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Skeletal muscle cells are responsible for the majority of movements that are under voluntary control. These cells can be very large for example in adult humans some can be 2-3cm long and 100 mm in diameter (2). Skeletal muscle is also known as striated muscle so named because it is transversely striped or striated. Skeletal Muscle is formed from Myoblasts which are spindle shaped muscle precursor cells, these myoblasts fuse together to form a new cell with two nuclei. It is when this single fusion event occurs hundreds of times that an elongated tubular cell is formed which is the mature multinucleated skeletal muscle fibre. The commitment for a myoblast to differentiate depends on two gene regulatory proteins, firstly the MyoD family of basic helix-loop-helix proteins, secondly the MEF2 family of MADS box proteins. These act together to give the myoblast a memory of its committed state, and, eventually, to regulate the expression of other genes that give the mature muscle its specialized character. The myoblasts then proliferate and undergo a dramatic switch of phenotype which depends on the coordinated activation of a whole cluster of muscle specific genes, a process known as myoblast differentiation. It is this differentiation that allows for the formation of multinucleate skeletal muscle fibres. Fusion of the skeletal muscle fibres involves specific cell-cell adhesion molecules that mediate recognition between newly differentiating myoblasts and fibres. Once differentiation has occurred, the cells do not divide and the nuclei can never again replicate their DNA. Appropriate signal proteins such as fibroblast or hepatocyte growth factor in the culture medium can maintain myoblasts in the proliferative, undifferentiated state; if these factors are removed the cells rapidly stop dividing, differentiate and fuse. The process of differentiation is cooperative: differentiating myoblasts secrete factors that apparently encourage other myoblasts to differentiate. In the intact animal, the myoblasts and muscle fibres are held in the meshes of a connective-tissue framework formed by fibroblasts. This framework guides muscle development and controls the arrangement and orientation of the muscle cells (3). In transverse sections the skeletal muscle fibres have a roughly circular outline in which you can see the many nuclei just beneath the surface membrane also known as the sarcolemma. The sarcolemma plays a central role in skeletal muscle structure and function. In addition to the housekeeping functions of a cell plasma membrane, the sarcolemma is directly involved in synaptic transmission, action potential propagation, and excitation-contraction coupling. The biological importance of the sarcolemma and surrounding membranous structures in skeletal muscle is underscored by the number of inherited muscle diseases caused by mutations in components of the sarcolemma protein complexes such as the critically important protein dystrophin. This large protein is absent in Duchenne muscular dystrophy and is reduced in Becker type dystrophy.(4) There are many hundreds of myofibrils each running the entire length of the fibre and they are all packed in a parallel arrangement into a muscle fibre. The striations which are visible through a light microscope are produced from the precise transverse alignment of the fibril banding pattern. Each myofibril consists of a series of sarcomeres; the sarcomere is defined as the distance between adjacent z disks. There can be thousands of sarcomeres within a single muscle cell. Sarcomeres are repeating units of the muscle cell and the proteins within them can change in length, which causes the overall length of a muscle to change. An individual sarcomere contains many parallel actin (thin) and myosin (thick) filaments .The sliding of myosin and actin proteins relative to each other allows for the sarcomere to get shorter or longer. This brings us on to the Sliding Filament Theory of Muscle Contraction. (5)
The sliding filament theory
Using high-resolution microscopy, A. F. Huxley and R. Niedergerke (1954) and H. E. Huxley and J. Hanson (1954) observed changes in the sarcomeres as muscle tissue shortened. (6)When a skeletal muscle fiber contracts, the H bands and I bands get smaller, the zones of overlap get larger, the Z lines move closer together, and the width of the A bands remains constant. The contraction ends once the fiber has shortened by about 30 percent, which coincides with the elimination of the I bands. These observations make sense only if the thin filaments are sliding toward the centre of the sarcomere, alongside the thick filaments.
Figure 1: Shows us the differences between a relaxed state and contracted muscle fibre and the essential proteins involved.
