\r\n\t
\r\n\tSince they involve very small amounts of energy, high sound pressure levels are increasingly simpler and cheaper to emit. Noise is everywhere - it can be emitted as an energy waste by traffic or factories, but also by teenagers looking for loneliness in an overpopulated world.
\r\n\t
\r\n\tWhen the noise emission ends, it will not be possible to find its footprint in the environment, hence it is necessary to be in the right place at the right time to measure it. Moreover, having adequate instruments, updated protocols and trained personnel are mandatory to achieve that. Even then, decision makers must clearly understand the reported situation to decide the need and importance of taking further actions.
\r\n\t
\r\n\tThis book will address issues of noise in the city, in the neighborhood or at work, aspects about management and consequences of exposure to high sound pressure levels ranging from the auditory, extra-auditory and psychophysics effects to the addiction to noise and the loss of solidarity.
\r\n\t
\r\n\tThe book aims to provide a various points of view and analysis of cases regarding this omnipresent pollutant.
Skeletal muscle growth and regeneration is dependent on the activation of mitotically quiescent resident cells known as skeletal muscle satellite cells (SC) located beneath the basal lamina (integral part of basement membrane) on the plasma membrane (sarcolemma) of adult skeletal muscle fibers. Activated by muscle injury including work overload (i.e., weight lifting), satellite cells proliferate making myogenic precursor cells (myoblasts) that migrate to the site of injury and after withdrawal from the cell cycle fuse collectively or with damaged fibers. The fusion process is mediated by plasma membrane proteins, some of which are the receptors for intermediate of lipid metabolism such as sphingosine 1-phosphate (sphingolipid, S1P). A great deal of plasma membrane surface and integral proteins at the extracellular site is glycosylated and prenylated, the processes indispensable for intracellular protein transport (from endoplasmic reticulum to Golgi apparatus, and from trans-Golgi network to the plasma membrane) as well as for lateral and vertical protein translocation within sarcolemma. In adult skeletal muscle, the self-renewing capacity of satellite cells contributes to muscle growth, and regeneration-associated hypertrophy as skeletal muscle-specific adaptation to workload. Hypertrophy also occurs in satellite cell-depleted skeletal muscle, although in this case neither increase in myonuclei in satellite cell-depleted fibers nor the muscle regenerates after BaCl2-induced severe muscle damage [1]. Accordingly, the biochemistry and structural modifications of plasma membrane are seemingly indispensable for the commitment of satellite cells and their progeny of myoblasts to skeletal muscle renewal. In this review, we hypothesized that changes in the sarcolemmal composition of proteome, glycoproteome, and/or lipidome are the major determinants of satellite cells and muscle fibers to regenerate skeletal muscle. From the experiments and clinical observations related to statin-induced myopathy [2–4] as well as the successful efforts aiming to correct plasma membrane integrity by the modification of skeletal muscle plasma membrane fluidity, we conclude that closer examination of the plasma membrane composition and structural organization might shed more light on the molecular mechanisms of satellite cell commitment to muscle rejuvenation.
Nowadays, it is obvious that skeletal muscle growth and regeneration is firmly linked to the activity of satellite cells adjacent to extrafusal and intrafusal muscle fibers. Intact skeletal muscle encloses satellite cells in the quiescent state, with a dense nuclear chromatin (heterochromatin), fine rim of the cytoplasm, and little organelles. Covered by a thin layer of basement membrane, the satellite cell rests closely applied to the sarcolemma of the muscle fiber (Figure 1). The notion that satellite cells donate nuclei to a growing or regenerating fiber, one at a time, is widely known from a half of the century [5]. Although quiescent in normal skeletal muscle, satellite cells (named by Mauro, [6]) become activated and recruited to the cell cycle when there is a requirement to increase myonuclear number [7]. In response to signals accompanying skeletal muscle injury, denervation, exercise, or work overload, the activation reverses the morphology of satellite cells to lower chromatin density (euchromatin), expanded cytoplasm, and additional organelles [8–9]. Several lines of evidence suggest numerous molecules including hormones, growth factors, cytokines, and reactive species as potent incentives in the activation of satellite cells, yet it is still not clear how these muscle progenitors become receptive to the stimuli. Rearrangement of plasma membrane lipids, proteins, and their glycosyl and lipid conjugates might be considered as possible beginning of satellite cell commencement to sense some of the signals. Despite great biological and clinical interest, our knowledge of in vivo N-glycosylation sites – a prerequisite for detailed functional understanding – is still very limited [10]. Similarly, the conception of plasma membrane lipidome input to sense and transduce the signals for the activation of satellite cells is limited [11]. Thus, any endeavor intended to decipher the details and mechanisms hidden behind the dynamic changes of plasma membrane organization is an attractive approach with promising perspective for future clinical application in the treatment of skeletal muscle myopathies.
Electron micrograph of a typical myonucleus (A) and a muscle satellite cell (B). Muscle satellite cells (S) were identified by their location inside the basal lamina (arrowheads) and outside the sarcolemma (arrows) and an independent cytoplasm. In contrast, a myonucleus (M) is located inside the sarcolemma of the muscle fiber and does not contain an independent cytoplasm. Bar, 1 mm., reprinted from Sinha-Hikim et al. 2003 [133].
Plasma membrane in skeletal muscle has several exclusive features related to the structure and composition as well as unique characteristics of membranoskeleton. Nonetheless, some properties are fairly common for any membrane as phospholipids spontaneously form lipid bilayers in aqueous environments due to the amphipathic nature of the molecules with a highly hydrophobic “tail” (acyl chains) and hydrophilic “head” (glycosyl or phosphatidyl) moieties. Lipids in membranes are distributed disproportionately accounting for substantial differences in the extracellular vs. intracellular face of plasma membrane (PM). Anyway, a given membrane has a stable and specific membrane composition dependent on cell type and organelle, and any changes are observed only in certain physiological situation or pathological anomaly. The asymmetry of the external leaflet of PM (exoplasmic) is featured by highly enriched in choline-containing lipids such as phosphatidylcholine (PC) and sphingomyelin (SM), whereas the cytoplasmic leaflet (protoplasmic) is rich in phosphatidylethanolamine (PE), phosphatidylserine (PS), and other phospholipids [phosphatidic acid (PA), phosphatidylinositol (PI), phosphatidylinositol-4-monophosphate (PIP), and phosphatidylinositol-4,5-biphosphate (PIP2)]. The latter participates in cell signaling. Despite cross-sectional diversity, membranes posses lateral asymmetry in basal, lateral, and apical regions [12–13]. Lipids are also capable of displaying different phases under different conditions (mesomorphism). Some lipids, however, as cone-shaped lysophosphatidylcholine (LPC) or PE can form nonlamellar finite structures such as spherical micelles or tubular structures in membranes [14]. Nonlamellar prone lipids are involved in membrane fission and fusion processes with the aim of enzymes such as scramblases, flippases, and floppases. Finally, intact PM is extremely elastic as it reseals after mechanical rupture allowing for the separation of cell fragments (i.e., synaptosomes).
As thin (5–10 nm) lipid bilayer in eukaryotes, PM plays several tasks emerging beyond defining simple cellular boundary. It can organize complex tools for transportation (ion channels, transport proteins, pumps, and invaginations for macromolecules) or molecular sensing (receptors, Figure 2). PM is also essential to control intercellular communication (flow of information) through highly dynamic microdomains acting as platforms for molecule interactions. Skeletal muscle cell plasma membrane is specifically adapted to resist consequences of muscle fiber shortening during contraction. Additionally, sarcolemma periodically invaginates, giving rise to the transverse tubule (TT) network liable for sensing depolarization by dihydropyridine receptor (DHP) essential to trigger of calcium flux evoked by activation of ryanodine receptor (RY). Dystrophin–glycoprotein complex (DGC), also known as dystrophin-associated protein complex (DAC), is embedded in sarcolemma (found in other cell types such as astrocytes) and plays paramount role in the aforementioned actions (Figure 3). It is composed of several proteins including, dystrophin (DP), dystrobrevin (DB), syntrophin (SP), dystroglycans (α- and β-DG), and sarcoglycans (α-, β-, δ-, and γ-SG). These proteins are assembled in order to transmit lateral force during isotonic twitch. Subsarcolemmal protein assemblies circumferentially aligned in schedule with the Z-disk or peripheral myofibrils are also known as costameres (assemblies of costameric proteins, Figure 4). They physically couple force-generating sarcomeres with the sarcolemma in striated muscle fibers and are thus considered a pitfall of skeletal muscle, a critical component of striated muscle morphology which, when compromised, is thought to directly contribute to the development of several distinct myopathies also termed sarcolemmopathies (Figure 5). Costameric proteins are found in a cholesterol (CHOL) rich membrane fraction pointing to lipid rafts (LR) as spatial localization of DGC [15]. Actually, LR are clustered at the level of DP complex through laminin-mediated interaction with dystroglycans [16]. Furthermore, CHOL depletion uncouples β-DG from sarcolemmal domains with related impairment of mechanical activity of skeletal muscle [17] (Figure 6), whereas DP repeats which interact with membrane lipids strengthen the sarcolemma providing flexible support to muscle fiber membranes (Figure 7) [18]. Additionally, DGC spatial organization is vital for physical interface between SP and sodium channels or neuronal nitric oxide synthase (nNOS), although not at the same time. DGC is regularly distributed along sarcomeres and aligned mainly with Z-disks to connect actin cytoskeleton with extracellular matrix (ECM) protein laminin (Figure 8). Laminin together with collagen IV, fibronectin, perlecan, entactins, agrin, and glycosaminoglycans is a component of basement membrane. Extrinsic protein β-dystroglycan is the laminin receptor and binds membrane-spanning (integral) α-dystroglycan that mediates interactions with DP and DB [19]. At the focal adhesions facing Z-lines, the integrin receptors (α7β1) connect fibronectin/laminin with actin filaments of sarcomeres (Figure 9). Tallin, vinculin, and paxillin are intermediate filaments forming a lever that hooks up integrins with thin filaments [20, 21]. Caveolin-3 is the muscle-specific form of caveolin found mainly as intrinsic (inner leaflet) membrane protein at the sarcolemma and TT [22]. The functions of caveolin-3, β-DG, DP, and SG are controlled by cholesterol and sphingolipid concentrations in the lipid rafts and caveolae [17–18, 23]. In striated muscle, signal transduction through cellular membranes can be regulated by the interaction of the cytoskeleton with caveolae (C) – caveolin-enriched membrane domains [24]. Mounting evidence demonstrates that lipids themselves regulate the location and activity of many membrane proteins, as well as defining membrane microdomains (lipid rafts, caveolae, and coated pits) that serve as spatiotemporal platforms for interacting signaling proteins [11]. Lipid rafts (single lipid raft is approximately 50 nm in diameter) are defined as detergent insoluble glycolipid (GL)-enriched planar domains (detergent resistant membranes, DRM) highly enriched in cholesterol (CHOL), SM, glycosphingolipids (GSL), and glycosylphosphatidylinositol (GPI)-anchored proteins. To sum up, membrane lipids are classified into three major groups: glycerol-based lipids (glycosyl-glycerides and phospholipids), sphingolipids (SL) with sphingoid-base backbone (SM and GSL), and cholesterol. Similar LR may differ in their size (fusion and fission), as well as in the proportions of lipids and proteins, somewhat modified by pathophysiological processes or nutritional and/or pharmacological interventions. Caveolae are dissimilar to LR as they are deficient in (GPI)-anchored proteins and poor in CHOL but rich in caveolins, the structural proteins assembled to stabilize membrane invaginations [25]. In extreme situations, PM may be subjected to disintegration, protein misfolding, and aggregation, and finally profound dysfunction causes cell death by necrosis. How these nanodomains are segregated within plasma membrane is a matter of debate, although cholesterol molecules establish closeness of PL, GL, GSL, SM, and proteins. Cholesterol (alcohol) acts as “glue” with hydroxyl group that combines with the phosphate head of phospholipids, whereas the hydrophobic steroid section works together with phospholipids acyl chains. Growing body of evidence points to physicochemical forces (intermolecular forces including electrostatic interactions, hydrogen bonds, Van der Waals forces, and hydration forces) which determine asymmetric geometry of membranes both laterally and in cross-section. Moreover, integral proteins also influence lipid structure in the membrane. One might bear in mind that according to lipidomics, more than 1000 different lipid forms are to be found in plasma membrane. To meet the requirements of fluidity, membrane components are also subject to considerable qualitative and quantitative seasonal changes adjusted by the cell [26]. It is determined by the environmental conditions (i.e., cold vs. heat) but also by needs of adaptation such as hyperplasia/hypertrophy or resistance to different types of stress (shear stress, oxidative stress including irradiation). In either case, physicochemical properties of membranes have to facilitate cell signaling and motility. In turn, cell signaling and motility are influenced by the glycosylation status of PM proteins, both integral represented by receptors and peripheral because they are heavily modified on the external leaflet.
