 0.1x SSC, 0.5% SDS at 68°C and exposed for 5 days to a phosphoimager (Molecular Dynamics, Sunnyvale, CA) for quantification with AIDA Array Easy software (Raytest Schweiz, Urdorf, Switzerland).
\n\t\t\tFor the rat experiment cDNA microarrays (Atlas Rat 1.2, no. 7854; Clontech Laboratories, Ozyme, France) were used. More details to this cDNA array can be found on Gene Expression Omnibus (GEO,
For the mouse experiment custom-designed low-density Atlas cDNA expression arrays with 229 double-spotted probes of mouse cDNAs associated with skeletal muscle form and function were employed. More details to this cDNA array can be found on GEO under GPL1097. For statistical analysis raw signals were normalized to total mRNA signal on the array and assessed with SAM.
\n\t\t\t\n\t\t\t\tMicroscopy - Fibre type analysis of mouse muscle was carried out on cryosections with specific antibodies using a two-step detection protocol as described (Fluck et al., 2002). In brief, 12 micrometer cryosections were prepared, fixed in cold acetone and wetted in phosphate-buffered saline (PBS). Tissue peroxidase activity was then quenched (10 min, 3% H2O2 in methanol), sections were washed in PBS and blocked with 3% BSA in PBS for 0.5 h. Subsequently the sections were incubated for 1 h at room temperature (20 °C) with 1:100 of a monoclonal antibody in 0.3 % BSA/PBS against slow (Chemikon Juro, Lucerne, Switzerland) or fast type myosin heavy chain (Sigma Chemicals, (Buchs, Switzerland), respectively. Following, 3 brief washing in PBS, the section was reacted for 30 min with peroxidase-conjugated goat anti-rabbit IgG (diluted 1:2000 in 0.3 % BSA/PBS; Jackson Laboratories, West Grove, PA, USA) and again washed with PBS. Immunoreactivity was detected with 3-amino-9-ethylcarbazole substrate (Sigma Chemicals, Buchs, Switzerland); the nuclei were counterstained with haematoxylin, and the sections were embedded in Aquamount (BDH Laboratory Supplies Poole, UK). The stain was visualised on film (Ektachrome 64T, Kodak) using a microscope/photograph system (Vanox-S, Olympus).
\n\t\t\tMicrographs were taken from corresponding fields and the fibre types were classified. Slow and fast type fibres were differentiated on the basis of the presence of immunoreactivity for either type I or type II myosin heavy chain isoforms. Subsequently the percentages of each fiber population were counted.
\n\t\t\tThe overexpression of FAK in muscle fibres was detected out with a Leica TCS SP5 confocal microscope on a DMI6000 stage powered by Argon laser and He–Ne lasers (Leica Microsystem CMS, Mylton Keynes, UK). In brief, 12 micometer cryosections were reacted with a 1 : 100 dilution of rabbit FAK antibody A-17 (Santa Cruz) and MHC2 antibody in 0.3% BSA in phosphate-buffered saline (PBS) and reacted with fluorescent-labelled secondary antibodies (Alexa488-conjugated anti-rabbit IgG, and Alexa555-conjugated anti-mouse IgG, Molecular Probes/Invitrogen). Sections were embedded in fluorescence-compatible mounting medium (DAKO, Denmark). Signal for FAK and the co-detected myosin protein was inspected with fluorescence after excitation at 458 nm, 476 nm and 488 nm with sampling in channels between 510–533 nm (Alexa 488) and 593–614 nm (Alexa 555).
\n\t\t\t\n\t\t\t\tMyography - Soleus muscles were harvested from anesthetized animals (pentobarbital, 50 microgram/gram body weight) and equilibrated in Tyrod solution (mM/l: 118.0 NaCl, 4.7 KCl, 2.0 CaCl2, 1.2 MgSO4, 1.1 KH2PO4, 24.0 NaHCO3, 4.5 glucose, pH 7.3–7.4; 5% CO2 / 95% O2 @ 25°C). Muscles were transferred to Tyrod solution in the contraction chamber, connected to the force transducer (KG7; Muscle tester ORG (SI-Heidelberg, Germany) and equilibrated for 5-10 minutes by gazing with 5% CO2 / 95% O2 @ 25°C. Contractions were initiated by point stimulation via an Ion Optix myopacer. Signals were recorded using a Powerlab system (AD instruments, Germany) and using Chart 5 software. Measurement of single twitch, tetanus and fatigue were carried out: First the length of the inserted muscle was optimized for maximal force at a stimulation of 1 Hz, 10 V, 0.4 ms. For single twitch contractions, the muscle was stimulated at 1 Hz, 10 V, 0.4 ms. For the assessment of fatigue, a repeated 3-minute tetanic contraction protocol was used (55/60 Hz, 10 V, 0.4 ms in trains of 4 seconds on and off). Fatigue was defined as the contraction cycle when force dropped below 50% of original force. Before each measurement the Tyrod solution was exchanged. The measured muscles were frozen in liquid nitrogen-cooled isopentane to determine fiber size and distribution. Twitch parameters (latency, twitch-time to peak, t1/2 relaxation, maximal force) were determined from the digital recording. Measures from contralateral muscles were considered as separate biological replica. Statistical analysis was carried out with an unpaired t-test (Statistica 6.1).
\n\t\t\tMuscle fibres of anti-gravitational muscles are active for a considerable duration during free movement and quiet standing (Hennig & Lomo, 1985). We wished to investigate transcript regulation of factors of the myelin sheet by muscle activity. Towards this end we carried out an exploratory microarray analysis with the slow oxidative soleus muscle of rats that was subjected to changes in muscle activity by hindlimb suspension. The model allows reducing load bearing activity to slow oxidative soleus muscle by non-invasive means with the suspension of hindlimbs with the option to increase muscle activity with subsequent reloading (Morey Holten model as referred by Dapp et al., 2004).
\n\t\t\t\t\tTranscript profiling of rat soleus muscle showed lowered expression of the myelin-specific transcripts, peripheral myelin protein 22 (pmp22), myelin protein zero (MPZ), myelin basic protein (mbp) as well as myelin proteolipid protein and myelin-associated glycoprotein with reduced muscle activity (Fig. 1). With reloading the abundance of all of these transcripts were sizably increased.
\n\t\t\t\t\tWe assessed the response of myelin-specific factors in human knee extensor muscle to exhaustive exercise. It has been pointed out before that this exercise stress induces a compensatory expression response during the first 24 hours of recovery from exercise (Pilegaard et al., 2000; Fluck, 2006). The analysis in the mixed vastus lateralis muscle consolidated the observation on the regulation of myelin-specific transcripts by muscle use. Pmp22, mpz and mbp transcript levels were increased by 1.2 to 1.8-fold (table 1).