The Control of skeletal muscle activity
Skeletal muscle fibers contract only under the control of the nervous system. Communication between the nervous system and a skeletal muscle fiber occurs at a specialized intercellular connection known as a neuromuscular junction as shown in figure 2. Each skeletal muscle fiber is controlled by a neuron at a single neuromuscular junction midway along the fibres' length. A single axon is branched and each branch ends at an expanded synaptic terminal. The cytoplasm of the synaptic terminal contains mitochondria and vesicles filled with molecules of Acetylcholine which is a neurotransmitter. Acetylcholine is a chemical released by a neuron to change the membrane properties of another cell. In this case, the release of ACh from the synaptic terminal can alter the permeability of the sarcolemma and trigger the contraction of the muscle fiber. The synaptic cleft, a narrow space, separates the synaptic terminal of the neuron from the opposing sarcolemmal surface. This surface, which contains membrane receptors that bind ACh, is known as the motor end plate. The motor end plate has junctional folds, which increase its surface area and thus the number of available ACh receptors. The synaptic cleft and sarcolemma also contain molecules of the enzyme acetylcholinesterase which breaks down ACh. When a neuron stimulates a muscle fiber, the stimulus for ACh release is the arrival of an electrical impulse, or action potential at the synaptic terminal. An action potential is a sudden change in the transmembrane potential propagated along the length of the axon. When that impulse reaches the synaptic terminal, permeability changes in the membrane trigger the exocytosis of ACh into the synaptic cleft. This exocytosis is accomplished when vesicles in the synaptic terminal fuse with the membrane of the neuron. Molecules of ACh diffuse across the synaptic cleft and bind to ACh receptors on the motor end plate. The binding of ACh changes the permeability of the motor end plate to sodium ions .When the membrane permeability to sodium increases, sodium ions rush into the sarcoplasm. This influx continues until AChE removes the ACh from the receptors. The sudden influx of sodium ions results in the generation of an action potential in the sarcolemma at the edges of the motor end plate. This electrical impulse sweeps across the entire membrane surface and travels along each T tubule. The arrival of an action potential at the synaptic terminal thus leads to the appearance of an action potential in the sarcolemma. Even before the action potential has spread across the entire membrane, the ACh has been broken down by AChE.
Figure 2: Shows the neuromuscular junction between the pre synaptic neuron and motor end plate. We can see the acetylcholine is stored in bubble like vesicles and upon activation the acetylcholine is released into the synapse by exocytosis. Acetylcholine binds to receptors on the muscle cell to stimulate muscle contraction.(7)
The link between the generation of an action potential in the sarcolemma and the start of a muscle contraction is called excitation-contraction coupling. Excitation contraction coupling in vertebrae skeletal muscle is mediated by homologous proteins. In skeletal muscle, the action potentials pass along the surface membrane and into a network of invaginations known as the transverse tubular system. The depolarization is detected by DHPR molecules, also known as 'voltage- sensors', Importantly, these DHPR only mediate a small, very slow influx of extracellular Ca2+ and, instead, in some way directly activate the Ca2+-release channels in the adjacent SR (8).
The change in the permeability of the SR to Ca2+ is temporary, lasting only about 0.03 seconds. Yet within a millisecond the Ca2+ concentration in and around the sarcomere reaches 100 times the resting levels. Because the terminal cisternae are situated at the zones of overlap, where the thick and thin filaments interact, the effect of calcium release on the sarcomere is almost instantaneous. The binding of Ca2+ to troponin exposes the active sites along the thin filaments, initiating the contraction. The contraction cycle then begins.
The Cross Bridge cycle
In the resting sarcomere each cross bridge contains an ATP molecule which provides the energy for contraction. The cross-bridge functions as an ATPase, an enzyme that can break down ATP. At the start of the contraction cycle, each cross-bridge has already split a molecule of ATP and stored the energy released in the process for the cross bridge cycle. The calcium ions entering the sarcoplasm bind to troponin. This binding weakens the bond between the troponin-tropomyosin complex and actin. The troponin molecule then changes position, pulling the tropomyosin molecule away from the active sites and allowing cross-bridges to form. When the active sites are exposed, the myosin cross-bridges can bind to them. In the resting sarcomere, each cross-bridge points away from the M line. In this position, the myosin head is "cocked" like the spring in a mousetrap. Cocking the myosin head requires energy, and the energy is obtained by breaking down ATP into ADP and a phosphate group. In the cocked position, both the ADP and the phosphate are still bound to the myosin head. After cross-bridge attachment has occurred, the stored energy is released as the myosin head pivots toward the M line. This action is called the power stroke. When this occurs, the ADP and phosphate are released. When an ATP binds to the myosin head, the link between the active site on the actin molecule and the myosin head is broken. The active site is now exposed and able to interact with another cross-bridge. Finally Myosin reactivation occurs when the free myosin head splits the ATP into ADP and a phosphate group. The energy released in this process is used to recock the myosin head. The entire cycle can now be repeated. If calcium ion concentrations remain elevated and ATP reserves are sufficient, each myosin head will repeat this cycle about five times per second. Because all the sarcomeres contract together, the entire muscle shortens at the same rate. (9)
Figure 3: When myosin initially binds to actin, the actomyosin is in a weakly bound low-force state (state c). With the subsequent release of Pi (step d), the cross bridge transforms into strongly bound high-force state and goes through the power stroke (state e). ADP is then released (state f), returning the cross bridge to the rigor complex. The strongly bound, high-force states (states d, e, f, and a) are thought to be the dominant form during a maximal isometric contraction, whereas during isotonic shortening skeletal muscle myosin spends only 5% of the cycle time in strongly bound states.