Schematic illustration of a biomembrane, depicting membrane lipid asymmetry as well as microdomains enriched in particular lipids and those induced by membrane proteins, reprinted from Escriba et al. [12].
The dystrophin–glycoprotein complex network. Shown in red are the constituents of the core dystrophin–glycoprotein complex, which copurify as a highly stable complex from skeletal muscle and which show greatly decreased abundance in dystrophin-deficient muscle. α-Dystroglycan and β-dystroglycan (α-DG, β-DG); the sarcoglycan complex (SGC); sarcospan (SPN); α-dystrobrevin-2 (α-Db 2); syntrophin (SYN). Also shown are structural proteins that interact directly with components of the dystrophin–glycoprotein complex, their direct binding partners, and their location within striated muscle cells. Cytokeratins 8 and 19 (K8/K19). Proteins highlighted in blue are present at increased levels when dystrophin is absent, reprinted from Ervasti 2007 [23].
Top: Simplified model of two muscle sarcomeres in parallel. The sarcomere is composed of the thin (mostly actin) filaments, the thick (mostly myosin) filaments, and the giant filamentous molecule titin. The thin filaments are anchored in the Z-line, where they are cross-linked by α-actinin. The thick filament is centrally located in the sarcomere and constitute the sarcomeric A-band. The myosin heads, or cross-bridges, on the thick filament interact with actin during activation. Titin spans the half-sarcomeric distance from the Z-line to the M-line, thus forming a third sarcomeric filament. In the I-band region, titin is extensible and functions as a molecular spring that develops passive tension upon stretch. In the A-band, titin is inextensible due to its strong interaction with the thick filament. Bottom: Electron microscopy photograph of the ultrastructural organization of sarcomeres in parallel, reprinted from Ottenheijm et al. 2008 [134].
Dystrophin as a molecular shock absorber. Shown is a hypothetical model for how dystrophin may function to dampen elastic extension during muscle stretch. (I) Relaxed muscle. (II) Muscle stretch imposes forces that uncoil spring-like elements within repeats 1–10 and 18–24. (III) Electrostatic interaction of basic actin-binding repeats 11–17 with acidic actin filaments dampens extension of the spring-like elements. The “nonspecific” electrostatic interaction between the basic spectrin repeats and actin filaments is optimal because it does not require a specific orientation for interaction and would allow sliding between dystrophin and actin. As muscle rapidly shortens during contraction, the electrostatic interaction of the basic actin-binding repeats with acidic actin filaments would also serve to dampen elastic recoil, reprinted from Ervasti 2007 [23].
A model of the effect of membrane cholesterol depletion on the sarcolemmal distribution of β-DG. The sarcolemmal lipid rafts close to the clear opening of the TT-membrane are enriched in cholesterol, GM1 (ganglioside M1), Cav-3 (caveolin-3), and β-DG (dystroglycan). The schematic diagram illustrates the diminished contact between β-DG and Dys (dystrophin) in the presence of MβCD (methyl β-cyclodextrin); the β-DG/Dys interaction is essential for lateral force transmission. SERCA1 (sarcoplasmic reticulum calcium ATPase) and RyR (ryanodine receptor (SR Ca2+ channel)) function normally. SL, sarcolemma; SR, sarcoplasmic reticulum; EM, extracellular matrix; LR, lipid raft; Dys, dystrophin; SG, sarcoglycan; CSQ, calsequestrin, adapted from Vega-Moreno et al. 2012 [17].
Schematic diagram of the sarcomere and costamere protein complexes of striated muscle cells. Major components of the mature sarcomere and costamere are shown, along with the cytoskeletal and motor filament systems, in context with the sarcolemma and organelles of syncytial myocytes. Known chaperone or cochaperone molecules are shown in bold, along with their substrates. Arrows indicate regions where chaperone-mediated protein folding is essential to incorporate polymeric filament proteins, adapted from Sparrow and Schock 2009 [135], reprinted from Myhre and Pilgrim 2012 [136].
This figure shows the structure of the costamere and known molecular interactions. Below the membrane bilayer shown is the intracellular space and above it is the extracellular space. In the intracellular space, the costamere is attached to the contractile proteins through dystrophins (for the dystrophin glycoprotein complex, DGC), vinculin, talin, and paxilin (for the integrin complexes; not shown). In the extracellular space, both DGCs and integrin complexes bind to the components of the basal lamina that is attached to the rest of the extracellular matrix that consists mostly of fibrillar collagens, reprinted from Voermans et al. 2008 [137].
Schematic representation of a costamere and the focal adhesion complex (FAC). Two laminin receptors, a dystrophin/glycoprotein complex and an integrin receptor complex, are among the sarcolemmal structures that link the contractile apparatus of muscle fibers with the surrounding basal lamina. Components of both receptors, i.e., both dystrophin and the integrin-associated cytoskeletal proteins (talin, vinculin, α-actinin), colocalize in subsarcolemmal complexes which connect through γ-actin and the intermediate-filament proteins desmin and vimentin to the Z-disk of skeletal muscle fibers, adapted from Patel and Lieber 1997; Rybakova et al., 2000 [138–139], adapted from Fluck et al. 2002 [20].
Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase reversible inhibitors, became the most frequently prescribed drugs in modern societies used clinically to improve the lipid profile of hyperlipidemic patients, thereby decreasing the incidence of primary or secondary ischemic cardiac events [27–28]. The primary mechanism of action of statins is to lower CHOL levels by the inhibition of mevalonate formation, the rate limiting step in the cholesterol biosynthesis [29]. Pleiotropic effects of statins which seem to be independent of the inhibiting effect on CHOL formation have also been reported [30–31], although statin-induced release of nitric oxide (NO) and prostaglandins (PGI2) does not explain side effects of statins on skeletal muscle cells (NO stimulates myogenesis, while PGI2 inhibits platelet activation). Even if statins are in general well tolerated and are safe for almost all patients, they were reported to induce different grades of myopathy in a significant part of the population, ranging from mild myalgia to morbid rhabdomyolysis [32–33]. There are risk factors for developing statin-induced myopathy (SIM), the significant component of statin intolerance during statin treatment, such as advanced age, excessive exercise, and multisystem disease as renal or hepatic insufficiencies, diabetes, or hypothyroidism [34]. Impaired metabolism of statins, pharmacokinetic interactions, and genetic effects are all probable causes of statin-induced myotoxicity (muscle toxicity), although the molecular mechanism has not yet been elucidated in full. The most frightening clinical adverse effect is drug-induced rhabdomyolysis (0.1–0.5% in patients treated with pravastatin) the frequency of which is further increased by coadministration of fibrates [35]. Reductions in skeletal muscle membrane CHOL were initially thought to account for the range of myopathic reactions. Additionally, the lowering the isoprenoid levels has been suggested to contribute to these pathologies as protein prenylation, and the potential consequences of a generalized insufficiency of this form of protein modification [36] are important for the activity and anchorage of plasma and other membrane proteins (nuclear envelope, dystrophin–glycoprotein complex, cytoskeletal G-proteins, etc.).
There is growing interest to decipher the molecular mechanism of the statin-induced myopathy, both by scientific community and pharmaceutical companies. One in three people over the age of 45 is taking a statin to reduce heart attack risk, the HMG-CoA antagonist with three orders of magnitude greater affinity to bind and subsequently to inhibit HMG-CoA reductase activity than that of natural substrate (HMG-CoA). Two in five women taking the statin are weaker than before, with one in ten reporting they felt “much worse”. As statins became the most frequently prescribed drugs to prevent cardiovascular crisis alongside with the effort to pace physical activity, the issue how to protect from statin-induced myalgia, myositis, and rare cases of rhabdomyolysis is of great concern. In fact, due to muscle toxicity, an estimated 5–10% of patients discontinue statin use due to myopathic symptoms. Reports of myositis and myopathic symptoms increase with increased statin dose [37], with different classes of statins, or when statins are coupled with other drugs [38], and with exercise [33]. The mechanistic underpinning of statin myopathy are believed to be multifactorial and partially attributed to the regulatory effects of statins on apoptosis of muscle cells [39] and proliferation [3]. As skeletal muscle resident satellite cells (RSC) represent physiological reserve of undifferentiated muscle progenitors, it is obvious that activation followed by proliferation and migration are crucial in muscle adaptation to mechanical overload and regeneration from injury [40]. Thus, if statins impair RSC activation these processes could not be initiated. To tackle the problem of reduced CHOL concentration in plasma membrane and associated changes in the function of LR in muscle cells seems to be fundamental. The focal point is LR, where changes (biochemical and morphological) are presumably attributed to the consequences of disturbed cell signaling. As HMG-CoA reductase activity is ubiquitous, while the side effects of statins are confined to skeletal muscle, it is suggested that muscle tissue is featured by unique response to lower CHOL. RSC are targeted by CHOL depletion and the consequences are cumulative as muscle growth is stopped at the initiation phase (signal transduction). This assumption is supported by the data obtained from sarcolemma examination (single molecule microscopy and molecular studies), which demonstrate the isolation and downregulation of LR and the recruitment of mitochondrial oxidative phosphorylation system during myogenesis [41–42]. CHOL and GSL/SL are also present in the membranes of cellular organelles such as ER and Golgi complex (GC). Their role, however, remains obscure as methods to study effects of CHOL depletion in organelles are limited. The main concern should be placed on the sarcolemma and mitochondria, since these organelles control both muscle growth and development [43, 44].