\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\tgene\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\tabbr\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\tmean\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\tSE\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\tp-value\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t
myelin basic protein | \n\t\t\t\t\t\t\t\tMBP | \n\t\t\t\t\t\t\t\t1.7 | \n\t\t\t\t\t\t\t\t0.3 | \n\t\t\t\t\t\t\t\t2% | \n\t\t\t\t\t\t\t
myelin expression factor 2 | \n\t\t\t\t\t\t\t\tMYEF2 | \n\t\t\t\t\t\t\t\t1.4 | \n\t\t\t\t\t\t\t\t0.2 | \n\t\t\t\t\t\t\t\t3% | \n\t\t\t\t\t\t\t
peripheral myelin protein 22 | \n\t\t\t\t\t\t\t\tPMP22 | \n\t\t\t\t\t\t\t\t1.8 | \n\t\t\t\t\t\t\t\t0.4 | \n\t\t\t\t\t\t\t\t5% | \n\t\t\t\t\t\t\t
myelin associated glycoprotein | \n\t\t\t\t\t\t\t\tMAG | \n\t\t\t\t\t\t\t\t1.1 | \n\t\t\t\t\t\t\t\t0.1 | \n\t\t\t\t\t\t\t\t5% | \n\t\t\t\t\t\t\t
myelin protein zero | \n\t\t\t\t\t\t\t\tMPZ | \n\t\t\t\t\t\t\t\t1.2 | \n\t\t\t\t\t\t\t\t0.1 | \n\t\t\t\t\t\t\t\t21% | \n\t\t\t\t\t\t\t
myelin oligodendrocyte glycoprotein | \n\t\t\t\t\t\t\t\tMOG | \n\t\t\t\t\t\t\t\t1.2 | \n\t\t\t\t\t\t\t\t0.1 | \n\t\t\t\t\t\t\t\t25% | \n\t\t\t\t\t\t\t
Expressional alterations in myelin-specific transcripts in human vastus lateralis muscle after endurance exercise.
Expression of myelin-specific transcripts depends on muscle activity. Bar graphs indicating mean ± standard error (SE) of level changes of five transcripts (per beta actin) in rat m. soleus with 7 days of hindlimb suspension vs. cage controls (A) and one day of reloading vs. hindlimb suspension (B). Asterisks denote significant effect based on a T-test. n=6. The line of identity is given. Abbreviations: mpz, myelin protein zero; pmp22, peripheral myelin protein 22; plp, myelin proteolipid protein; mag, myelin-associated glycoprotein; mbp, myelin basic protein.
Pmp22-tg mice show reduced pmp22 protein expression, lack myelination, and demonstrate neurogenic muscle atrophy (Magyar et al., 1996).
\n\t\t\t\tWe compared the muscles of pmp22-tg mice vs. strain matched controls to identify contractile defects with pmp22-dependent moto neuron aberration. Soleus muscle of pmp22-tg mice demonstrated a shift towards an atrophic, slow phenotype. This was indicated by the reduced muscle weight (Fig. 2D) and elevated percentage of slow type muscle fibres (Fig. 2A-C). This became manifest in prolonged time-to-peak and half time of muscle relaxation (Fig. 2D). The aberrations resulted in a reduction in RNA messengers for the slow oxidative expression program concomitantly with the elevated abundance of gene transcripts for fast type myogenesis (Fig. 3). The only exceptions were GAPDH and CA3 being involved in pH regulation of slow type muscle fibres.
\n\t\t\tTowards understanding the functional implication of motor unit recruitment for control of muscle gene expression we subjected pmp22-tg mice to 3 days of hindlimb suspension. Microarray experiments identified important alterations in transcript expression in soleus muscles with 3 days of reduced muscle activity (Fig. 4). The differences between suspended and cage control muscle distinguished between wildtype and pmp22-tg mice. This concerned gene ontologies defining the contractile and metabolic muscle phenotype of
\n\t\t\t\tContractile aberrations in anti-gravitational muscle of pmp22-transgenic mice. A, B) Micrographs visualizing cross sections of soleus muscle from a wildtype (A) and pmp22-tg mouse (B) after staining for slow type myosin heavy chain. C, D) Bar graphs indicating mean ± SE of percentage of slow type muscle fibres (C) in soleus muscle and weight (D) of wildtype (white bar, n=5) and pmp22-transgenic mice (black bar, n=6). E) Mean ± SE and standard deviation (SD) of contractile parameters in soleus muscles of wildtype (n=6) and pmp22-transgenic mice (n=5). Asterisks denote significant effect based on a T-test.
skeletal muscle. Thereby transcript levels of factors of myogenesis, fast contraction, glycolysis and oxidative metabolism altered in opposite ways between wildtype and pmp22-tg muscle.
\n\t\t\t\tAberrant transcript expression in pmp22-transgenic mice. Bar graphs representing the mean fold difference in transcript levels between pmp22tg and wildtype mice for gene ontologies which set the phenotype of soleus muscle. Data were generated with custom mircrarrays for 229 selected factors, normalized to total mRNA and assessed with unpaired test using SAM (n=4). Black and grey bars denote significantly up-regulated and significantly down-regulated transcripts, respectively. Transcripts reflected by white bars were not significant altered. The line of identity is given. Abbreviations: Glut2, facilitative glucose transporter member 2; LDH2, lactate dehydrogenase 2; GAPDH; glyceraldehyde-3-phosphate dehydrogenase; COX IVa, cytochrome c oxidase subunit 4 isoform 1; COX Vb, cytochrome c oxidase subunit 5B; COX VIa2; cytochrome c oxidase subunit 6a2; CPTI, carnitine O-palmitoyltransferase 1; FAT/CD36, cluster of Differentiation 36/Fatty acid transport protein; HADH, 3-hydroxyacyl-CoA dehydrogenase; H-FABP; fatty acid binding protein of the heart; LPL, lipoprotein lipase; MCAD, medium-chain specific acyl-CoA dehydrogenase; MHC I; myosin heavy chain type I; MHC IIA; myosin heavy chain type IIA; MHC IIB; myosin heavy chain type IIB; MHC IIX, myosin heavy chain type IIX; IGF-I, Insulin-like growth factor I; SRF, serum response factor; Rb, retinoblastoma-associated protein; myoD, Myoblast determination protein 1; p21, cyclin-dependent kinase inhibitor 1; myf6/herculin; myogenic factor 6.
We assessed whether overexpression of the governor of slow-oxidative gene expression, focal adhesion kinase (FAK), can control myelin factor expression and pmp22-dependent gene transcripts. Using gene electro transfer we introduced a constitutively active expression plasmid for FAK, pCMV-FAK, in soleus muscle of the right leg of Wistar rats. Transfection of the contralateral muscle with empty pCMV plasmid served as intra-animal control. Immunofluorescence experiments showed that overexpression of FAK was confined to muscle fibres but was not observed in contralateral controls (Fig. 5). Microarray analysis demonstrated that FAK overexpression increased transcript levels of pmp22 along with the one of MBP in soleus muscle of active rats. Concurrently the expression of a battery of slow oxidative genes was increased (Durieux et al., 2009).
\n\t\t\t\tAnomalous expression response of pmp22-transgenic mice to reduced muscle activity. Bar graph representing the mean fold difference in transcript levels in soleus muscle between wildtype mice (A, n=8) and pmp22tg (A, n=4) with 3 days of reduced load bearing (suspension) vs. cage controls. Data were generated with custom microarrays for 229 selected factors, normalized to total mRNA and assessed with a paired test between values from suspended and cage control muscle using SAM. Black and grey bars denote significantly up-regulated and significantly down-regulated transcripts, respectively. Transcripts reflected by white bars were not significant altered. The line of identity is given.
Abbreviations: Glut 4, facilitative glucose transporter member 4; IGF-BP5, Insulin-like growth factor binding protein 5. For others consult legend to figure 3.