Impact of inflammation on skeletal muscle
Cachexia is the loss of body mass that cannot be reversed nutritionally, which develops in a number of chronic pulmonary and non-pulmonary disorders including chronic obstructive pulmonary disease(10), cancer(11), heart failure(12) and AIDS(13). Wasting disease is distinct from starvation, age-related loss of muscle mass, primary depression, malabsorption and hyperthyroidism and is associated with increased morbidity. Systemic inflammation in muscle cells is a common underlying theme in the range of chronic diseases in which cachexia develops. We can see this in both in vivo and ex vivo experimental models which have shown increased levels of circulating cytokines in human experimental models associated with loss of muscle mass(14). Systemic inflammation is able to induce muscle wasting by the combined effects of inequity between muscle protein synthesis and degradation, as well as impaired muscle regeneration (15). In ageing systems we see the increased release of many inflammatory mediators, such as Tumour necrosis factor(TNF-a)(16), advanced glycation products (AGEs)(17) and matrix metalloproteinases(MMPs)(18) aswell as seeing an increase in mediator storage vesicles such as mast cells.(19) Intermuscular adipose tissue content and intramyocellular lipid deposits increase with age, and this adipose tissue appears to replace muscle tissue. Intermuscular adipose tissue may accumulate in skeletal muscle of elderly people as a result of satellite cells differentiating into adipogenic cells. Both adipocytes and fibroblasts produce proinflammatory cytokines and growth factors, and these cell types may contribute to the inflammatory state of skeletal muscle in the elderly. Macrophage numbers are higher in muscle homogenate samples from obese people compared with lean people. Furthermore, TNF-Î± mRNA, SOCS3 mRNA, toll-like receptor (TLR) 4, and JNK proteins are elevated in muscle homogenate samples of people with Type 2 diabetes compared with lean people. Increased fat mass and insulin resistance may therefore, explain, at least in part, the observations that TNF-Î± mRNA, TLR4 mRNA, SOCS3, and JNK proteins are expressed in greater abundance in muscle homogenate samples from elderly people compared with young people. Sarcopenia is the degenerative loss of skeletal muscle mass, quality and strength associated with ageing(20). IL-6 is a cytokine produced from muscle, and is elevated in response to muscle contraction. (21) IL-6 usually precedes the appearance of other cytokines. Il- 6 is a true myokine with endocrine and paracrine effects, it is expressed in response to muscle contractions in both type 1 and type 2 muscle fibers and exerts its effects locally within the muscle for example in the activation of the AMPK pathway which plays a key role in the regulation of cellular energy homeostasis or phosphatidylinositol 3-kinase to increase glucose uptake and fat oxidation (16). Transforming growth factor beta (TGF-Î²) is a protein that controls proliferation, cellular differentiation, and other functions in most cells. It is a type of cytokine which plays a role in many diseases for example Cancerous cells increase their production of TGF-Î², which also acts on surrounding cells. TGF-Î² can induce apoptosis in numerous cell types. Studies have shown that although there is no definitive increase in cytokines such as IL-6 and TGF-Î² with ageing, there is an increase in mRNA expression of IL-6 receptor and TGF-Î² receptor in muscle homogenate samples with age (22). This shows that it is not simply an increase in cytokine production with ageing that leads to muscle wasting, it is an increase in factors related to the cytokines also. Degens published a comprehensive study on the effects of TNF-Î± on muscle atrophy;(23) TNF-Î± stimulates apoptosis to a greater extent in muscle precursor cells from old rats compared to muscle precursor cells in young rats, these findings may be due to the upregulation of both IL-6 and TGF- Î² with age which decreases the protein content of the muscle, therefore decreasing the muscle cell size and increasing the sensitivity to TNF-Î± with age. In vivo TNF-Î± induces muscle wasting in healthy rodents as well as rodents with conditions such as cancer cachexia, chronic pulmonary inflammation and sepsis (24) These findings are supported indirectly by observations in elderly humans (25). C2C12 is a mouse myoblast cell line, originally obtained by Yaffe and Saxel through serial passage of myoblasts cultured from the thigh muscle of C3H mice after a crush injury. These cells are capable of differentiation.