The development of statin-induced rhabdomyolysis is a morbid side effect of HMG-CoA reductase inhibition, occurring in less than 1 in 1000 statin-treated patients [45]. Even though occurrence of myopathy in statin-treated individuals has been estimated to range from 1 to 10%. Studies performed on rats confirmed that atorvastatin treatment reduces exercise capacity manifested by higher fatigability [46]. It is more common in statin users regularly exercised or statin-treated athletes pointing to the high correlation between the muscle contractive activity and muscle-associated complications of statin administration. Among several hypotheses raised to explain the aforementioned causal relationship between statins and physical exercise, growing body of evidence indicate both reactive oxygen species (ROS) and abnormal mitochondrial activity as probable inciting factors implicated in the deleterious effects of statins [47–48]. Actually, the inhibition of HMG-CoA reductase that hampers the mevalonate pathway in addition to impaired cholesterol synthesis also reduces the synthesis of isoprenoids such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), intermediates affecting number of nonsteroid isoprenoids including coenzyme Q10/ubiquinone [49], and finally it adversely affects selenoprotein synthesis as well as the biosynthesis of dolichols, which are involved in the process of protein glycosylation (Figure 10). The latter mechanism is rate limiting by dolichyl phosphate, which acts as a donor of oligosaccharides in glycoprotein synthesis [50]. The importance of glycoproteins in skeletal muscle growth and regeneration is further emphasized by the examination of N-linked glycoproteome of C2C12 mouse myoblasts and myotubes [51]. It is clear from this study that approximately 128 (117 transmembrane, 4 glycosylphospatidylinositol-anchored, 5 ECM, and 2 membrane-associated) proteins were identified, while a few N-linked glycoproteins (including aquaporin-1 and β-sarcoglycan) were apparently of paramount value when myoblasts differentiate to myotubes. There was an evident decrease of aquaporin-1 and cadherin-2, whereas β-sarcoglycan expression level increased as the myoblasts fused and formed multinucleated syncytium. Ubiquinone is an important electron carrier between the complex I and complex III of respiratory chain in mitochondria. Thus, decrease in nonsteroid isoprenoids such as CoQ10 leads to the inhibition of complex I, incomplete reduction of oxygen at the level of cytochrome c oxidase (complex IV), and induces oxidative stress (augmentation of superoxide anion radical, hydrogen peroxide, and finally hydroxyl radical) postulated to cause myotoxicity of statins [48]. Myotoxicity is therefore at least in part the consequence of damage to lipids, proteins, and DNA, although lipids in cellular membranes are most likely targets of ROS (extensive lipid peroxidation). Additionally, limited access of proteins to prenylation impairs important lipid anchorages essential for PM attachment and function of a variety of proteins involved in cell signaling (i.e., heterotrimeric guanine nucleotide-binding protein-coupled receptors – GPCRs, GTP-binding small/G-proteins Rap1, Ras, Rac, and Rho).
The biosynthetic pathway of cholesterol and other cometabolites, reprinted from Vaklavas et al. 2009 [58].
GPCRs, the most abundant PM receptors, regulate wide range of cellular processes through intracellular heterotrimeric G protein (GTP-binding protein). The latter acts as a signal transducer to control the activity of several catalytic proteins central to the message amplification and its intracellular broadening to effector proteins. Heterotrimeric proteins are composed of three subunits (Gαβγ). Agonist-mediated activation of GPCRs brings about conformational changes which lead to the exchange of guanosine diphosphate (GDP) for GTP on the Gα-subunit which then dissociates from Gβγ dimer. Now, Gα may translocate to the target protein(s), whereas Gβγ dimer inactivates the receptor through phosphorylation (it recruits G protein–coupled receptor kinase – GRK to inactivate the receptor). As GPCRs constitute the largest family of membrane receptors, there are at least 16 types of Gα subunits, 5 of Gβ subunits, and 12 types of Gγ subunits [52]. Gα signaling is stopped when GTP is converted to GDP by the intrinsic GTPase activity of the protein itself. In consequence, Gα-GDP is reassembled with Gβγ dimer and G-protein complex is reestablished. Importantly, target proteins for heterotrimeric G-proteins are membrane bound suggesting that lipid–protein and/or lipid–lipid interactions are fundamental for G-protein-mediated signaling. Actually, all known Gγ proteins undergo isoprenylation on cysteine residues (either geranylgeranyl or farnesyl moieties) pointing to increased affinity to hexagonal nonraft phase (e.g., PE) of PM [53–54]. In contrast, Gα subunits are modified by myristoylation (Gαi) and/or reversible palmitoylation (Gα) allowing them to get access to lamellar regions of PM (e.g., lipid rafts). It also explains how Gα subunits migrate to their cognate targets in LR after dissociation form Gβγ assembled to GPCRs. Minetti et al. [55] have showed in elegant study that skeletal muscle hypertrophy and differentiation are greatly influenced by signaling induced by lysophosphatidic acid (LPA) acting on GPCRs which in turn activate a Gαi protein. Besides, Gαi enhanced muscle regeneration and caused switch to oxidative fibers and can act as a counterbalance to MuRF1 and MAFbx/atrogin-1. To sum up, lipid structures play active role in signal propagation with resulting localization of Gα and Gβγ proteins.
Uncommon myopathic changes resultant from statin therapy offer the opportunity to gain new insight for the function of biochemical pathways downstream to HMG-CoA reductase in skeletal muscles. Irrespective of the type of statin treatment (hydrophilic or hydrophobic), the viability of skeletal muscle cells is considerably reduced, though the effect depends largely on the pharmacokinetic and pharmacodynamic properties of statins [56–57], while the signaling pathway(s) and molecular mechanisms are still not fully understood. Sometimes, signal transduction is dependent on small GTPase proteins that cycle between an inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound state. The posttranslational prenylation of these proteins occurs by the covalent addition of only two types of isoprenoids, FPP and GGPP, to cysteine residues at or near the C-terminus. Upon tyrosine kinase receptor activation, the prenylated (PM protoplasmic/inner leaflet attached) small GTPase protein Ras (MAPK kinase kinase kinase) binds GTP and becomes activated to initiate MAPK cascade ending with the stimulation of muscle cell growth (hyperplasia). In addition, small GTPase protein Rab1 (more than 60 Rab small GTPase isoforms have been identified) is involved in organelle biogenesis and intracellular vesicular trafficking [58]. Overall growth and survival signals depend on the activation of both protein receptor and nonreceptor tyrosine kinases.
Several lines of evidence suggest particular significance of IGF-1/PI3-K/AKT cascade in maintaining muscle cell growth and viability [59–61] likely through the suppression of FOXO-dependent activity of atrogin/MAFbx ubiquitin ligase gene required for the development of muscle atrophy [62–63]. Moreover, the statin-induced muscle damage is controlled by PGC-1α, a transcriptional coactivator that induces mitochondrial biogenesis and protects against the development of statin-induced muscle atrophy [64]. In in vivo model, simvastatin downregulated PI3-K/AKT signaling and upregulated FOXO transcription factors and downstream gene targets known to be implicated in muscle cachexia [63]. Insulin and IGF-1 are widely known agonists of their cognate receptors (IR and IGF-1R, respectively), although at concentrations higher than physiological cross-reactivity of insulin to IGF-1R and IGF-1 to IR were observed. On the other hand, LR have been shown to be platforms to initiate cellular signal transduction of IGF-1 and insulin-inducing skeletal muscle differentiation and hypertrophy. Notably, the impaired insulin/IGF-1 signaling [65–67] mimics the side effects of statin administration, whereas insulin and/or IGF-1 were reported to overcome statin-induced myopathy [61]. IR and IGF-1R with their intrinsic tyrosine kinase activities transduce the signal by recruiting insulin receptor substrate-1 (IRS-1) with its src-homology 2 domains (SH2) to the receptor phosphotyrosines. IRS-1 activates PI3-K/AKT/mTOR and Ras/Raf/MEK/ERK pathways, however, phosphoinositide 3-kinase (PI3-K) as a lipid kinase converts plasma membrane phosphatidylinositol-4,5-biphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3). The latter attracts kinases with pleckstrin homology domain (PH) downstream to PI3-K including phosphoinositide-dependent kinase 1 and 2 (PDK1, PDK2) and AKT. Depletion of CHOL and sphingolipids blocks IGF-1-induced AKT membrane recruitment, whereas LR reconstitution in CHOL- and sphingolipid-deficient cells restored AKT membrane recruitment and phosphorylation [68]. Thus, LR-localized PIP3 is essential for AKT membrane association, while AKT seems to promote formation of PIP3-containing rafts.
While human and animal studies have demonstrated that statin treatment may reduce serum CoQ10 levels [2, 69], ubiquinone levels in human skeletal muscle do not appear to be affected by statins [61, 70]. Possible significance of some reactions and intermediates in CHOL synthesis indicate that GGPP and FPP as isoprene units play very important role in muscle cell survival and regeneration. The posttranslational prenylation of proteins such as heterotrimeric G proteins, small G-proteins, and lamins enables these proteins to anchor to cell membranes, whereas N-linked glycosylation of insulin and IGF-1 membrane receptors mediated by dolichols establishes their proper biological functions (sensitivity to ligands). Dolichols serve as carriers and situate the core oligosaccharide to be assembled to protein molecules. From some studies, it appears that it is mevalonate and isoprene units (GGPP and FPP) as their downstream intermediates rather than CHOL play the key role in statin-induced myotoxicity. Consequently, replacement of depleted mevalonate reversed the changes induced by statins, where squalene synthase or squalene epoxidase (steps in CHOL synthesis) inhibitors at concentrations sufficient to inhibit entirely CHOL synthesis did not affect muscle cell viability [71–72]. These observations point to cardinal role played by isoprenoids in physiology of skeletal muscle cells. Interestingly, statins which are sometimes harm to skeletal muscle cells do not act adversely on myocardium, a type of striated musculature. Substantial difference in the sensitivity of skeletal muscle cells and cardiomyocytes to the statin-induced myopathy could be related to dissimilar mechanisms that control viability of these cells [73]. Alternatively, it was postulated that Ca2+ homeostasis alterations could account for statin-induced muscular side effects [74, 75].