\n\t\t\tFAK signals mechanical stimuli in muscle to gene expression and protein synthesis (Durieux et al. 2009; Klossner et al., 2009). We subjected the FAK-transfected soleus muscles to 7 days of hindlimb suspension and subsequent one day of reloading to assess the interaction of muscle activity with gene therapy. Pmp22 transcript expression was little affected by reduced load bearing. With subsequent reloading however pmp22 levels were reduced. This effect was transient and was gone 5 days after reloading
\n\t\t\tSkeletal muscle is the largest tissue of vertebrate species and most muscle groups rely on muscle activity to maintain their phenotype (Booth & Thomason, 1991). This is most pronounced in slow oxidative muscle types which are typically involved in control of gait and posture (Roy et al., 1996). This resembles the preferential affection of oxidative muscles
\n\t\t\tFAK driven expression of myelination factors is dependent on muscle activity. A) Representative micrograph from a cryosections of a pCMV-FAK transfected soleus muscle of a rat after double staining for FAK (red) and fast type myosin heavy chain (MHC, yellow) as recorded with a confocal microscope. B) Bar graph representing the mean difference + SE of transcripts for three myelination factors pmp22, mpz and mbp between pCMV-FAK vs. empty (pCMV) transfected soleus muscle. Black, white and grey bars reflect data from cage controls, 7 days suspended and one day reloaded mice. Asterisks denote significant effect based on a T-test.
Implication of excitation-transcription coupling in muscle control. Sketch summarizes a concept whereby moto neuron excitation (feed forward) with muscle use triggers the expression of myelination factors which exert feedback control on the muscle-nerve interaction.
in the trembler model of CMT disease (Gale et al., 1982). This use-dependent control of gene expression and protein synthesis (Fluck & Hoppeler, 2003; Wilkinson et al., 2008) is not taken into consideration in current gene therapy of neurological muscle disorders.
\n\t\t\tHere we prove the concept that muscle fibre targeted somatic transgenesis can affect nerve-related gene expression. The results point out that muscle activity importantly modifies the pre-translational effects of the somatic overexpression of the governor of the slow oxidative muscle program, FAK, on the expression of myelin-specific transcripts. This was shown by a similar regulation of pmp22, MPZ and MBP transcripts by muscle disuse with reduced load-bearing (down-regulation) in rats, increased load-bearing muscle activity in rats and with endurance exercise (up-regulation) in man (table 1, Fig. 1). The direction of the transcript levels points out that that myelin-specific transcript expression is related to fibre recruitment. Such a mutual control of the muscle-nerve interaction is known from the action of neurotrophic factors during normal development of the slow muscle fiber phenotype (Carrasco & English, 2003). These findings support the novel concept that in addition to feed forward control of muscle gene expression by muscle use (Calvo et al., 2001) a feedback mechanism exists whereby muscle activity in return regulates moto neurons (Fig. 6).
\n\t\t\tThe functional consequences of use dependent expressional alterations in myelin sheet-specific factors in skeletal muscle remain to be explored. Pmp22 is a major component of myelin expressed in the compact portion of essentially all myelinated fibres in the peripheral nervous system and is produced predominantly by Schwann cells. Pmp22 is expressed in cranial nerves but not in the mature central nervous system. Studies in injured nerve suggested a role during Schwann cell growth and differentiation and maturation of the neuromuscular junction (Spreyer et al., 1991; Patel et al., 1992; Magyar et al., 1996). Interestingly the identified transcript level changes in our study are in line with the degeneration of NMJ with disuse (Deschenes et al., 2001) and neurological adaptation which improves fibre recruitment early with exercise (Roy et al., 1996). This supports a hypothesis whereby elevated myelin-specific transcript expression may allow the preservation and improvement of neuromuscular control of muscle fibres.
\n\t\t\tPrevious examinations of soleus and EDL muscle in the trembler mouse model of CMT revealed that the deep/oxidative and soleus muscles are particularly affected by CMT but fibre type differences were not described (Gale et al., 1982). Our measures in the pmp22-tg model of CMT emphasize that in addition to altered muscle contractility, slow fibre size and transcript expression in the anti-gravitational muscle, m. soleus, is anomalous. The reduction in RNA messengers for the slow oxidative expression program (Fig. 3) is possibly explained by volumetric alterations in fibre size as suggested by visually larger CSA ratio between fast and slow type fibres reflecting atrophy of slow type fibres. Smaller type I fibres in animal models for pmp22-dependent motor and sensory neuropathy type has been noted before (Schuierer et al., 2005). This would increase the contribution of transcripts in fast type muscle fibres. The concomitantly elevated abundance of transcripts for fast type myogenesis between pmp22-tg and wildtype mice likely reflects altered regulation in fast muscle fibres (Deschenes et al., 2001).
\n\t\t\tA main finding of our investigation was that differences between pmp22 and wildtype mice were preserved in an ‘opposite’ transcript response of soleus muscle to reduced load-bearing. Altered transcript expression is a potentially important indicator of pathological changes with reduced muscle activity (Bey et al. 2003; Chen et al., 2007). In this regard it is important that the response of soleus muscle from wildtype mice to 3 days of unloading reproduced the changes reported in a different mouse strain after 7 days of reduced load-bearing (Dapp, Schmutz et al. 2004). This overlap concerned contractile (MHCIIB) and metabolic factors (COXVb, COXVIa2, LDH2). Exceptions concerned those involved in myogenesis which were not altered after 3 days in this study. Strikingly, the transcript response of soleus muscle of pmp22-tg mice to suspension “mirrored” the differences seen between the pmp22-tg mice and wildtype mice at baseline. These observations imply the existence of use-dependent mechanism that “inverts” expression responses in model of CMT.
\n\t\t\tThis observation relates to the effects of current occupational therapy by exercise. We have shown before that FAK overexpression controls contractile performance of soleus muscle in a activity-dependent manner via the regulation of transcript expression (Durieux et al., 2009). Intriguingly with FAK overexpression and the resumption of loading bearing muscle activity, the transcript level of myelination factors were reduced compared to controls (Fig. 5). Our previous findings in the suspension model show that reduced myogenic factor RNA expression after 24 hours of the reloading stimulus is related to a concomitant increase is the encoded protein (Fluck et al., 2008). This relates to the observation that FAK acts as a molecular switch for transition between anabolic and catabolic reactions in skeletal muscle and controls the protein synthetic pathway via p70S6K (Durieux et al., 2009; Klossner et al., 2009). This suggests that transcript level changes in the early phase of reloading may reflect inverse alterations in protein synthesis. These relationships imply that the ’muscle activity’ is a confounding variable which would be valuable to be considered in somatic gene therapy of skeletal muscle. The fact that activity dependent gene regulation is reflected by the mechano-regulation of FAK activity by pTyr-397 phosphorylation (Durieux et al., 2009) indicates possible venues to stimulate this directly in situations where muscle activity is not an option.
\n\t\t\tThe extent to which differences between slow and fast motor neurons are involved in the coupling between muscle excitation and gene expression (excitation-transcription coupling) is currently not well understood (Schiaffino & Serrano, 2002; Wakeling & Syme, 2002). Based on a preferential atrophy of slow type muscle fibres (Roy et al., 1996; Dapp et al., 2004), hindlimb suspension is expected to affect slow motor units more that fast type units. Our findings on the distinction of basal and disuse-induced transcript expression with slowed signal propagation down the motoneuron (Magyar et al., 1996) highlight the importance of correct excitation for control of gene expression (Calvo et al., 2001).