(26)The effects of TNF-Î± may depend on other factors present in the local environment, Al-Shanti et Al(27)demonstrated that on its own, TNF-Î± did not influence survival or proliferation of C2C12 myoblasts. When cells were incubated with TNF-Î± for 24h and IL-6 for a further 24h, cell survival increased almost two fold and cell proliferation increased threefold, this suggests that IL-6 may modulate the effects of TNF-Î± on muscle cell growth (28). Haddad et al. demonstrated that 14 days of intramuscular infusion of IL-6 reduced total protein content and myofibrillar content in tibialis anterior in rats which supports the fact that IL-6 cytokine is associated with muscle wastage (29). Research has shown many varied effects of cytokines on muscle growth, that are similar to TNF-Î±, like IL-6 which can also promote muscle growth under certain conditions(30). Baeza-Raja and Munoz-Canoves observed that recombinant IL-6 stimulated C2C12 myoblasts to differentiate. Furthermore short interfering RNA against IL-6 prevented myoblast differentiation. Al Shanti et al. have also demonstrated that IL-6, in combination with TNF-Î± stimulated growth of C2C12 myoblasts by activating gp130, a cytokine receptor which contains an amino acid motif to ensure the correct protein folding and ligand binding, and IGF-1 receptor which mediates the effect of IGF-1 which plays an important role in growth and continues to have anabolic effects in adults where it can induce hypertrophy of skeletal muscle cells. The circulating concentrations of cytokines and C-reactive protein are often elevated in people with age-related diseases(31), including obesity(32) and Type 2 diabetes(33), atherosclerosis(34) , dementia(35) , osteoporosis(36) , rheumatoid arthritis (37), and chronic heart failure(38) . Local inflammation in adipose, vascular, and synovial tissues is a causative factor in all of these disease states, but it is unclear whether "spillover" of inflammatory cytokines and reactive oxygen/nitrogen species from these tissues into the circulation also causes inflammation in other tissues, such as skeletal muscle. (39)
Muscle as an endocrine organ
Skeletal muscle is an endocrine organ, and its secretion of hormone-like factors may influence metabolism in tissues and organs(40). It was also suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert autocrine, paracrine or endocrine effects should be classified as 'myokines'(41) Adipose tissue has been regarded as the major source of cytokines (adipokines) (42)however, the finding that muscles produce and release cytokines suggests that working skeletal muscle in addition to adipose tissue may be a major source of secreted molecules. Myokines provide a conceptual basis to explain how muscles communicate to other organs. Thus, an overall idea is that contracting skeletal muscles release myokines, which work in a hormone-like fashion, exerting specific endocrine effects on other organs or which work locally via paracrine mechanisms. In the year 2000, it became clear that contracting human skeletal muscle releases significant amounts of IL-6 into the circulation during prolonged single-limb exercise (43). Research during subsequent years highlighted the fact that muscle-derived IL-6 is an important player in metabolism. Today, it appears that skeletal muscle has the capacity to express several myokines(44). Langberg et al. demonstrated that IL-6 is produced by the peritendinous tissue of active muscle during exercise. In an attempt to determine which cells produce the IL-6, Keller et al. isolated nuclei from muscle biopsies obtained before, during, and after exercise. With the use of RT-PCR, it was demonstrated that the nuclear transcription rate for IL-6 increases rapidly and markedly after the onset of exercise. This suggested that a factor associated with contraction increases IL-6 transcriptional rate, probably in the nuclei from myocytes, given the observation that IL-6 protein is expressed within muscle fibers (45). Further evidence that contracting muscle fibers themselves are a source of IL-6 mRNA and protein has been achieved by analysis of biopsies from the human vastus lateralis using in situ hybridization and immunohistochemistry (46). Accordingly, IL-6 appears to accumulate within the contracting muscle fibers as well as in the interstitium during exercise (47). Although IL-6 released from the contracting muscles may account for most of the IL-6 found in the circulation, other studies have demonstrated that skeletal muscle is not the sole source of exercise-induced IL-6. (48) A number of studies both in vitro (49) and in rodents in vivo (50) demonstrate that IL-6 is capable of inducing insulin resistance. In the rodent studies, IL-6 seems to induce insulin resistance via adverse effects on the liver. The IL-6-induced insulin resistance appears to be due to an increase in suppressor of cytokine signalling 3 (SOCS-3) expression (51), as SOCS-3 may directly inhibit the insulin receptor (52). In resting human skeletal muscle, the IL-6 mRNA content is very low; although small amounts of IL-6 protein predominantly in type I fibres