Acute application of simvastatin on human skeletal muscle fibers led to a large release of Ca2+ into the sarcoplasm [76]. The authors showed that mitochondrial Ca2+ efflux through both permeability transition pores (PTP) and Na+/Ca2+-exchanger (NCE) was a major initiator of the large sarcoplasmic reticulum (SR) Ca2+ release by affecting ryanodine receptor 1 (RyR1, Figure 11). Furthermore, the effects of simvastatin on Ca2+ homeostasis were not linked to the disturbed cholesterol synthesis pathway as GGPP and FPP treatments did not prevent statin-induced Ca2+ waves. They were caused by simvastatin-dependent fall in mitochondrial membrane depolarization and Ca2+ efflux to the cytoplasm. Next, Ca2+ was recaptured by the SR that in turn triggered the SR release of Ca2+ by at present unknown molecular mechanism as “calcium-induced Ca2+ release” is implausible since the main RyR isoform in mammalian skeletal muscle is poorly sensitive to Ca2+ [77]. It is apparent from this study that mitochondria played critical role, and that Ca2+ efflux from mitochondria resulted from alteration of mitochondrial respiratory chain, as mitochondrial membrane potential (MMP) decreased with concomitant rise in NADH concentration. Nonetheless, with regard to these experiments some criticism has to be reserved, as simvastatin concentrations (50–200 μM) were much above the pharmacological range. Summing up, these observations point to ubiquitin/proteasome (UP) proteolysis and mitochondria as skeletal muscle target of statins, while the exact nature of their detrimental action (direct or indirect) remains to be elucidated. Recently, some interesting data were obtained from transcriptomic analysis of biopsies collected from atorvastatin-treated and exercised vs. nonexercised skeletal muscles of healthy volunteers. The authors complement severalfold rise in UP pathway gene expression in 8-hours eccentrically exercised vastus lateralis muscles baseline compared to the right leg after statin/placebo treatment [78].
A possible direct pathophysiological effect of statins. Although statin myotoxycity may occur through the reduction of cholesterol synthesis, a direct effect of statins has been reported in vitro and in vivo in muscle fibers from both animal and human models. This diagram summarizes some of the most recent data suggesting a pathophysiological mechanism. Statins diffuse into muscle fibers and inhibit complex I of the mitochondrial respiratory chain (RC). This depolarizes the inner membrane (Dc) triggering a calcium release through the permeability transient pore (PTP) and sodium-calcium exchanger (NCE). This results in a first elevation of cytoplasmic calcium that will be partially uptaken by the sarcoendoplasmic reticulum calcium pump (SERCA) to the sarcoplasmic reticulum (SR). When overloaded, SR may spontaneously release calcium through the ryanodine receptor (RyR1) to generate a calcium wave. A direct effect of statins on RyR1 may not be excluded (dotted line). Impaired mitochondrial function and consequently calcium signaling may account for muscle symptoms, reprinted from Sirvent et al. 2008 [48].
Deregulation of calcium ion (Ca2+) homeostasis in mitochondria is indicated as initial step in cascade of events leading to statin myopathy [76, 79]. In several experiments carried out on C2C12 myoblasts and human muscle biopsies, statins impaired mitochondrial respiration and sensitized muscle fibers to calcium signaling. Accordingly, muscle fibers showed reduced level of ATP and higher frequency of Ca2+ waves [46, 79]. Disturbed regulation of Ca2+ homeostasis (elevated cytoplasmic concentrations) is known to trigger activity of calpains [80], whereas raise in ROS is associated with caspase cascade [81–82]. As RSC are enriched in SM, they obviously should have high LR/C representation. Modulation of SL modifications with sphingomyelinase inhibitors would provide closer look on LR/C impact cell viability/morbidity. Next to statins widely used as hypocholesteremic drugs, polyunsaturated fatty acids (PUFA) are frequently recommended to lower blood plasma concentration of low density lipoproteins (LDL) and triglycerides (TG). There is evidence that PUFA (n–3) synergize with statins in their positive effect, furthermore some PUFA (EPA and DHA) prevent statin-induced myopathy [83–84]. It was found that statins evoke endoplasmic reticulum stress (ERS) and ERS inhibitors as well as PUFA attenuate this response most likely through PPARγ-dependent mechanism. Detailed outline of PUFA protective effect has, however, not been explained. Scientific problem is to find out if LR contribute to the activation of RSC. Furthermore, if LR/C are essential to recruit RSC to enter the differentiation program, what would have been if LR are ablated? The study aimed to shed more light on the side effects of statin administration to skeletal muscle is urgently needed. Novelty of research should address etiology to abnormal function of sarcolemma in skeletal muscle cells of statin-treated subjects. We found only one report showing that CHOL depletion impaired muscle function [17]. CHOL is essential in holding together lateral assemblies of lipids in LR nanodomains. The latter are indispensable to cell signaling as they form platforms for signalosomes (proteins assembled in order to provide signal transduction from PM receptors). Their role has been corroborated for PI3-K/AKT and JAK/STAT but not Ras/Raf/MEK/ERK signaling pathway. We assume that former cascades (PI3-K/AKT and/or JAK/STAT) are involved in RSC activation while the latter are important to initiate proliferation. As muscle cell differentiation proceeds, the representation of SL in LR is subjected to additional modifications [85–88]. We guess these changes are related to the activation of sphingomyelinases and other SL converting enzymes. Ceramides and sphingosines were reported to frequently affect cell functions including proliferation, differentiation, and viability [89, 90], and other bioactive lipids are also important players in muscle growth and regeneration. At the same time, involvement of ROS and mitochondria, Ca2+ homeostasis, and proteolytic systems should be examined.
Plasma membrane is not uniform in state of matter, i.e., fluid portion is represented by glycerophospholipids spontaneously mounted into lipid bilayer in disordered manner (Ld – liquid disordered). As mentioned before, in such membrane, numerous nanodomains known as lipid rafts contain sphingolipids and CHOL as well as lipid-modified integral membrane proteins. Nanodomains (Lo – liquid ordered) are buoyant in fluid portion of membrane and have tendency to coalesce into larger platforms to form signalosomes essential for signal transduction [22]. Thus, in muscle cells deprived of mevalonate due to statin administration, one should expect lower level of LR/C and decreased availability of prenylated proteins (farnesylated and geranyl-geranylated). It is important to stress that muscle growth, adaptive hypertrophy, and regeneration are directly attributable to the PM representation of LR determined by CHOL and sphingolipids [87, 91] found in RSC. The mononucleated RSC are located beneath the basal lamina that surrounds multinucleated myofibers [6]. They are activated by signals from injured myofibers and macrophages to enter the cell cycle and produce myogenic precursor cells that then differentiate and fuse into multinucleated myotubes or existing myofibers [92]. The molecular mechanisms responsible for the transduction of such extracellular signals in satellite cells remain poorly defined, and the potential role of lipid-mediated signaling has not been previously considered in this context. There is an assumption that satellite cells are capable to rearrange PM composition in order to respond to extracellular signals and allow cell multiplication and migration which is followed by fusion. Actually, muscle cells were reported to change the lipid representation in PM according to the particular step of differentiation [87, 91, 93]. While phosphatidylserine (PS) is highly expressed during myoblast fusion [88], phosphatidylethanolamine (PE) is involved in cell motility [94]. Both mentioned are the glycerophospholipids of Ld phase located in the protoplasmic leaflet. On the other hand, sphingomyelin (SM) is found exclusively in the Lo phase where it forms LR nanodomains with other SL, GSL, CHOL, and proteins. CHOL is essential to organize LR as it helps both to position SL and GSL and provides the most advantageous energy status between Lo and Ld phase [95]. Nowadays, it is widely accepted that these nanodomains facilitate cytoplasmic signaling by acting to concentrate signaling molecules [96]. Additionally, SL metabolites, such as ceramide, sphingosine, and sphingosine 1-phosphate, are emerging as important regulators of a variety of cellular events, including cell proliferation, differentiation, and apoptosis [97–98]. With respect to SM, another important issue is that it is highly represented in PM of RSC but during satellite cell proliferation and subsequent differentiation it is almost undetectable [85]. One has to bear in mind that RSC as being stem cells undergo either symmetric or asymmetric division and that in the identical culture conditions they adopt characteristics consistent with a return to quiescent-like state [99]. Thus, it is apparent that certain activated satellite cells (ASC) by unknown mechanism are withdrawn from the cell cycle and they escape from the differentiation program. Cell decision whether to differentiate or not to differentiate is determined by the composition of PM and LR representation in particular. Under the appropriate conditions, SC differentiate into muscle cells with phenotype characterized by the accumulation of muscle contractile proteins and increased sensitivity to insulin. In these differentiated cells, insulin accelerates myogenesis [43]. Insulin initially stimulates proliferation, and subsequently, it stops cell divisions and stimulates metabolic pathways to promote protein synthesis. A clear explanation of how these signaling pathways elaborate such radically different physiological responses in this differentiated tissue has remained elusive, although compartmentalization and switching-off signaling molecules has been proposed [43]. Insulin activates their respective tyrosine kinase receptors to phosphorylate key residues on a “docking protein” or the receptor, respectively, which recruits multiple adaptor proteins. Recruited proteins include the GDP exchange factor Son of Sevenless (SOS), which activates the Ras/Raf/MEK/ERK mitogen-activated protein kinase cascade (mitogenicity), or the p85 regulatory subunit of PI3-kinase, which stimulates signaling pathways ultimately leading to AKT/PKB activation. PI3-K is strongly implicated in metabolic, but not mitogenic signaling in muscle cells, as is its downstream effector AKT [44]. In the latter paper, an important role of mitofusin 2 (Mfn2) protein has been shown as a partner and inhibitor of Ras. Thus, it become clear why studying the ability of different approaches to regulate numerous signaling molecules, statins and CHOL chelators, particularly PI3-K and AKT (PI3-K/AKT), are essential due to their relevance to anabolic metabolism in myotubes and LR reliance. Comparative studies concerning Ras/Raf/MEK/ERK and JAK/STAT would be crucial as these pathways are involved in muscle cell proliferation and they compromise muscle differentiation [100]. It is not clear if reactive oxygen species (ROS) are involved as a cause or an effect of disturbance [46, 79, 101]. Lower production of ATP would explain faster muscle fatigue observed during exercise in statin-induced myopathy [102]. Interestingly, appropriate muscle exercise (physical training) might protect skeletal muscles from undesired statin-induced side effects [103]. This is of particular importance as the widespread use of statins and more active lifestyle might foster the incidence of SIM.