\n\t\tOur observations indicate that muscle dysfunction with Charcot-Marie-Tooth (CMT) is not due to a single, central mechanism. A novel, contraction-dependent feedback mechanism is identified that controls myelin-specific transcripts via a muscle fibre-related pathway. Somatic transfection of muscle fibres with the mechanosensor FAK prove the concept that pmp22 expression which is lowered in CMT can be stimulated when combined with skeletal muscle use. This indicates that muscle activity is a confounding variable that warrants exploration in future gene therapeutic strategies to treat and manage neuromuscular disease.
\n\t\tThe study was financially supported by grants from the Région Rhône-Alpes, the Association Française contre les myopathies, and the Swiss National Science Foundation. The experiments were performed at the University of Berne (Switzerland), the University of Lyon (France), and Manchester Metropolitan University. The assistance of Dominique Desplanches, Anne-Cécile Durieux, Damien Freyssenet and Prof. Hans Hoppeler during the suspension experiments is greatly acknowledged.
\n\t\tNowadays, it is evident that, processing lignocelluloses biomass, specifically, lignin into different industrial chemicals via the biorefinery approach; has become economically attractive. Biorefinery, is a pinnacle of simple and advanced technologies, put together; in converting biomass such as lignin into sustainable fuels, intermediates and chemical products [1]. Therefore, lignin processing, including hydrothermal liquefaction (HTL) route is expected to ensure only useful products are produced. Pollutants, waste, and losses are limited, in what is referred to as an atom economy model [2].
Lignin, the second largest biomass after cellulose is largely underutilized. It is largely available in woody biomass, agricultural waste, and as an industrial process by-product from paper milling, and pulping industries [3], and waste stream in organosolv process [4]. It is also the only natural source of aromatic and phenolic compounds. Therefore, development of well-defined technologies targeting value addition of products and by-products from lignin, would undoubtedly give way to emerging markets in the industry.
Detailed literature review papers focused either on the general HTL processing of biomass and algae [5, 6]; HTL of food waste and model compounds [7]. Other areas covered included; the techno-economic, and life cycle assessment of lignocelluloses biomass via thermo-chemical conversion technologies [1]. A few case studies, such as the environmental profile of algae HTL have been reported [8]. However, review on HTL of specific feedstock other than algae and whole biomass are scarcely available; just as the detailed review on HTL of feedstock into specific value-added products, is equally rare. Except for the detailed review on catalytic valorization of lignin for the production of fuels and chemicals [9], such reviews are rare until recently.
It is therefore imperative to, amid the expanding research into biomass conversion, to accord necessary attention towards lignin degradation into value added chemicals, specifically, its hydroxylphenyl derivatives (H-type), guaiacyl derivatives (G-type), and Syringyl derivatives (S-type). In so doing, economically viable, and environmental friendly technology like HTL needs to be explored. This review paper, is aimed at appraising the literature information available on lignin degradation into valuable chemicals, with emphasis on HTL route.
Lignin is largely made up of polymerized monolignols (G-type, H-type and S-type), which are interconnected by well-defined benzodioxane linkages in a radical recombination coupling reaction [10]. The chemical structure of lignin according to different authors [11, 12]; suggested that it consisted of complex 4-phenylpropanol macromolecular units. Figure 1 depicts the monomeric units of lignin. Principally; it consists of phenylpropane monomer units of phenyl, guaiacyl and syringyl geometry (Figure 1), linked together via ether bonds (α–O–4; β–O–4; 5–O–4) and carbon–carbon bonds (β–1; β–5; β–β; 5–5). The β–O–4 is the most pointing ether bond in lignin, where different reactions take place.
Different monomeric units of lignin.
Authors have reported different simple and complex reactions taking place during lignin degradation. Even though, multitude of reactions are taking place, at this point (β–O–4), it was proposed that at supercritical point of water, for example; less energy intense reactions are a preferentially favored. Greater scheme of reactions take place at the bonds, forming different products depending on the relative thermodynamic stability of the bond, determined by the strength of double bond equivalence.
According to Berstis et al. [10], during lignin HTL, the reactivity of particular bond is depending on its reaction enthalpy, bond strength, and geometry. It was observed that, α–bonds are slightly weaker than their corresponding β–bond counterparts, and similar in strength to that of the conventional β–O–4 linkage. According to Beauchet et al. [13], the α- and β-aryl-ether-bond followed by the aryl–aryl bond, are the weakest bonds in the lignin polymers, thus; hydrocracking, and thermal hydro-deoxygenation have frequently been employed for depolymerisation, targeting these weak bonds. Table 1 presents the predominant bonds in lignin. According to Forchheim et al. [14], reactions including mild alkylation, hydro deoxygenation, reploymerization, and depolymerisation are predominant in lignin HTL. Liguori and Barth [15], reported reactions like hydro-deoxygenated, demethylated and demethoxylated at the ether bond positions. In addition, radical recombination and decomposition chemistry; are dimensional factors in the reaction rate.
Types of bonds existing in lignin structure.
Lignin, is the only natural source of phenolic compounds, thus; its liquefaction is increasingly been investigated. Although it was envisaged that the complex nature of lignin makes it valorization a difficult task; recent discoveries in selective bond cleaving of the predominant β–O–4 bond [16], is encouraging further research. The increasing research interest in C3 and C5-ortho reactivity and production of genetically modified lignin, have instigated lignin valorization work. The HTL of lignin into substituted Phenol, and aromatic ethers was conducted by Singh et al. [17]. These authors attributed the presence of Phenol, and aromatic ethers from the selective cleaving of β–O–4 and α–O–4 bonds, forming hydroxyl and alkyl groups, respectively. Similarly, Zhou [18] successfully converted Kraft lignin into value-added chemicals, specifically, guaiacol (2-methoxy Phenol), was formed by the degradation of β–O–4 bond. The cleavages of other functional groups including hydroxyl, aromatic, and carbonyl resulted in increased phenolic –OH presence.
Literature has availed different proposed schemes for lignin degradation. For example, According to Kruse and Dahmen [19], during biomass liquefaction, steam explosion occurs within 140–240°C leading to its structural disruption, just as the hydrothermal carbonization begin to manifest at around 200°C. Finally, liquefaction sets-in, between 300 and 350°C, and gasification reaction completes the liquefaction cycle around 450–600°C; depending on the feedstock. This temperature range was found to be perfect for the thermal degradation range of lignin which is 200–600°C [20]. Apart from HTL route, other biomass conversion techniques found suitable for lignin degradation, including pyrolysis [21, 22], hydrolysis [23], and gasification [24] have been reported.
Hydrothermal liquefaction (HTL), is one of the emerging biomass conversion technologies gaining desirable attention. This thermo-chemical processing method, has superior advantages in comparison to other processes. Figure 2 presents the modified vapor pressure curves for HTL processes.
Modified vapor pressure curves for hydrothermal conversion process.
Water, as the solvent in HTL makes the route environmental friendly; in addition to its bifunctional role as catalyst and solvent for multiple reactions taking place [19]. This is because, water, on approaching its supercritical point (above 375°C) exhibits good solvent ability, resulting from its improved properties like polarity, solubility and transportation properties [6, 7].