may be detected using sensitive immunohistochemical methods (30). By obtaining arterial-femoral venous differences over an exercising leg, it can be seen that exercising limbs release IL-6(53). In an attempt to determine which cells produce the IL-6; Keller et al. isolated nuclei from muscle biopsies obtained before, during, and after exercise. Using RT-PCR, it was demonstrated that the nuclear transcription rate for IL-6 increases rapidly and markedly after the onset of exercise (31). This suggested that a factor associated with contraction increases IL-6 transcriptional rate, probably in the nuclei from myocytes, given the observation that IL-6 protein is expressed within muscle fibres (32). Further evidence that contracting muscle fibres themselves are a source of IL-6 mRNA and protein has been achieved by analysis of biopsies from the human vastus lateralis using in situ hybridization and immunohistochemistry(54). It appears that, unlike IL-6 signalling in macrophages, which seems to be dependent upon the activation of the nuclear factor Îº light chain enhancer of activated B cells (NFÎºB) signalling pathway (55), intramuscular IL-6 expression is regulated by a network of signalling cascades that among other pathways are likely to involve crosstalk between the Ca2+/nuclear factor of activated T-cells (NFAT) and glycogen/p38 mitogen-activated protein kinase (MAPK) pathways(56). Thus, when IL-6 is produced by macrophages, it leads to an inflammatory response, whereas muscle cells produce and release IL-6 without activating classical pro-inflammatory pathways. The fact that IL-6 can sometimes act as a pro-inflammatory and sometimes as an anti-inflammatory agent appears to be more dependent on the environment (muscle versus immune cell) than on whether IL-6 is activated in an acute or chronic fashion(57). AMP-activated protein kinase (AMPK) regulates skeletal muscle metabolic gene expression programmes in response to changes in energy status (58). While AMPK may influence the transcription of metabolic genes, AMPK exerts most of its effects via its role as a protein kinase, regulating the activity of key metabolic enzymes by phosphorylation(59). A recent study suggests that IL-6 activates AMPK in skeletal muscle by increasing the concentration of cAMP and, secondarily, the AMP:ATP ratio (60). Work from several groups (61) has demonstrated that leptin may activate AMPK in peripheral tissues such as skeletal muscle. Thus, it appears that IL-6 acutely mediates signalling through the glycoprotein 130 (gp130) a cytokine receptor and exhibits many 'leptin-like' actions such as activating AMPK and insulin signalling (62). Although most studies point to an effect of IL-6 on AMPK, Glund and colleagues provided evidence that AMPK-dependent pathways regulate IL-6 release from isolated oxidative skeletal muscle (63). Skeletal muscle cells are capable of producing IL-6 in response to various stimuli such as lipopolysaccharide, reactive oxygen species (ROS), and inflammatory cytokines as well as during contraction (64). The neuronal nitric oxide (NO) synthase isoform is abundantly expressed in human skeletal muscle, and a number of observations provide evidence that NO production is significantly increased within contracting skeletal muscle (65) .In vitro studies suggest that NO may alter signalling networks by redox-sensitive modification, by nitrosation of proteins within the cytoplasm or nucleus, or it may exert effects on transcription via an increase in cGMP (66). However in aged muscle there doesn't seem to be any increase in NO which may mean IL-6 activates an alternative pathway (67). In cultured skeletal muscle cells, inflammatory stimuli may elicit the production of IL-6 via signaling pathways that involve c-Jun NH2-terminal kinase and the transcription factor NF-ÎºB. Increased ROS formation in skeletal muscle after exercise has been demonstrated directly in animals and indirectly in humans (68). NF-ÎºB is a redox-sensitive transcription factor that may be activated by ROS tumor necrosis factor alpha (TNFÎ±), interleukin 1-beta, bacterial lipopolysaccharides, isoproterenol, and ionizing radiation (69). Murine skeletal myotubes release IL-6 when exposed to oxidative stress in an NF-ÎºB-dependent way. In addition, supplementation with different antioxidants attenuates the systemic increase of IL-6 in response to exercise (70). The observation that nonsteroidal anti-inflammatory drugs, which inhibit NF-ÎºB activity, reduce the exercise-induced increase of IL-6 further supports the idea that NF-ÎºB represents a link between contractile activity and IL-6 synthesis (71). On the other hand, a number of stimuli, including oxidative stress, low glucose availability, low glycogen content, catecholamines, and hyperthermia, which are all features of exercise, are capable of inducing heat shock proteins which may in turn