Although the molecular mechanisms that regulate the differentiation of satellite cells and myoblasts toward myofibers are not fully understood, cell membrane lipids and proteins that sense and respond to their environment must play an important role. Heat alters PM physical state into more fluidic form, and similar effect may be artificially induced by membrane fluidizers [104]. Interestingly, heat-induced hyperfluidization in animal PM is associated with the activation of the cholesteryl glucoside (CG) synthetase (glucosyltransferase) located in LR, the enzyme that catalyzes the transfer of the glucose moiety from glucose donor sphingolipid glucosylceramide to cholesterol [105]. CG production alters membrane physical properties and forms thermostable solid-ordered domains. Notably, CG and other steryl glucosides act as important lipid mediators in the process of heat shock factor-1 (HSF-1) activation. This transcription factor regulates the expression of heat shock proteins (HSPs), which are critical for the survival of cells [104]. Some authors showed that the alteration of membrane fluidity by heat or membrane fluidizer treatment causes the reorganization of lipid rafts linked to activation of heat shock response mediated by HSF-1 activation and HSP induction [106–108]. It is suggested by Kunimoto et al. [110–111] that PM fluidity leads to CG formation and the latter mediates HSF-1 activation and HSP induction. There is growing body of evidence that strategies aimed at increasing levels of HSPs may be successful in protecting cells in neurodegenerative diseases. At least in the animal model of amyotrophic lateral sclerosis (ALS), increasing HSP levels by treatment with arimoclomol (hydroxylamine derivative) delayed disease progression in mice [112, 113]. Another hydroxylamine derivative, namely, BGP-15 inhibited acetaminophen-induced caspase-independent apoptosis of hepatocytes [106]. The prime HSPs induced by heat stress or membrane fluidizers are HSP70 and HSP90. Importantly, HSP72 preserves muscle function and slows progression of severe muscular dystrophy [114]. Under normal circumstances, chaperone proteins involved in protein quality control can prevent protein aggregation by binding of misfolded proteins as soon as they are produced during translation or later during their organization into supramolecular structures, thereby assisting protein refolding or else in targeting for degradation [115].
Sphingolipids (SL) and cholesterol (CHOL) create LR in plasma membrane, but it is the biochemistry of SL that is apparently decisive for skeletal muscle biology including its growth and differentiation. PM sphingomyelin is a target for both acidic and neutral sphingomyelinases (aSMase and nSMase) bringing ceramide (Cer) as product. Ceramides are LR modulators believed to alter PM fluidity and favor receptor oligomerization [116]. Cer has been suggested to fulfill a second-messenger function but the evidence for this action is scarce and controversial, while support is emerging for its indirect impact on cellular signaling resulting from changes in membrane structure. Cer could be further converted to sphingosine by ceramidase, whereas sphingosine 1-phosphate is synthesized from sphingosine by a phosphorylation reaction catalyzed by the sphingosine kinases (SKs) SK1 and SK2, which are highly conserved enzymes activated by numerous stimuli including transactivation induced by IGF-1 [117]. From studies carried out on C2C12 myoblast cell line as progeny of mouse satellite cells, it is clear that IGF-1 evokes two mutually exclusive biological responses (hyperplasia vs. hypertrophy). This cytokine plays a key role in skeletal muscle regeneration as it is able to recruit satellite cells and stimulate myoblast proliferation and myogenic differentiation. As mentioned before, myoblasts must not fuse unless they are withdrawn from the cell cycle. How then, IGF-1 regulates two opposite responses? In recent years, the sphingosine 1-phosphate (S1P) attracts special attention with regard to physiology of resident skeletal muscle satellite cells as well as proliferating and differentiating myoblasts. First, several lines of evidence indicate significant role of S1P in skeletal muscle regeneration and repair [85, 117–122]. The extracellular action of S1P present in micromolar concentrations in peripheral blood is exerted by binding to five specific cell surface heterotrimeric G protein–coupled S1P receptors (S1P1–S1P5). In turn, S1P agonist levels are tightly controlled by the balance between biosynthesis catalyzed by SKs, reversible conversion to sphingosine mediated by specific and nonspecific lipid phosphatases, and S1P lyase (SPL)-dependent degradation. Second, S1P receptors are coupled to one or more G-proteins so they can elicit distinct and even contrasting final cellular effects (Figure 12). In skeletal muscle cells, major role is played by S1P1, S1P2, and S1P3 receptors [117, 119–122]. Actually, in myoblasts, S1P1 and S1P3 receptors via SK activation negatively regulate the mitogenic effect elicited by IGF-1, whereas S1P2 receptor is involved in myogenic effect of the growth factor (Figure 13). Thus, in myoblasts, SK/S1P axis upon IGF-1 action regulates two opposing biological effects – transducing its myogenic response on one side and inhibiting its mitogenic effect on the other. The IGF-1-dependent transactivation of S1P receptors was also observed in other cell types pointing to the conservation of the IGF-1/SK/S1P circuit in tissues other than skeletal muscle [123]. How IGF-1 does affect SKs leading to two divergent biological effects in skeletal muscle? Among the various signaling pathways activated by S1P in skeletal muscle cells, the activation of ERK1/2 and p38 MAPK, both identified as downstream effectors of S1P2 in response to growth factors, was required for cell proliferation and the stimulation of myogenic differentiation, respectively [124]. The inhibition of ERK1/2 activity with specific U0126 metabolic inhibitor prevented SK1 phosphorylation induced by IGF-1, demonstrating that the activation of SK1 induced by the growth factor was mediated by ERK1/2 [116]. Similarly, the S1P-induced differentiation was prevented in myoblasts where p38 MAPK was inactivated by the overexpression of the dominant negative mutant or by the use of specific p38 MAPK inhibitors SB203580 and SB239063 [118].
Role of sphingosine 1-phosphate on cell proliferation and migration in myoblasts and activated satellite cells, adapted from Donati et al. 2013 [125].
Schematic diagram of the biological actions evoked by S1PR transactivation by some growth factors in C2C12 myoblasts, adapted from Donati et al. 2013 [125].
One has to keep in mind, however, that S1P receptors are differently expressed in satellite cells, myoblasts, and muscle fibers, moreover their expression may vary in response to the action of particular factor. PDGF stimulates myoblasts proliferation and motility, while these effects are blocked by SK1/S1P1 signaling axis [126]. In contrast, TGF-β1 was demonstrated to convey its detrimental profibrotic effect through S1P3 receptors (Figure 13) [127]. These observations complement widely known activities of PDGF and TGF-β1 in wound healing. In the second intention healing as it is observed in the severe skeletal muscle injury or late stages of myopathy, the major role is played by myofibroblasts which cause fibrosis, a hallmark of in which myofibers are replaced by progressive deposition of extracellular matrix proteins [128]. The main task is therefore to facilitate skeletal muscle regeneration rather than repair, as the first one restores tissue structure and contractile function while the latter is limited to structural return. There are efforts observed to improve muscle healing by regeneration rather than fibrosis [129]. Collectively, taking into account the knowledge on how sphingosine 1-phosphate influences RSC and how it might prevent muscle fibrosis, it will be interesting to further investigate in this context the crosstalk between IGF-1 and S1P signaling pathway.
Primary stem cells in adult skeletal muscle known as satellite cells drive postnatal muscle growth and regeneration-associated hypertrophy. They reside beneath the basal lamina of the myofibers suggesting close contact between the adjacent cytoskeletons and chemical communication between the cells. One of the major unexplored areas of satellite cell biology is the identification of signals that are conferred from adjacent myofibers and the surrounding extracellular matrix. Equally important are soluble endocrine, paracrine, and autocrine factors that maintain satellite cells quiescent and control their preference to activate. For example, the maintenance of skeletal muscle requires notch signaling and greatly depends on delta upregulation for RSC activation [130]. In addition to the loss of notch activation, nonregenerating skeletal muscle produces excessive transforming growth factor (TGF)-β (but not myostatin), which induces unusually high levels of TGF-β pSmad3 and interferes with their regenerative capacity [131]. Thus a balance between endogenous pSmad3 and active notch controls the regenerative competence of muscle stem cells, and the deregulation of this balance in the old muscle microniche interferes with regeneration. The molecular mechanisms that regulate satellite cell quiescence, activation, and self renewal (asymmetric divisions) are not well understood, even though a possible clue for the ambiguous behavior of satellite cells could be associated with the membrane segregation of rafts and bioactive lipids such as PS that seems to accelerate myoblasts fusion into myotubes [132]. It seems plausible to affirm sarcolemmal differentiation as the leader constituent of stimulated skeletal muscle progenitors and subsequent populations of daughter cells (myoblasts, myotubes, and juvenile myofibers) involved in myogenic program. Lipid moiety of plasma membrane is not merely a boundary or the component in intercellular communication. Nowadays, it is widely accepted that specific lipids associate to form functional units (LR/C), creating substructures that actively modify its own composition including proteins and triggering a myriad of different signaling pathways. Lipid segregation seems to account for the adaptability of skeletal muscle to a variety of stimuli, where the critical role is played by the myogenic signals represented by growth factors and cytokines. Cholesterol, isoprenoids, dolichols, and sphingolipids all contribute significantly to the physiological responses of skeletal muscle to injury. These bioactive lipids mediate most, if not all, of the signals elicited at the plasma membrane receptors. Recent advances in muscle research suggest key position occupied by sphingosine 1-phosphate, protein prenylation, and “caveolar” and “noncaveolar rafts” in skeletal muscle regeneration process.
Support for this work was provided by grant No UMO-2013/11/B/NZ5/03106 from the National Science Centre in Poland.
Household waste is something that is common among most, if not all, living residences. Like any industrial facilities that handle potentially hazardous materials, households too dispose and use hazardous substances. The chemical complexion in the waste substances makes it so if disposed improperly, it could ignite, explode, poison, or corrode. Household hazardous waste (HHW) becomes what it is once thrown away. Methods of the waste being improperly disposed is pouring the substance down the drain, into storm sewers, on the ground, and throwing it in among the trash. It may not be obvious that these substances, once disposed, will be a danger, but particular varieties of HHWs have the prospective to:
cause somatic injury to sanitation workers;
if poured down drains or toilets, adulterate septic tanks or wastewater treatment systems;
pollute—if poured down storm sewers—bodies of water;
become a danger to young or unknowing children and pets if left open in the house;
contaminate ground and/or surface water that is used as a way of obtaining drinking water, if directed to exposed landfills.
A big problem that occurs/can occur through improper disposal of HHW would be the deconstruction that the sewage treatment plants are able to obtain. These plants are not able to deconstruct HHW compounds that people would drain or flush, which will end up traveling into lakes and rivers, unprocessed. As a result, one of the main releasers of dioxins and furans was from sewage systems. The substances proved to threaten human health due to the fact that they were highly carcinogenic. Other than the fact of the carcinogenic dangers, interference with the treatments plants could transpire. The toxins that would be processed could poison the microorganisms in the biological process. That would bring us to the position where our water systems would be more susceptible to harmful contaminants.
\nAs a given, hazardous waste is poisonous to all life forms, exposure of such hazardous substances to any living organism (plants and animals) could devitalize it. As a consequence, to the environment, hazardous waste could diminish natural resources and be contaminating to humans. Giving the young/fetuses, whether human or animal, exposure to these hazards would be substantially dangerous, as they are in a process or rapid growth. Introduction to chemicals for the living body would also interfere with biological structure, causing malfunction of organs and limbs.
\nIn addition to the effects to the human and animal bodies, hazardous waste would hinder plant growth. The impeding of plants that are of much use to the human race through manufacturing and consumption would affect our habitat. If the plants were slowly changing, for the worse, it would affect the animals that are needed for food, farm work, and would cause a whole new era of extinction.