In economic terms, HTL reduces the energy consumption required during biomass drying, as it is suitable for conversion of high moisture content feedstock into good quality and stable products [7]. For these reasons, HTL has turned out to be a super-specialty method, found to be appropriate for converting different feedstock. These including cyanobacteria [25]; low-lipid and high protein algae [26]; sewage sludge [27]; bio-cakes [28]; and lignocelluloses model systems [29] etc.; into different targeted products such as protein, lipids, heterocyclic and their derivatives (nitrogenous and sulfur) [30]; phenolic and aromatic compounds [17]; fatty acids and light gases [31]; and nitrogenated compounds [32] etc. Yang et al. [33] identified Phenol and benzene derivatives from Corncob, with the two compounds showing improved active sites than the parent lignin. Thus, making the former suitable substituents in the synthesis of Phenol formaldehyde adhesive.
The use of co-solvent system in biomass liquefaction and by extension, lignin degradation has been investigated. A co-solvent hydrothermal degradation of alkali lignin into bi-phenolic compounds was investigated by Cheng et al. [12], suggesting an improved yield from the water-ethanol co-solvent system for sub/supercritical conditions. Whereas, time had negligible effect on the yield and quality of liquefaction products, temperature and co-solvent ratio had significant effects on yield and quality of bio-crude oil. Singh et al. [17], employed ethanol and methanol (1:10) co-solvent system for the synthesis of substituted Phenol and aromatic ethers. Figure 3 presents a semi-continuous process biomass liquefaction flow chart.
A semi-continuous process biomass liquefaction flow chart [34].
Lignin HTL is therefore suitable technology for effectively converting it into useful products with high selectivity, and quality. Table 2 reviewed the literature works on the HTL of lignin into reported products, highlighting the recounted yields and the major bifunctional chemicals obtained.
Lignin source | Liquefaction preview | Yield | Reported biomolecules | Ref. |
---|---|---|---|---|
Organosolv hardwood and wheat straw lignin | The liquefaction involved the preheating of lignin and formic acid in a supercritical fluid consisted of CO2/acetone/water in molar ratios of 2.7/1/1. The reaction was completed within 3.5 h at 300°C and 10 bar pressure. | 10–12% monomeric aromatic compounds | Phenolic oil was obtained consisting monomeric phenol and oligomeric aromatic compounds. | [35] |
Agricultural fibrous feedstocks | The reactor was loaded with lignin and ethanol/methanol (1:10 by weight) within 30 min and 200°C. | Liquid products yield (85%) was reported. | Substituted phenol and aromatic ethers. | [15] |
Sugarcane bagasse | The biomass loading was fixed at a solid:liquid ratio of 1:10 (w/w) including NaOH. | Not reported. | Major products included phenol, guaiacol and syringol. | [36] |
Alkaline lignin | HTL was conducted in a 250 mL autoclave with heating power of 1.5 kW. An alkaline lignin (8.0 g) and 100 mL of water are added and reactor was purged with nitrogen and agitated using a stirrer (200 rpm). The temperature was varied for 30 min. | Not reported. | Isolated products include benzenediols, monophenolic hydroxyl products, weak-polar products, and water-soluble products (low-molecular-weight organic acids, alcohols, etc.). | [37] |
Grass silage pressed cake | Lignin is extracted from the solid lignin residue from the mechanically supported enzymatic hydrolysis and subjected to ethanolic organosolv processing, at a reaction temperature and time of 195°C and 80 min, respectively. | Maximum yield obtained was 41–57 wt%. | Not reported. | [38] |
Lignin-rich residue from ethanol production | A mixture of lignin and deionized water was added and reactions were carried out at different temperatures (593–653 K). The residence time varied between 15 and 480 min. | Methoxyphenol (12 wt%), catechols (8 wt%) and phenol (15 wt%). | Phenol, catechols and methoxy phenol. | [21] |
Enzymatic hydrolysis lignin | The lignin, water and RANEY Nickel (dry matter) were placed in a 5mL autoclave. The autoclave was purged with nitrogen. The reaction mixture was heated at different temperatures for different reaction times. | Varying yields ranging from 3 to 15 mg/g lignin. | Phenol, catechol and guaiacol. | [13] |
Kraft lignin | Kraft lignin, heterogeneous catalyst (K2CO3), phenol and deionized water, is uninterruptedly pumped by high pressure diaphragm pump at a flow rate of 1 kg/h. This was a continuous reactor set-up. The reaction temperature was 350°C and 25 MPa. | With respect to dry lignin fed into the reactor, approximately 70 wt% of lignin oil was obtained. | Phenol, alkylphhenols, phenolic dimers, catechol and guaiacol. | [11] |
Organosolv lignin | HTL tests were completed in batch autoclave. The reactor was heated with an electric heating jacket. Temperature and pressure were checked online. A 700 mL chilled condenser was connected to the autoclave exit port. Lignin, catalyst, and deionized water with and without catalysts. | Approximately 25 wt% of monomeric phenol. | A complex mixtures of monomeric catechol and methoxylated and alkylated phenol. | [4] |
Wheat straw biomass | Sequential biomass pretreatment and followed by room temperature extraction with an activated resin. The biorefinery approach also included supercritical CO2 extraction of phenolic compounds. | Not reported. | High molecular weight phenolic compounds, targeting Tricin. | [39] |
Kraft lignin | The treated Kraft lignin, ionic liquid catalyst and, and Pd/C catalyst were placed in a 75 mL autoclave reactor. The reactor was sealed and purged with H2. The reaction was conducted at 200°C at a stirring speed of 800 rpm. | Maximum liquids products yield was 50 wt%, while based on Kraft lignin was 13 wt% yield. | Phenol, catechol and guaiacol. | [24] |
Kraft lignin | Kraft lignin and deionized water were reassigned into the reactor. The system was vented with nitrogen three times. For each experiment the reactor was heated in 30 min from ambient to a working temperature of 130°C or 180°C or 230°C, after which the experiment was continued for 15 or 60 min. | Phenolic oil content ranges from 5.4 to 10.6 wt%, with 78 wt% guaiacol. | Guaiacol | [19] |
Reviewed HTL of lignin degradation into different bio-chemicals.
The reaction temperature is the predominant factor in thermo-chemical processes like liquefaction. Lignin HTL is a temperature dependent process, since the degree of liquefaction increases with increasing reaction temperature. A careful selection of the heating rate is desired in reducing the rate, at which, condensation of unsaturated oligomeric phenol occur [38]. Depending on the temperature, HTL is sub-divided into subcritical liquefaction and supercritical liquefaction. Figure 4 presents the effect of reaction temperature on yield of different feedstock reported in the literature.
Effect of reaction temperature on lignin liquefaction for different feedstock. Data obtained from feedstock reported including; sugarcane bagasse [38, 42, 43, 44]; agricultural waste [15]; Loblolly pine [45]; Pinewood [25].
From the reported result, degradation temperature for lignin feedstock is between 200 and 300°C. Higher temperature beyond 300°C tends to reduce bio-crude oil yield. According to Hu et al. [40], lignin degradation is temperature dependent, in a manner that, increasing temperature in degradation of black liquor lignin was found to have favored bond cleavage, and elimination of functional groups, and carbonization. To add to this, Yang et al. [33] found that, temperature affected products distribution much more than reaction time.
Different classes of catalysts have already shown positive impact during lignin degradation. From Table 3, it could be argued that homogenous catalyst like NaOH, were found suitable [37, 41]. Also, mixed oxide catalysts [12] are increasingly been investigated. However, recent literature trend, suggested a paradigm shift towards ionic liquids.