activate IL-6 synthesis (72). Membrane depolarization activates voltage-dependent Ca2+ channels and induces Ca2+ release, which is obligatory for skeletal muscle contraction. A low sustained intracellular concentration of Ca2+ has been shown to activate nuclear factor of activated T cell (NFAT) through the action of calcineurin and IL-6 gene expression in cultured human muscle cells(73). Thus, whereas the Ca2+/NFAT pathway represents one arm of the IL-6 gene regulation, intramuscular glycogen content has also been shown to play an influential role in this process (74). It appears that, unlike IL-6 signaling in macrophages, which seems entirely dependent on activation of the NF-ÎºB signaling pathway, intramuscular IL-6 expression is regulated by a network of signaling cascades that among other pathways are likely to involve cross talk between the Ca2+/NFAT and glycogen/p38 MAPK pathways (75). Work from several groups has demonstrated that leptin, signaling through the leptin receptor (LRb), may activate AMPK in peripheral tissues such as skeletal muscle (76). Thus it appears that IL-6 acutely mediates signaling through the gp130 receptor and exhibits many "leptin-like" actions such as activating AMPK and insulin signalling (77). Although most studies point to an effect of IL-6 on AMPK, Glund et al. (78) provided evidence that AMPK-dependent pathways regulate IL-6 release from isolated oxidative skeletal muscle. IL6 is expressed by human myoblasts(79), human cultured myotubes(80), growing murine myofibres(81) and associated muscle stem cells (satellite cells). In addition, IL6 is released from human primary muscle cell cultures from healthy individuals and even from patients with type 2 Diabetes Mellitus (82). Today, muscle cells are known to be the dominant source of IL6 production during exercise(83). Furthermore, the hepatosplanchnic viscera remove IL6 from the circulation in humans during exercise(84). The removal of IL6 by the liver could constitute a mechanism that limits the negative metabolic effects of chronically elevated levels of circulating IL6(85). Human skeletal muscle is unique in that it can produce IL6 during contraction in a strictly TNF-independent fashion(86). This finding suggests that muscular IL6 has a role in metabolism as well as in inflammation. In support of the hypothesis that IL-6 predominantly plays a role in metabolism, both intramuscular IL6 mRNA expression and IL-6 protein release are markedly enhanced when intramuscular glycogen levels are low, which suggests that IL6 works as an energy sensor (87). This idea is supported by numerous studies showing that glucose ingestion during exercise attenuates the exercise-induced increase in plasma IL6 and inhibits the IL6 release from contracting skeletal muscle in humans.(88)
Muscles, exercise and obesity: skeletal muscle as a secretory organ
Figure 4 : Skeletal muscle is a secretory organ. LIF, IL4, IL6, IL7 and IL-15 promote muscle hypertrophy. Myostatin inhibits muscle hypertrophy and exercise provokes the release of a myostatin inhibitor, follistatin, from the liver. BDNF and IL6 are involved in AMPK-mediated fat oxidation and IL6 enhances insulin-stimulated glucose uptake. (89) Importantly, IL6 is a myokine with cardinal biological activity, as it contributes to hepatic glucose production during exercise(90). The mechanisms that mediate the tightly controlled production and clearance of glucose during muscular work are unclear. An unidentified 'work factor' has been suggested to exist that influences the contraction-induced increase in endogenous glucose production. Acute administration of recombinant human IL6 infused at physiological concentrations into resting human individuals has no effect on whole-body glucose disposal, glucose uptake or endogenous glucose production. By contrast, IL6 contributes to the contraction-induced increase in endogenous glucose production. When recombinant human IL6 was infused into healthy volunteers during low-intensity exercise, to mimic the circulating concentration of IL6 observed during high-intensity exercise, the glucose output was as high as during high-intensity exercise. The study demonstrated a direct muscle-liver crosstalk. IL6 appeared to have a role in endogenous glucose production during exercise in humans; however, its action on the liver was dependent on a yet unidentified muscle contraction-induced factor. (91)
Perspective of inflammation towards ageing