\nIf our plant growth can affect our way of living easily, dumping the HHW into landfills gives us a much bigger problem. Landfills that are improperly maintained are major problem; even if they seem to be isolated from any contact, they can contaminate the environment around them. These landfills produce foul-smelling and toxin gases. Along with the gases and toxins, landfills generate leachate, which can travel to our water sources of lakes, rivers, and oceans. This would dig us into a deeper problem of both environmental and human existences. Thereby, leaving HHW unattended and improperly disposed could potentially destroy the ecosystem.
\nSeparate management of HHW from nonhazardous waste is rare. It is estimated that in countries within the Organization for Economic Cooperation and Development (OECD), household waste contributes to 67% of 540 million tons of municipal solid waste (MSW). The estimated amount of HHW varies considerably due to an unclear definition of what constitutes to household waste as opposed to MSW. In the USA, for the Environmental Protection Agency (USEPA), household products that contain corrosive, toxic, ignitable, or reactive ingredients are considered to be HHW. In general, the HHW is a solid, semisolid, or nonaqueous liquid that can cause or significantly contribute to potential hazard to human health or environment when it is improperly treated, stored, transported, disposed of, or otherwise managed. The portion of HHW in MSW has been estimated to be from less than 0.01–3.4% in several studies. The large variability is due to lack of standard definition as to what constitutes HHW, variability in generation, variability in weighing methods, and limited sample size. Nevertheless, 1% by weight is widely accepted as the fraction of HHW in MSW. Because of this small percentage of HHW produced, households are not practically considered to be hazardous waste producers [1]. While HHW represents a relatively small proportion of current urban solid residues, it is the most toxic part of the waste stream.
\nHHWs in the household waste are often excluded from management as hazardous waste unless collected separately. However, if these waste materials were generated industrially or commercially, they would be subject to strict disposal guidelines. As a result, HHWs are handled the same way as nonhazardous material with no specific regulation or monitoring. Of recent, this mismanagement constitutes a greater problem as the waste stream not only increases in amount but also becomes more diverse with the introduction of more products into the consumer market.
\nAt the source or point of generation, HHW can be placed in the garbage, down the drain, dumped on the ground, or diverted for reuse, energy recovery, or recycle. No matter where HHW is disposed, due to its toxicity as well as municipal treatment facilities that are not equipped to deal with hazardous material, improper management can adversely impact the quality of the environment:
Contaminate ground water bodies.
Contaminate surface water bodies.
Pollute air.
Affect the human health (children and pets if left around the house, cause physical injury to sanitation workers).
On the other hand, in many third world countries, solid waste management facilities are underdeveloped and sometimes nonexistent. The United Nations reported that between 20 and 80% of all household waste that is generated is often dumped in open spaces, water bodies, drains, and burnt or buried. This creates unsanitary environments leading to health hazards. The portion of HHW in household waste generated by developing countries is much less than in developed countries. The small amount of HHW produced as well as unavailability of funds to direct toward implementing sound practices for waste management has led the United Nations Environment Program to suggest HHW with MSW for disposal in landfills [2]. Regardless of the development level of the country, proper management of HHW can be achieved by understanding the environmental and societal impact of poor practices, HHW contaminants, government legislations, and well-developed schemes.
\nUnavailable facilities for proper HHW management discourage even their voluntary participation. While the products in the HHW list vary from country to country, below are categories that represent majority if not all products that can be classified as HHW:
Photochemicals
Pesticides
Mercury-containing wastes
CFC-containing equipment
Nonedible oil and fat
Paints, inks, resins, and adhesives
Detergents
Pharmaceuticals
Batteries
Waste electrical and electronic equipment
Wood preservatives
Aerosols
Personal care products
The risks that a hazardous product poses to the environment depend on certain characteristics of the toxic compounds:
Solubility
Mobility
Persistence
Degradability
Toxicity to nonhuman target species
Potential for penetrating landfill liners
Potential to be broken down in wastewater treatment system
HHW is likely to be disposed of improperly because residents do not always understand the level, effect, and potential impact of toxicity in the products that they use. In Figure 1, the disposal trend of households in the UK is presented after a survey with 400 respondents was carried out. One can observe that the predominant method for disposing HHW in households is into the garbage in spite of the toxicity level. A large portion of photochemicals and pharmaceuticals are discarded down the drain with little regard for the compounds that they contain and the consequences for this mode of disposal [4].
\nUsual HHW disposal regime of UK households [3].
Since information about the impact of HHW on the environment is not exhaustive and data relating to disposal are not well known, the potential impact of each of these products in the environment and health is considered as well as the amount that is approximately generated by households where available.
\nOn the other hand, Figure 2 shows a similar study conducted by Statistics Canada in 2009 with over 3800 respondents. While the garbage is still a significant disposal route for HHW, more households reported utilizing drop-off centers and returning products to suppliers and retailers [5].
\nUsual disposal routes in Canadian households (source: Statistics Canada).
These are liquid chemicals used in home developing and printing. Many of the ingredients in these products are toxic solvents and are predominantly disposed of in sewers. The unused portions of these chemicals are hazardous, but also the packaging can be problematic as it can contain some of the chemicals, which end up in the landfill and thus contaminate both soil and groundwater because these chemicals can penetrate the liners transporting to the groundwater and might end up to the surface water through the movement of groundwater. While the amount entering the sewers cannot be estimated, the packaging in the UK is estimated to be about 270 tons/year, most of which will end up in the landfills [6].
\nRapid growth in pesticide use has been observed, and this suggests a proportional increase in the amount that is being disposed of. According to the UK Pesticide Safety Directorate, many of the active compounds have been observed in landfill leachate of which research shows that they pose carcinogenic and endocrine disruptive risks [6]. On the other hand, incineration of pesticides is acceptable, provided that they do not contain mercury or arsenic. In Belgium, around 80% of waste pesticides are collected and incinerated [7].
\nHousehold products that contain mercury include fluorescent bulbs, stockpiled paint, dental amalgam, thermometers, and barometers. Of these, fluorescent bulbs contribute the highest amount of mercury waste. However, as the use of these is reported to have better energy and environmental impacts than regular light bulbs, they are so encouraged [8]. Improper disposal of fluorescent bulbs is where the risks lie. In the UK, it is estimated that 80 million are disposed of each year, of which only a small portion are recycled or processed for mercury extraction. In Brazil, lamps containing mercury contribute 1000 kg of mercury disposed of per year. Mercury exposure poses some health risks such as genetic damage and neurotoxicity damaging the kidney, liver, and central nervous system [6].
\nRefrigeration and air-conditioning appliances/equipment may contain chlorofluorocarbon (CFC) and hydrochlorofluorocarbon (HCFC) refrigerant. CFCs and HCFCs are ozone-depleting substances (ODS). If they released to the environment, they will destroy the protective ozone layer above the earth and potent greenhouse gases, contributing to global climate change. Examples of these types of equipment include motor vehicle and motor vehicle-like air conditioners, central and room air-conditioning units, refrigerators, freezers, chillers, drinking water coolers, dehumidifiers, research equipment, vending machines, etc. Manufacturing of such freezers and refrigerators has been phased out with the CFC component being replaced. However, disposal of these is still ongoing because of their 8- to 12-year life span leaving 4500 tons of CFC in the UK to be safely disposed of. Disposal of equipment that contains ODS is regulated in the EU by the WEEE directive where separate collection is mandatory [6].
\nNonedible oil and fat constitutes to about 15% of HHW in the UK. The waste section comprises mineral oils that often contain additives, which make it hazardous. While they are sometimes collected and rerefined or burned for energy, a significant portion is disposed of by end users down the drain or via oil filters and end up in the landfills. There, the oils can disrupt artificial landfill liners. Preferably, the steel component oil filters can be recycled after the oil is pressed for recovery and processed into fuel by companies [7]. Other examples are maintenance lubricants and greases for vehicles, which contain solvents and hydrocarbons that can be just as harmful.
\nDisposal of paints is the most significant in this category with the solvent-based paints posing the higher risk. In the UK, paints contribute to 17% of the total HHW with large quantities ending up in the sewers or mixed with MSW. However, schemes developed by local charities exist to collect unwanted paint and redistribute them at no charge. This scheme is limited by the quality of paint that can be used and quantity that can be accepted in any given location. Collected paint needs to meet certain criteria to be acceptable for redistribution such as age or packaging. Barely, 1% of the available excess paint is collected due to a small number of collection points [6, 7].
\nThe use of detergents in household is widespread. It has been reported that 5–20% of the phosphate that is found in surface and ground water in northern Europe originates from detergent use. However, not all detergents are classified as hazardous, but those containing acids, bases, and chlorinated solvents are of particular concern [7]. In addition, the biodegradability, the aquatic toxicity, endocrine disruptiveness of the surfactants, and other ingredients in the detergent contribute to its classification as hazardous. When combined, some compounds in detergents can release fumes that affect the eyes and mucous membranes, leading to respiratory failure and death after prolonged exposure [6].
\nIn the US, all over-the-counter (OTC) medicines are regarded as hazardous. However, in the EU, only those that are cytotoxic are classified as hazardous. Consumer disposal is not particularly regulated, as it would be problematic, but also due to the relatively low toxicity. As a result of the inability for wastewater treatment plants to remove pharmaceuticals from the waste stream, in many countries, they are now regarded as water contaminants. This is because they eventually make their way into drinking water supplies. They are transferred to sewage sludge during treatment, which is then applied to agricultural land or sent to a landfill [6].
\nPrimary, lead-acid, and nickel-cadmium batteries are those that fall into this category in HHW making up 6–14% of the HHW in the UK. Mercury in consumer batteries has been banned in Europe and many states in the US. However, many unregulated countries still use batteries containing significant concentrations or mercury, which often ends up in landfills. When buried in landfills, the casing of dry cell batteries can degrade and release heavy metals [9]. Most rechargeable batteries are used in consumer devices and nickel cadmium batteries. In the EU, these types of batteries must be easily removed from electronic devices, and separate collection for recycling is encouraged. However, these end up in MSW where recycling facilities are not well established because it is not mandatory. Cadmium is known to cause health effects like kidney damage. Lead-acid batteries comprise those found in vehicles, or smaller batteries in fire and security alarms. The recycling program for lead-acid batteries in the UK is well established, and 85% collection of the automotive variety has been recorded. However, the batteries from the alarms and from some battery changes carried out at home still end up in MSW. Lead acts as a chronic and acute neurotoxin affecting the kidney [6].
\nFor many years, home electric and electronic equipment has been disposed of in landfills along with their hazardous components. The amount that is being disposed continues to grow as consumer interest in current devices keeps increasing, which leads to discarding of obsolete electronics. WEEEs often have toxic compounds such that special handling is a requirement [8]. Many countries have prohibited the disposal of WEEE in landfills because of the toxicity and the strain of such large quantities of waste on the landfills. In the EU, this group of equipment is regulated under the WEEE directive such that they are collected and treated as hazardous waste. The directive also lists the substances that should be removed and collected from WEEE. Restrictions have also been placed on the use of certain materials in the manufacture of newer equipment [6].