Catalyst | Chemical composition | Feedstock used | Efficiency/findings | Ref. |
---|---|---|---|---|
NaOH | - | Sugarcane bagasse. | The efficiency was achieved using 4% NaOH caused a decrease in ester linked p-coumarates in the residues, while at 9% NaOH both p-coumarates and ferulates decreased. The last was symbolic for the degradation of particular β–O–4 linkages. | [36] |
RANEY Nickel | Nickel (88 wt%) and aluminum (12 wt%). | Enzymatic hydrolysis lignin. | The catalyst produced more carbon dioxide in the gaseous phase at the expense of low C2–C4 and much phenol in the organic phase in comparison to catechol and guaiacol. Low char formation was also observed. | [13] |
Raney Nickel 2400, 4200 | Nickel (81 wt%), aluminum (6 wt%), iron (2 wt%) and chrome (2 wt%). | Organosolv lignin. | The catalyst favored the production of phenol in all cases. However, the efficiency depends on the Ni/Al ratio and other promoter metallic composition of the catalysts. | [4] |
Ionic liquids | 1-ethyl-3-methylimidazolium acetate ([emim][OAc]). | Wheat straw | The use of the ionic liquid was effective in selective fractionation of cellulose, hemicellulose and lignin into relatively high purity fractions. The catalyst was also effective in the valorization of the phenolic fraction. | [39] |
Dual catalyst (choline-derived ionic liquids and Pd/C). | [Ch][Ace]; [Ch][CF3CO2]; [Ch][H2PO4]; [Ch][Lev], and [Ch]-[MeSO3] with Pd/C. | Kraft lignin | The phenol and catechol production was virtually the same, since the catalytic activity was dependent on the cation and anions combinations | [24] |
K2CO3 | LignoBoost Kraft lignin | Increasing mass fraction of K2CO3 resulted in remarkable increasing in phenolic oil yield, showing selectivity towards anisole, alkylphenol and catechol | [11] | |
NaOH | - | Kraft lignin | The base-catalyzed lignin de-polymerization yielded 8.4 wt% monomeric-rich fraction. The catalyst favored deoxygenated aliphatic OH and guaiacyl groups. | [46] |
Ionic liquids | The ILs including 1-(4-sulfobutyl)-3-methyl imidazolium hydrosulfate ([C4H8-SO3Hmim]HSO4), N-methyl imidazolium hydrosulfate. HSO4), 1-butyl-3-methyl imidazolium hydrosulfate ([bmim] HSO4), and 1-(2-carboxyethyl)-3-methyl imidazolium chloride ([C2H4COOHmim]Cl). | Sugarcane bagasse | All ILs studied were very effective towards total degradation of lignin components, showing excellent recyclability up to five times. However, the results into numerous products which caused characteristic separation difficulty. | [43] |
Palladium catalysts | Commercially available catalysts, (10%) Pd/C, (30%) Pd/C, Pd(OH)2/C, Pd(OAc)2, Pd-PEPPSI-iPr and Pd/Lindlar. | Spruce lignin; lignin from acidic hydrolysis; enzymatic hydrolysis; acidic hydrolysis; strong acidic hydrolysis; desulfonated Kraft lignin. | [14] | |
Mixed oxides catalysts | A γ-Al2O3 and active carbon (AC) supported metallic (Pt, Ru, and Ni). | It was reported that the metallic catalysts did not have significant change in the yield, generally, but Ni and Ru showed preferential improved yield than Pt | [12] | |
Ionic liquids | Dialkylimidazolium-based e.g ([C4mim]MeSO3); ([C4mim]OAc); ([C4mim]Cl). | Regenerated lignin | The pH, IL composition, and IL content were established to significantly affect the degradation and chemical conversion of lignin structure. It was concluded that low pH helped lignin depolymerization nevertheless destroyed the substructure of lignin. | [40] |
Effect of catalysts on lignin degradation for different feedstock.
Ionic liquids [ILs] application in biomass refining has received increasing attention, recently. ILs catalysis in lignin degradation, specifically, have received appreciable attention. Different classes of ILs including biocompatible, bio-renewable, protonic ILs have been investigated [42]. The main factor affecting lignin HTL using ILs as catalysts, and/or co-solvents is their selectivity. This selectivity of ILs revolves around the cationic alkyl chain length, anionic hydrophobicity, temperature and solvent type among others. The catalytic activity of acidic ILs, for example, is largely associated with the Lewis/Bronsted acidity of the alkyl chain length.
Significant acidity of ILs catalysts is derived from inter-molecular bonding interactions. This is in contrast to the acidity of conventional acid catalysts, whose acidity is derived from their protonation. Therefore, the former exhibited the tendency towards eliminating reactor corrosion; a major reaction engineering problem that has been posing serious challenges. It was postulated that, lignin dissolution was aided via a π–π interaction between an alkyl imidazolium chloride catalyst and the π–bond in the aromatic rings structure of lignin, suggesting the additional dissolution potentials of alkyl based ILs [9]. According to Zhuo et al. [44]; the acidity of 2-phenyl-2-Imidazoline based ILs with shorter-side chain length at C-1, was found to be higher than same ILs having longer-side chain length; and were both lower than –SO3H functionalized ILs.
Dual-functionalized ILs have even greater acidity. Products distribution is also associated with the acidity of ILs as catalysts/co-solvent medium employed. Highly acidic medium preferentially favored hydrolysis reaction, yielding water-soluble products. While basic medium promotes liquefaction reactions, yielding organic products [23].
However, the most attractive ILs in this field, nowadays, are the deep eutectic solvents (DESs) [45, 47]. Additional properties of DESs including; low volatility, thermal and chemical stability, high selectivity, green characteristic; ease of preparation [28, 48] are among their added advantages of DESs as catalysts. The chemistry of these catalysts suggests that their delignification efficiency was dependent on the acidic amount, its strength, chemical composition of the quaternary salt and the nature of the hydrogen bond acceptor or both [45, 49]. Liu et al. [23], conducted the selective hydrogenolysis of Kraft lignin into mono-phenol, catalyzed by using Choline-derived DESs, in which, [Ch][MeSO3] showed excellent lignin dissolution, resulting from its strong acidity and better thermal stability.
Accordingly, Wu et al. [47] investigated among others, the lignin extractability of monocarboxylic acids, dicarboxylic acids and polycarboxylic acids based DESs. The authors reported monocarboxylic acids with high acidic strength showed improved lignin extractability, as compared to low acidic monocarboxylic acids and dicarboxylic acids, due to carbon dioxide liberation in case of using dicaroxylic acids. Controversially, the low viscosities of polycarboxylic acids makes their hydroxyl group available for interaction with the etherified hydroxyl components of the lignin, thus; resulting in high lignin extraction [47].
Apart from their general applications in biomass refining including lignin degradation, ILs have been reportedly used in selective production and isolation of biorefinery products such as furfural [48], total reducing sugars [44, 50], and glycerin separation [51]. For example, in place of microwave assisted methylation, the selective oxidation of these benzylic alcohols in lignin into benzylic ketones, prior to the β–O–4 hydrogenolysis treatment has been reported [52].
Technically, two-step lignin depolymerization involving the selective oxidation of primary benzylic alcohols into benzylic ketones on one side and its succeeding β–O–4 cleavage; would have been the most favorable conversion route. However, challenges associated with the low products yields and poor selectivity remained unresolved. Unlike the methylation route, the benzylic ketone (selective oxidation) route, showed low products yield and selectivity as well. In addition, products separation becomes challenging on a large scale [41].