With ageing even in the absence of disease it is not unusual to see two to four fold increases in circulating levels of pro inflammatory cytokines such as IL-6 and TNF- Î± as well as acute phase proteins such as C-reactive protein in the elderly compared with the young. With ageing in all physiological systems we see significant declines in immune function that promote inflammation, but the chronic low grade inflammatory state in the elderely is clearly a consequence of age related disease. (92) It is well established that ageing is associated is associated with increases in circulating Reactive oxygen species as well as decreases in antioxidant capacity.Recent studies have emerged suggesting Reactive oxygen species activation of toll like receptors on a variety of immune cells plays an important role in activating the inflammatory cascade.(93) There has been no decisive study to suggest whether inflammation is a cause or consequence of disease states such as obesity, cardiovascular disease, diabetes and Alzheimer's which all increase in prevalence with ageing. It has been suggested that the difference in inflammatory markers in patients with disease symptoms may be due to differences in the actual health status of the subjects. (94) While transient inflammation is necessary for recovery from injury and infection, it has been hypothesized that the excessive inflammation in aging may also be caused by an exaggerated acute-phase response that may be a cause or consequence of a delayed recovery from an insult that promotes inflammation. This suggests that at least under certain conditions the elderly are capable of mounting an adequate immune response, but are unable to completely terminate the response in a normal timeframe. This failure to completely resolve an immune response may contribute to the chronic state of low-grade inflammation associated with aging. Furthermore, chronic, low grade inflammation also may serve to prime the body to mount an exaggerated response to future insults that would normally be dampened if the immune system were not previously activated. Thus, a vicious cycle exists in which the incomplete resolution of previous immune responses in ageing is responsible for promoting exaggerated future immune responses. (95) IL-6 and TGF-Î² mRNA expression is similar in muscle homogenate samples from young and elderly males (96). In contrast, mRNA expression of IL-6 receptor and TGF-Î² receptor III is higher in muscle homogenate samples from elderly men compared with young men (97). The lack of any difference in mRNA expression of TGF-Î² in muscle homogenate samples from elderly vs. young people (98) is also surprising. Similar to TNF-Î±, TGF-Î² inhibits the proliferation of myogenic cells both in vitro and in vivo (99). Furthermore, TGF-Î² stimulates myoblasts to differentiate into myofibroblasts in vitro (100) and in vivo (101). This process is mediated through signaling pathways that involve the Smad protein family, sphingosine kinase, and sphingosine 1-phosphate (102). This process may account for the increase in fibrosis in skeletal muscle of elderly humans/animals (103). In contrast with TGF-Î² itself, expression of TGF-Î² receptor III is higher in muscle homogenate samples from elderly men compared with young men (104). This increase may be functionally important, because TGF-Î² receptors inhibit the myogenic activity of satellite cells (105). In addition to TGF-Î², IFN-Î³ regulates the growth and differentiation of muscle cells (106). We know there is a strong correlation between inflammation and the progression o many age related chronic diseases, due to this strong correlation a variety of strategies have been utilized to minimise inflammation associated with ageing. Pharmacological interventions may provide one alternative and it has been suggested that medications such as angiotensin converting enzymes and non steroidal ant inflammatory drugs among others may have a clinical role in reducing inflammation, even though they may not be currently indicated to do so(107). The side effects associated with these drugs coupled with the frailty of the ageing immune system, as well as the financial burden have limited the use of these treatments (108). Therefore changes in lifestyle of the elderly such as exercise training or dietary modifications may be the effective long term alternative to limit inflammation in the elderly. Reductions in calorie intake resulting in weight loss may provide one mechanism to dampen age-related inflammation (109). Other research has focused on modifying nutritional components to reduce inflammation, such as micronutrients (110), macronutrients (111), plant stanols and sterols (112), and a variety of prebiotics and other dietary components (113). Acute, unaccustomed exercise can cause muscle and tissue damage, especially if the exercise is carried out at high intensities for long periods. In some cases inflammatory cytokines can be detected in peripheral blood of people after high intensity, unaccustomed exercise.(114)This damaging response is attenuated if exercise is carried out repeatedly as the tissue can adapt to the new overload stress. Many, studies have demonstrated that regularly performed cardiovascular exercise training may reduce markers of systemic inflammation (115).