\nThere are three types of treatments that are used to preserve wood, all of which can cause the treated wood to be hazardous, as they have hazardous properties. The types are tar oils, organic solvent-based, and water-based formulations. Creosote, an aquatic contaminant, is often used in tar oils. It is known to be a skin irritant, which causes photosensitivity and skin tumors following long exposure. Tributyltin is an example of organic solvent-based compound that is strictly regulated. A hazardous water-based substance is copper-chrome arsenate (CCA), which contains concentrations of heavy metals that have large health and environmental risks [6]. Arsenate is a priority carcinogenic contaminant of waste, which easily leaches in a landfill and can volatilize during incineration. Landfilling is not acceptable for disposal, and specialized air pollution control equipment is required for incineration [7].
\nAerosols are a large portion of HHW making up 26% of the HHW in the UK. In the past, CFC was widely used in the production of aerosols. However, CFC has been replaced with alternative propellants and solvents, which contribute significantly to the content in HHW. These replacements are often flammable and explosive. Exposure to aerosols can lead to nausea, skin, and throat irritation [6].
\nThe harmful nature of PCP has been supported by the discovery of certain long-term effects on health and the environment. While most PCP will end up in the sewers, unused products are stockpiled and end up in MSW.
\nIt is important to understand the fate of compounds in HHW when mixed with MSW for disposal. This has led to stricter disposal regulations in many developed countries to improve HHW management [6].
\nImproper disposal of HHW eventually leads to the presence of hazardous contaminants in the environment. All the facilities that are used to manage discarded HHW are in direct contact with environment media, air surface water, groundwater, and soil (Figure 3). These media are in constant contact with each other. As a result, when facilities cannot adequately break down hazardous compounds in HHW, the immediate environment is at risk.
\nThe contaminants enter the water cycle via groundwater or lakes, rivers, and streams traveling through the cycle [10] via different paths:
Precipitation from the atmosphere
Percolation through the soil
Direct disposal from a wastewater treatment plant (WWTP) into a surface water body
Residents pouring liquids down the stormwater drain that empties into a lake
In addition, toxic gases from HHW can be emitted into the air from the hazardous compounds that are used in producing them during controlled incineration or sometimes, uncontrolled fires [8].
\nLandfills can be the most economic way for waste management, especially in countries like Canada with large open spaces. However, poorly managed landfills have the potential of causing a number of environmental issues such as contamination of groundwater or aquifers or soil contamination. Modern landfills are not just holes in the ground to be packed with garbage. They can be considered as highly engineered contaminated systems. A modern landfill uses a number of technologies to ensure that the wastes are properly managed to avoid environmental pollution (e.g., ground water contamination, gas emission). Figure 4 shows schematic of a modern landfill process. Advanced protective liners (both natural and manufactured) are typically used to isolate the waste and leachate from leaking into the surrounding ground or ground water. Single, composite, or double liners can be used depending on the nature of the waste materials being deposited (see Figure 5). At minimum, a composite liner should be used for hazardous waste landfill facilities. However, landfills are not usually engineered to handle toxic compounds from HHW [9]. Hazardous liquid waste can be transported from a landfill into the environment if there are no barriers. Leachate that has been contaminated with hazardous material (soluble or insoluble) may destroy synthetic liners and render existing barriers ineffective, and thus, the hazardous waste comes in contact with the soil. Its fate is determined by the characteristics of the soil such as porosity, geological factors, and the contaminant like viscosity. The contaminant may percolate downward and affect the groundwater or spread and contaminate surrounding area [10]. Even if the leachate is collected, the treatment plants are not usually equipped to remove hazardous contaminants and end up releasing them into water bodies [11].
\nImproper disposal path of HHW from household to environment.
Schematic of modern landfill process (source: www.oocities.org).
In addition, the conditions of the landfill such as the air and moisture content can affect the fate of hazardous contaminants such as the rate of degradation or violent reactions [10]. For example, phthalic acid esters (PAEs) are used as plasticizers that are used in furniture, clothes, food packaging, etc., which are items that will invariably end up in the landfill. While readily degradable under aerobic conditions, those that are found in the landfill environment tend to retard biodegradability of PAEs. When the environmental impact of PAE in a landfill in China was studied, it was discovered the more complex congeners were found absorbed in deeper soils and in the groundwater [12].
\nCertain volatile organic compounds can be partially degraded and are readily absorbed by MSW in a landfill rather than volatilize. The moisture in the leachate enhances this process. Leachate-containing toxic compounds can be detoxified faster by recirculation within the landfill, which reduces the potential for leakage from the landfill liner. HHWs contribute volatile organic compounds (VOCs) to landfill gases such as benzene, methylene chloride, trichloroethylene, vinyl chloride, etc. VOCs from landfill gases contaminate off-site groundwater through migration [11].
\nThe quality of air emissions and ash residue is as a result of the fuel being incinerated. Incinerators usually have pollution control devices; however, some of the components that are found in HHW can pose a challenge to be captured. For example, mercury found in dry cell batteries, fluorescent light bulbs, and old paint can be converted to gaseous form and be emitted from the stack. Even the use of air treatment technologies can only remove 75–85%. Once it becomes in the atmosphere, mercury can be solubilized by rain and end up in water bodies. Other contaminants such as hydrogen sulfide and carbon monoxide that enter the atmosphere as gases may react with other compounds to become even more hazardous or remain in the atmosphere if stable, causing damage. Also, toxic metals have been found in the fly ash residue of incinerated MSW containing HHW. Damaging explosions have been reported due to a flammable liquid container being heated, which can lead to a few hours to few years of lost work time [11].
\nHazardous material dumped down the drain will end up in the on-site septic system or wastewater treatment plant depending on which system is employed. HHW can enter into wastewater treatment systems through its intended use or as a disposal method. Local governments usually prohibit disposal of HHW into stormwater drains. Recommended disposal may depend on the product and the industry. Some may be dumped down the drain with lots of running water, while others should be kept for collection [11].
\nConventional wastewater treatment plants combined physical, chemical, and biological treatment methods depending on the nature of the pollutants and desired level of removal. Modern wastewater treatment process consists of four levels, including preliminary, primary, secondary, tertiary, or advanced treatment, in addition to the solid waste management. Preliminary and primary treatments are mainly physical/mechanical (screening and gravity settling), while secondary and tertiary treatments use combination of biological, physical, and chemical treatment process (Figure 6). Preliminary treatment removes larger inorganic materials and floating particles, primary treatment removes a major portion (50–60%) of suspended solids from raw wastewater, and secondary treatment process removes organic matters and suspended solids. Secondary treatment usually consists of biological treatment of wastewater. Most of the WWTPs use aerobic activated sludge process for secondary treatment. The objectives of secondary treatment are to reduce BOD and SS of the effluent to an acceptable level according to the discharge regulation. In some cases, nutrient removal may be also an objective of secondary treatment. Biological treatment processes rely upon the ability of the organisms to utilize the contaminants as substrates and results in the generation of new biomass and biodegradation by-products.
\n(A) Single liner, (B) composite liner, and (C) double liner system.
Typical municipal wastewater treatment process.
Lye and bleach found in cleaning products and other hazardous components can hinder the bacteria that are utilized in the biological treatment processes and will significantly affect the process efficiency. This will cause wastewater to pass through the system without treatment and ultimately will reach the groundwater and/or surface water [10]. This can contaminate aquatic life; nitrates, and phosphates can cause eutrophication (algal bloom), leading to the use of more herbicides for control.
\nExcess loading of nutrients like nitrates and phosphates results in the uncontrolled growth of phytoplanktons and macrophytes. The growth and subsequent death of these organisms form a greenish slime layer at the surface of water bodies. This slime layer reduces the amount of sunlight that can penetrate through and the oxygen that can be replenished into the water. In addition, the excessive growth causes high competition for resources among aquatic organisms and death such that the biodiversity in the water body may be severely affected over time. This is the water pollution phenomenon known as eutrophication. Aside from the negative effects on water esthetics, eutrophication can hamper recreation activities, navigation, and aquatic life [13].
\nOn the other hand, heavy metals are toxic, persistent, and mobile and tend to accumulate. They generally have very low acceptable concentrations in drinking water standard. In WWTP, low-concentration volatile solvents can evaporate from the aeration tank and become air pollutants. However, high concentrations, acids, bases, poisons, and solvents can affect the WWTP workers’ safety and effluent quality and contaminate the sludge. Even if the wastewater flow does not contain HHW, leachate from landfills and combined sewer flow can introduce contaminants from pesticides and motor oil, which originate in the households of which even a small amount of pesticide concentration can cause a WWTP to fail toxicity test [11].
\nMajority of the e-waste collected in the US and other developed countries end up in developing countries in Asia and Africa, which often have less than adequate concern for the environmental impacts of the primitive recycling activities that are conducted. Illegal e-waste recycling activities in Guiyu, China, have led to the release of hazardous chemicals into the environment. Harmful concentrations of heavy metals and compounds such as polybrominated diphenyl ethers (PBDEs) were reported in local children and workers of the recycling facilities likely due to open dumping activities that contaminated the soil and river sediments. Polychlorinated biphenyls (PCBs) released during manual dismantling of electronics and from open combustion of the waste material resulted in the presence of significant concentrations in the local residents as a result of bioaccumulation in fish and inhalation [14, 15].
\nProper disposal of HHW starts with differentiating between hazardous household products and nonhazardous waste products. Mixing of household waste at the source must be addressed and banned. By collecting similar HHWs together, they can be more efficiently managed with regard to environmental safety, human health, and costs. When separated, arsenic-treated wood can be incinerated using proper pollution control technologies reducing any form of carcinogenic environmental impact, which may otherwise be present if it had been landfilled. Even more popular in developed countries is the separation and collection of cleaning products and pesticides. Majority of which can be incinerated according to best practices unless they contain mercury [7].
\nSome HHW products can be of value as they can be recycled for a different purpose or may contain material, which can be extracted for use in manufacturing other products, as in the case of antifreeze, which can be repurposed as an engine coolant. Another example is waste motor oil, which can be refined as lubricating oil or processed as low-grade fuel oil. Lead-acid batteries contain lead, which can be extracted to produce new batteries. Dry cell batteries, on the other hand, contain many different heavy metals, which may pose a problem for extraction. By collecting a significant amount separately, they can be disposed of more cautiously as hazardous waste [10]. Many EU states collect and recycle fluorescent tubes; however, in Germany, all the components of fluorescent tubes aside from the fluorescent powder have been reported to be reused [7].
\nRather than discard surplus products in the garbage or down the drain, items such as paint and wood preservatives can be given out to those who require them when in good condition. Charities that facilitate these have been established in certain countries.
\nFor any management system to be successful, efforts from the municipalities, manufacturers, and residents must be combined. Legislation that assigns responsibility for hazardous components and clarifies handling requirements of household hazardous products encourages manufacturers to consider sustainable methods of recycling waste from their products. Collection programs and proper management schemes fostered by municipalities and industries working together can reduce the amount of HHW that is discarded dangerously. At the core of these programs is the voluntary source separation by residents within their households. The participation of municipalities, manufacturers, and retailers is also required for these programs to be successful at HHW management (Figure 7) [1].