The effect of reaction time during lignin degradation was studied by Yuan et al. [53]. The authors discovered that; long reaction time was needed to ensure complete degradation of all ether bonds in lignin, and gradual degradation of the stable C–C bonds, afterwards. Long reaction induction period of the intermediates enabled secondary reactions including re-polymerization, cross-linking and rearrangement, thereby forming marginally higher products yields. Reaction time has significantly influenced the properties of individual lignin liquefaction products. According to Chen et al. [12], reaction time had no significant effect on products yield.
The composition of lignin is yet, another important factor in its degradation. Zhou [18] observed that, the yield of water-soluble hydrocarbons during HTL of Kraft lignin was low as compared to the yield of same components in liquefaction of sawdust. They attributed their finding to the composition of Kraft lignin, having low carbohydrate content. Another important factor in lignin degradation is the composition of the solvent. According to Yuan et al. [53], the composition of solvent greatly influenced the products distribution. They observed that; phenol addition in the reaction medium hindered side reactions like re-polymerization of products intermediates, resulting in low residue formation. Using co-solvent system showed improved lignin degradation, specifically, water-ethanol co-solvent degradation was much effective as compared to individual mono-solvent systems [12].
As earlier discussed, decomposition of the different classes of lignin components (p-coumaryl, coniferyl and sinapyl alcohols) results in complexing chemical products, intermediates and by-products during liquefaction. Characteristically, p-coumaryl alcohols decomposed into corresponding hydoxyphenyl derivatives (H-type) including Phenol, Phenol-methyl-, Phenol-di-methyl-, Methylphenol and other secondary Benzoic acid hydroxyl- derivatives.
The guaiacyl derivatives (G-type) are largely containing methoxyphenol, methyl methoxyphenol, vinylphenol, methoxy propyl and vanillin. According to Zhou [15], the products distribution from an organosolv liquefaction of Kraft lignin, for example; suggested up to 65 wt% constituted of volatile products, of which 78 wt% was made up of 2-methoxyphenol.
Phenol and its derivatives are probably the most interesting products of lignin liquefaction. Phenol and its derivatives formed the major composition of HTL of lignin and its compounds. Selective cleavage of the different ether bonds (C–O–C), yield highly phenolic products, showing excellent fuel additive properties, when the oxy-aromatic configuration is retained [11]. Phenolic compounds formed the greater composition in bio-crude oil obtained from Corncob lignin degradation. Generally, phenolic products from lignin degradation are classified as G-phenols (methoxy phenols), S-phenols (dimethoxyphenols) and H-phenols (methylphenols).
Khampuang et al. [54], conducted an alkali catalyzed Corncob liquefaction in supercritical water-ethanol, with phenol and its derivatives (phenol, 4-methoxy-acetate; phenol, 2-ethyl-; phenol, 4-ethyl-2-methoxy-; phenol, 2,6-dimethoxy-), constituting major proportion of the bio-crude oil. Figure 5 presents some selected Phenolic products from HTL of lignin.
Some phenolic products from HTL of lignin.
Similarly, Riaz et al. [55], confirmed the presence of monomeric phenol as one of the major components of bio-crude oil obtained from the acid hydrolysis lignin degradation in supercritical ethanol. The authors noted that, though, phenol (C6H5OH) was the major product, traces of methyl, methoxy, and ethyl groups were equally observed. Base catalyzed HTL of lignin seems to promote phenol formation. According to Nazari et al. [56], phenol derivatives (mainly 2-methoxy phenol), and aliphatic compounds, constituted significant composition of bio-crude oil yield, resulting from the use of base catalyst (KOH). Yuan et al. [53], reported that, higher temperature, and long reaction time increased the phenol combination rate, leading to re-polymerization, and cross-linking among phenol and the side chains of the degraded lignin. Yang et al. [33], found that, compounds in bio-crude oil had extra active sites than the parent lignin, signifying that the bio-crude oil obtained from lignin degradation was a promising feedstock for industrial synthesis of phenol formaldehyde adhesive. Decomposition of p-coumaryl alcohol (H-type), yield significant bio-crude oil with high amount of phenol.
The widely accepted mechanism for the production of guaiacol is via β–O–4 bond cleavage. Recalling that, β–O–4 bond is the predominant in lignin structure, large quantity of guaiacol is expected during HTL. The production of guaiacol depends on the cleavage of C–O and C–C bonds during lignin degradation [14]. Increasing reaction temperature reduces the yield of guaiacol-derivatives at the expense of their benzendiol counterparts (Catechol). This was confirmed by the work of Nguyen et al. [11], who reported that, base catalysts, such as K2CO3 tend to decrease the yield of guaiacol and increasing the yields of catechol. Zhou [18], conducted the HTL conversion of Kraft lignin, indicating the predominance of guaiacol (19–78 wt%), depending on reaction conditions. The bio-crude oil yield was indicated by improved sum of phenolic –OH groups present in Kraft lignin and, diminished amount of β–O–4 linkages, hydroxyl groups, carbonyl groups, aromatic rings. Thus, suggested that, the guaiacol yield obtained via HTL of lignin was much higher than that obtained from its liquefaction. Figure 6 presents some Guaiacol derivatives reported from HTL of lignin. Figure 6 presents the relative distribution of products.
Some guaiacol derivatives from HTL of lignin.
Catechol exists in different monomer forms including pyrocatechol, 3-methylcatechol, 4-methylcatechol, propylcatechol, 4-ethylcatechol and so on. Its production mechanism reported by authors differ. For example, Beauchet et al. [13] proposed the production of pyrocatechol, and methanol via direct hydrolysis of O–CH3 bond, while its decarboxylation at ether bond of 3-hydroxy-4-methoxybenzeneacetic acid, yielded significant proportion of methylcatechol. Figure 7 presents some selected catechol derivatives.
Structures of some catechols.
Forchheim et al. [14], proposed lignin degradation, and found that, RANEY Nickel catalyst favored ether bond cleavage near critical water condition. Authors also noted the conversion of catechol into phenol as the secondary degradation product. Guaiacol degradation also yield catechol, whereas, catechol losses one –OH group to form phenol at high temperature [9]. Generally, high-temperature and short time favored the formation of catechol, and subdues the formation of char and gaseous components [14]. Depending on the temperature, HTL is sub-divided into subcritical liquefaction and supercritical liquefaction. Figure 8 presents the relative products distribution in lignin degradation on yield of different feedstock reported in the literature.
Relative products distribution in lignin degradation. Palm kernel shell, wheat straw, and pine sawdust [31], cotton exocarp and mushroom substrate of cotton [22], hardwood [35], and sugarcane bagasse [38].
Catechol formation was discussed by Hu et al. [40] suggesting that; it is largely formed by the preferential elimination of methoxyl group depending on the truncated strength of the Aryl–OCH3 (DBE = 273 KJ/mol) to the Aryl–O–CH3 (DBE = 416.7 KJ/mol) bond. Specifically, with increasing reaction temperature, simultaneous pyrolysis and hydrolysis reactions taking place favored catechol formation. Lignin depolymerisation kinetics designated the decomposition of catechol into phenol, preferentially at high temperature and long reaction time [20]. Berstis et al. [10], demonstrated the use of density functional theory in predicting the relative energetics as well as bond dissociation enthalpies of the different benzodioxane linkages in lignin (C–C, C–S, C–G, C–H).