\nCollaboration between municipalities, producers, and consumers for proper HHW disposal.
The member states of the European Union (EU) are subject to the Waste Framework Directive (WFD) or the Directive 2008/98/EC of the European Parliament concerning general requirements for waste management. Established in 1975, this directive has been substantially amended with the latest revision provided in 2008. HHW is covered in article 20 of this directive, and as with previous directives, it is excluded from the definition of hazardous waste, while it is mixed with other types of household waste. The exclusion also applies when HHW has been separated from mixed household waste and remains until it has been collected properly. Under this legislation, there is no guidance to the management of HHW or legal obligation to the house owners [1, 16].
\nDirectives exist for specific categories of hazardous waste. These documents provide some direction for member states on collection and disposal of the waste and encourage the education of householders on the importance of separating HHW from mixed municipal waste and of the collection and recycling programs that are available to them. The categories include waste from electrical and electronic equipment (WEEE), batteries and accumulators, and waste oils.
\nWaste oils are covered under the WFD directly in article 21. About 3 million tons of waste oil need to be managed annually in the EU that can severely damage soil and water. The directive prohibits any type of disposal that may adversely affect the environment and human health, discourages mixing of different types of waste oils, and encourages separate collection. The directives for ‘batteries and accumulators’ and WEEE call for accessible and free collection points and requires producers and distributors to take back waste batteries, accumulators and electrical and electronic equipment (EEE). However, while the disposal of industrial and automotive batteries and accumulators in landfills and incinerators are prohibited, no such legislation is put forth for household batteries. On the other hand, disposal of WEEE is prohibited until proper treatment has been carried out [17].
\nHHW in the US is regulated under Subtitle D of the Resource Conservation and Recovery Act as solid waste. It is excluded from hazardous waste, provided that it is material from a permanent or temporary residence [18]. However, since solid waste is regulated by the state and local authorities, some states have more stringent regulations for the management of HHW.
\nAn example is Hawaii. Many of the items that are on the federal list as HHW are the same in Hawaii. However, lamps that contain lead and/or mercury and lead-acid batteries are managed more strictly. In addition, an electronic bill was passed that required computer manufacturers to establish recycling programs. There is also a prohibition on placing motor oil on the ground, in the drainage ways, in sewers, or into water bodies [19].
\nIn Canada, the disposal of solid waste falls under the care of the municipalities with the provinces monitoring operations. While HHW is limited to paint, aerosols, solvents, pesticides, and other products containing hazardous properties, the Waste Diversion Act sets the requirements and guidelines for management of HHW, WEEE, and waste oils in Ontario. Under this act, manufacturers are financially responsible for HHW program, which was developed in 2006 to manage waste from their products. Similarly, WEEE management is mandatorily funded by industry though some retailers charge consumers an environmental fee at the time of purchase of electronic equipment. However, recycling of mercury-containing lamps is voluntary for consumers [20].
\nMunicipalities may establish frequent HHW curb-side pickup as part of the general waste collection program. While convenient for households, this mode can be expensive and time-consuming for waste management authorities [1, 19]. Other options include less frequent collection such as biannually, residents requesting special wastes pick up or personal drop-off at central locations. Such programs for proper disposal and recycling are well established in many countries including the US, Australia, Germany, Denmark, and Sweden [1, 7].
\nThe Extended Producer Responsibility (EPR) is a government policy approach that places the main responsibility of managing a product on the producers or manufacturers. The EU’s WEEE directive and Hawaii’s computer recycling program are primary examples of such a legislative approach. Companies within an industry can collaborate to develop initiatives for handling waste from their products. The Rechargeable Battery Recycling Corporation (RBRC) is a company that was created by the efforts of battery manufacturers in North America. RBRC is responsible for collecting and processing certain types of batteries in order to extract metals that can be used in manufacturing new batteries [11].
\nVery similar to the EPR is the Product Stewardship (PS) approach. The manufacturers, retailers, and consumers share the responsibility for the end of life management of a product. The EU has programs similar to these for the management of pesticides and air fresheners [11]. The US also has a well-established PS system and enforces these programs in some states through laws, subsidies, fees, and mandatory take-backs [1]. The retail take-back system provides a setting for retailers to collect waste materials from consumers whether for exchange or refunds. It is particularly attractive because retailers tend to be within reach and more convenient for consumers. However, there is the potential for such a program to place financial burden on the retailers due to handling and storage requirements. In North America, it has been used successfully for the management of all kinds of waste including automotive batteries, fluorescent lamps, mercury thermostats, etc. Likewise, Japan has a take-back program for home appliances, but it is mandatory and requires consumers to pay the retailer for the waste handling [3].
\nIn this chapter, the adverse impacts of improper disposal of HHW on the environment were discussed. Improper disposal of HHW introduces harmful compounds, which cannot be removed by treatment facilities into the environment, and these chemicals end up in human, animal, and plant tissues. What constitutes to inadequate disposal varies from pouring down the sink or drainage, dumping in the garbage or even out on the ground outdoors. Even when proper disposal routes are provided by municipalities such as drop-off centers are available, many classes of HHW are still disposed in the garbage. Public education, source separation, and recycling are key strategies to reducing the quantity of HHW stream into municipal facilities and by extension of the environment. The success of these strategies for HHW disposal requires voluntary action from residents, legislation from governments mandating manufacturers to take better responsibility, and schemes that make proper disposal more accessible to residents.
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\\n"}]'},components:[{type:"htmlEditorComponent",content:'Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
\n\nIntechOpen only publishes manuscripts for which it has publishing rights. This is governed by a publication agreement between the Author and IntechOpen. This agreement is accepted by the Author when the manuscript is submitted and deals with both the rights of the publisher and Author, as well as any obligations concerning a particular manuscript. However, in accepting this agreement, Authors continue to retain significant rights to use and share their publications.
\n\nHOW COPYRIGHT WORKS WITH OPEN ACCESS LICENSES?
\n\nAgreement samples are listed here for the convenience of prospective Authors:
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\n\nWork - a Chapter, including Conference Papers, and any and all text, graphics, images and/or other materials forming part of or accompanying the Chapter/Conference Paper.
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\n\nVideo Lecture – an audiovisual recording of a lecture or a speech given by a Lecturer, recorded, edited, owned and published by IntechOpen.
\n\nTERMS
\n\nAll Works published on the IntechOpen platform and in print are licensed under a Creative Commons Attribution 3.0 Unported License, a license which allows for the broadest possible reuse of published material.
\n\nCopyright on the individual Works belongs to the specific Author, subject to an agreement with IntechOpen. The Creative Common license is granted to all others to:
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\n\nAll Works are published under the CC BY 3.0 license. However, please note that book Chapters may fall under a different CC license, depending on their publication date as indicated in the table below:
\n\n\n\n
LICENSE | \n\t\t\tUSED FROM - | \n\t\t\tUP TO - | \n\t\t
\n\t\t\t Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported (CC BY-NC-SA 3.0) \n\t\t\t | \n\t\t\t\n\t\t\t 1 July 2005 (2005-07-01) \n\t\t\t | \n\t\t\t\n\t\t\t 3 October 2011 (2011-10-03) \n\t\t\t | \n\t\t
Creative Commons Attribution 3.0 Unported (CC BY 3.0) | \n\t\t\t\n\t\t\t 5 October 2011 (2011-10-05) \n\t\t\t | \n\t\t\tCurrently | \n\t\t
The CC BY 3.0 license permits Works to be freely shared in any medium or format, as well as the reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as the source Work is cited and its Authors are acknowledged in the following manner:
\n\nContent reuse:
\n\n© {year} {authors' full names}. Originally published in {short citation} under {license version} license. Available from: {DOI}
\n\nContent adaptation & reuse:
\n\n© {year} {authors' full names}. Adapted from {short citation}; originally published under {license version} license. Available from: {DOI}
\n\nReposting & sharing:
\n\nOriginally published in {full citation}. Available from: {DOI}
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\n\nDISCLAIMER: Neither the CC BY 3.0 license, nor any other license IntechOpen currently uses or has used before, applies to figures and tables reproduced from other works, as they may be subject to different terms of reuse. In such cases, if the copyright holder is not noted in the source of a figure or table, it is the responsibility of the User to investigate and determine the exact copyright status of any information utilised. Users requiring assistance in that regard are welcome to send an inquiry to permissions@intechopen.com.
\n\nAll rights to Books and all other compilations published on the IntechOpen platform and in print are reserved by IntechOpen.
\n\nThe copyright to Books and other compilations is subject to separate copyright from those that exist in the included Works.
\n\nAll Long Form Monographs/Compacts are licensed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license granted to all others.
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\n\nNo additional restrictions that apply legal terms or technological measures that restrict others from doing anything the license permits are allowed.
\n\nThe CC BY-NC 4.0 license permits Works to be freely shared in any medium or format, as well as reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as it is not used for commercial purposes. The source Work must be cited and its Authors acknowledged in the following manner:
\n\nContent reuse:
\n\n© {year} {authors' full names}. Originally published in {short citation} under {license version} license. Available from: {DOI}
\n\nContent adaptation & reuse:
\n\n© {year} {authors' full names}. Adapted from {short citation}; originally published under {license version} license. Available from: {DOI}
\n\nReposting & sharing:
\n\nOriginally published in {full citation}. Available from: {DOI}
\n\nAll Book cover design elements, as well as Video image graphics are subject to copyright by IntechOpen.
\n\nEvery reproduction of a front cover image must be accompanied by an appropriate Copyright Notice displayed adjacent to the image. The exact Copyright Notice depends on who the Author of a particular cover image is. Users wishing to reproduce cover images should contact permissions@intechopen.com.
\n\nAll Video Lectures under IntechOpen's production are subject to copyright and are property of IntechOpen, unless defined otherwise, and are licensed under the Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. This grants all others the right to:
\n\nShare — copy and redistribute the material in any medium or format
\n\nUnder the following terms:
\n\nUsers wishing to repost and share the Video Lectures are welcome to do so as long as they acknowledge the source in the following manner:
\n\n© {year} IntechOpen. Published under CC BY-NC-ND 4.0 license. Available from: {DOI}
\n\nUsers wishing to reuse, modify, or adapt the Video Lectures in a way not permitted by the license are welcome to contact us at permissions@intechopen.com to discuss waiving particular license terms.
\n\nAll software used on the IntechOpen platform, any used during the publishing process, and the copyright in the code constituting such software, is the property of IntechOpen or its software suppliers. As such, it may not be downloaded or copied without permission.
\n\nUnless otherwise indicated, all IntechOpen websites are the property of IntechOpen.
\n\nAll content included on IntechOpen Websites not forming part of contributed materials (such as text, images, logos, graphics, design elements, videos, sounds, pictures, trademarks, etc.), are subject to copyright and are property of, or licensed to, IntechOpen. Any other use, including the reproduction, modification, distribution, transmission, republication, display, or performance of the content on this site is strictly prohibited.
\n\nPolicy last updated: 2016-06-08
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