The index of hydrogen deficiency or double bond equivalence is calculated by the formula proposed by Pedersen and Rosendahl [29] as given below:
Figure 9 presents the relative distribution of products. Guaiacol – catechol – phenol interaction was considered as an important factor in lignin degradation kinetic studied by Forchheim et al. [14], because, phenol has better stability than either of guaiacol or catechol. Figure 9, proposed reaction pathways for hydrothermal lignin degradation.
Proposed reaction pathways for hydrothermal lignin degradation [14].
A significant number of chemicals compounds are theoretically and practically obtainable from HTL process. According to the broad literature available, these compounds are classified into phenols, guaiacols and catechols. However, derivatives of these principal groups have been widely reported. For example, lignin phenolic compounds have been produced by different research groups.
HTL products are largely rich in ortho-methoxyphenolic compounds which are detected by the presence of –OCH3 in their NMR spectra. This high volume product has chemical and biochemical applications including the manufacture of drugs and in clinical diagnosis. For example, the monitoring of wood smoke exposure by urinary assay was conducted by measuring the ortho-methoxyphenols. The production of perfumes, disinfectants resulting from its anti-oxidant properties, and as starting material for the synthesis of guaiacol compounds has been reported. Similarly, 3-methoxyphenol have dual functions as catalyst and building block in synthesis of anti-oxidants. Guaiacol is obtained by destructive distillation of phenol fraction of coal tar.
Pyrolysis of lignin has been one of the degradation techniques reported. Wang et al. [57] compared the pyrolytic behavior of different lignin (Manchurian ash and Mangolian Scot pine). The authors concluded that, the differences in pyrolytic behavior of the lignin studied were attributed to variation in their composition, and degradation temperature. High methanol yield was observed from degradation of hardwood, due to its higher methoxy group content, while the secondary methanol yield was attributed to aromatic ring degradation at high temperature.
Although HTL and pyrolysis of lignin are closely related, there exist some fundamental differences in their products. For example, Haarlemmer et al. [7], observed that, bio-crude oil (obtained from HTL) had higher acidity and iodine value as compared to an inverse relationship observed in bio-oil (obtained from pyrolysis) from the same feedstock. According to these authors, HTL oils are very viscous, and had strong black oil smell. It also had higher heating value (35–40 MJ/kg). HTL bio-crude oil is typically proposed as diesel substitute after catalytic upgrading. On the contrast, Pyrolysis oil is often presumed as substitute for fuel oil, and had smoky odor, and is less viscous, with heating value similar to that of the parent biomass. Table 4 presents the comparative properties of biomass fuels with standards.
Standard | Diesel | Biodiesel | Marine heavy fuel oil | Hydrothermal oil | Pyrolysis oil |
---|---|---|---|---|---|
NF EN 228 | NF EN 14214 | NF ISO 8217 | In progress | ||
Density at 15°C (kg m−3) | 820–845 | 860–900 | 920–1010 | 1.14 | 1.1 |
Carbon residue (%) | <0.3 | <0.3 | <2.5–20 | 17–24 | 11–13 |
Total acid number (mg KOH/g) | <0.5 | <0.5 | <0.5 | 32–67 | 45–109 |
Iodine value (g12/100 of fuel) | NA | <120 | NA | 126–127 | 147–203 |
Higher heating value (MJkg−1) | 45 | ≥35 | NA | 27–30 | 21–30 |
Water content (%) | <0.02 | <0.05 | <0.033 | <1 | 8–20 |
Viscosity at 40°C (mPas) | 3–4 | <4 | 8.5–690 | 67,000 | 13–70 |
Comparative physico-chemical properties of different biomass oils [7].
Like HTL of lignin, the products distribution during pyrolysis of lignin also depends on the composition of the feedstock. Chang et al. [24], conducted the Py-GC/MS degradation of palm kernel shell. Accordingly, the primary composition of the feedstock indicated the predominance of p-hydroxyphenyl structural units, resulting in high phenolic products, often its degradation. In contrast, pine sawdust and wheat straw contained largely guaiacyl units, and often degradation, yielded significant proportion of methoxy groups. Similarly, Biswas et al. [58], reported the slow pyrolysis of prot, alkali and dealkaline lignin for the production of chemicals. Among these types, alkali lignin was reported to have highest bio-oil yield (34.1%). Bio-oil products showed the presence of guaiacol, syringol, alkylphenols and catechol; depending on the pyrolysis conditions and nature of lignin used.
Pyrolysis of lignin-rich biomass from cotton by-product was conducted by Chen et al. [21]. Maximum bio-crude oil yield from fast pyrolysis was 58.13 (wt%) and 45.01 (wt%) at 600°C for cotton exocarp and spent mushroom substrate of cotton by-products, respectively. As compared to cellulose and hemicellulose, lignin degradation occur slowly and within wide temperature range (150–780°C).
Raiz et al. [55], conducted the concentrated sulfuric acid hydrolysis of lignin in supercritical ethanol, reporting significant reduction in oxygen content (44 wt%), resulting from improved deoxy-liquefaction. Bio-oil obtained from this work, had higher heating value, improved energy recovery, and energy efficiency.
Like liquefaction, hydrolysis bio-oil was rich in Phenol, esters, hydrocarbons, furan and alcohol. Ji et al. [59], conducted the hydrolysis of wheat straw in a dilute sulfuric acid medium using a continuous reactor. The maximum reducing sugar yield obtained was as high as 60.8 wt%, constituting furfural as the major by-product.
A number of emerging lignin degradation techniques are coming up by the day. Recently, a two-step lignin depolymerisation was reported, in which, lignin was methylated using micro-wave irradiation in the presence of benzylic alcohols. The first step of the reaction proceeded via catalytic hydrogenolysis of β–O–4 bond [52]. Similarly, in place of microwave assisted methylation, the selective oxidation of these benzylic alcohols in lignin into benzylic ketones, prior to the β–O–4 hydrogenolysis treatment has been reported [60]. Technically, two-step lignin depolymerization involving the selective oxidation of primary Benzylic alcohols into Benzylic ketones on one side, and its succeeding β–O–4 cleavage; would have been the most favorable conversion route. However, challenges associated with the low products yields and poor selectivity remained unresolved. Unlike the methylation route, the benzylic ketone (selective oxidation) route, showed low products yield and selectivity as well. In addition, products separation becomes challenging on a large scale [41].
Lignin degradation chemistry revolves around its β–O–4 bond cleavage. Products selectivity during its degradation is largely dependent on the catalysts employed, while the yield partly depends on the feedstock and reaction conditions. Temperature is the predominant factor influencing the reaction. Ionic liquids catalysts showed increasing research interest in biomass, and lignin liquefaction, owing to their interaction with lignin structure. Phenolic products are formed from selective cleavage of the different ether bonds (C–O–C). Increasing reaction temperature reduces the yield of guaiacol-derivatives at the expense of catechol. Catechol is formed via hydrolysis of O–CH3 bond, and decarboxylation at ether bonds. Guaiacol – catechol – phenol interaction was considered as an important factor in lignin degradation kinetic studies. Although HTL and pyrolysis of lignin are closely related, there exist some fundamental differences in the products.
The principal author wishes to sincerely thank the support of all the Prof. Naveen Kumar of Delhi Technological University, New Delhi-India, the management and staff support of the management of the National Research Institute for Chemical Technology, Zaria-Nigeria.
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