Perspective of inflammation towards obesity
Sarcopenic obesity is associated with muscle loss and is common among aged obese adults or those obese people with severe disease burden or injury.(116) Obese individuals in high inflammatory states will preferentially mobilise muscle and not fat. Chronic low level inflammation will also contribute to erosion of muscle mass. As obese individuals age, they become increasingly susceptible to chronic disease, and become increasingly sedentary, further contributing to loss of muscle mass. Quality of muscle is also a concern in sarcopenic obesity, as fat-selective MRI reveals increased "marbling" with fat deposition in skeletal muscle.(117) Elevated intracellular triglyceride concentrations in skeletal muscle are associated with decreased insulin sensitivity.(118) The Trial of Angiotensin Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors Study(119) found that IL-6 and CRP were positively associated with BMI and total fat mass, and inversely associated with fat-adjusted appendicular lean mass. Obesity remained significantly associated with elevated IL-6 and CRP levels, even after adjustments for sarcopenia. These observations suggest that obesity-related inflammation may have a role in age-related sarcopenia. (120)
Perspective of inflammation towards critical illness
Critical illness myopathy as with critical illness polyneuropathy, this form of acute muscle injury is strongly associated with sepsis and multiple organ dysfunctions. Muscle injury may result from the direct effects of microorganism-associated toxins, as is observed in toxic shock syndrome and in occasional infections with influenza or other viruses. In other systemic infections, muscle is probably damaged by the same inflammatory mediators that are implicated generally in the systemic inflammatory response syndrome. The incidence of critical care myopathy is unknown. However, one study suggested that skeletal muscle is commonly injured as a consequence of severe sepsis (121). Critical illness myopathy is characterized by loss of myosin and thick filament proteins, muscle fibre atrophy and disorganisation of myofibrils. Along with critical illness myopathy we also have critical illness polyneuropathy, which is characterised by distal axonal degeneration often coexist with critical illness myopathy(122). Many patients however show weakened muscle function prior to detectable muscle atrophy. Multiple organ failure, hyperglycaemia mechanical ventilation have also been identified as risk factors that could lead to critical illness myopathy(123). Muscle wasting in critical illness myopathy is attributed to the activation of Calpain, the Ubiquitin Proteasome system and the autophagy lysosomal pathway(124). Presence of apoptotic myonuclei and proapoptotic proteases are reported in skeletal muscle of the critically ill patients that suggest muscle fiber atrophy and myosin loss may be due to an apoptosis cascade(125). Cancer cachexia is characterized by severe weight loss, early satiety and muscle weakness. Weight loss in cancer cachexia is due to both the loss of skeletal muscle mass and adipose tissue(126). The host genotype presentation of cachexia also contributes to variation of disease presentation. Single nucleotide polymorphisms in for example the IL-1 or IL-6 genes are associated with production rates of the respective cytokines that are linked to prevalence of muscle wasting in certain types of cancer. These findings suggest that the immune system plays a key role in the variable presentation of cancer cachexia(127). Cancer cells are thought to depend on pro-inflammatory cytokines for growth and survival from apoptotic signalling and angiogenesis. Pro inflammatory cytokines such as TNF-Î± are synthesised and secreted in many models of cancer cachexia(128). TNF-Î± promotes atrophy by induction of E3 ligases, MURF-1 and atrogin-1. TWEAK, the structural homolog of TNF- Î± also induce E3 ligase MURF-1 and degrade myosin heavy chain. IL-6 in contrast to TNF-Î± has been shown to correlate with weight loss and reduced survival rates in cancer patients (129). IL-6s role in regulating cancer cachexia is further strengthened by experiments which have shown weight losing lung cancer patients have responded positively to monoclonal IL-6 antibody treatments by reporting reversal of fatigue and anorexia although no change has been reported in lean body mass. Advanced cancers involve pain which can lead to the activation of the neuroendocrine stress response such as release of glucocorticoids(130). Elevated inflammation is a common feature in cancer cachexia and glucocorticoids can mediate a role in muscle wasting via suppression PGC-1Î² protein that lead to the increased expression of E3 ligases, MURF-2 and atrogin-1(131). PGC-1Î± protein is down regulated in various muscle arophy models, but when it is over expressed PGC-1Î± rescues muscle loss by inhibiting the human protein FOXO3(132). Dystrophin glycoprotein complex dysfunction leads to induction of E3 ligases, MURF-1 and atrogin-1 both expressed during muscle atrophy via the NF ÐºB dependant pathway(133). The loss of the Dystophin Glycoprotein complex components is also observed in cancer patients with cachexia. A specific treatment for critical illness myopathy is not available; however electrical muscle stimulation is implicated in reducing the prevalence of critical illness myopathy(134). The most effective treatment strategy is the early, targeted physiotherapy for critically ill patients. The first prospective cohort study comparing intensive care unit mobilisation with usual care involving over 300 patients showed that early mobility protocol is associated with decreased Intensive care unit patient admittance and hospital length stay of survivors.(135)
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Figure 5: Schematic representation of the factors regulating muscle mass and function in critically ill patients(136).
Perspective of inflammation towards Myositis
As discussed previously Inflammation is the protective response of tissue to injury. When inflammation occurs in muscle cells it is known as myositis (137). The inflammation may vary in severity and may be isolated to one muscle, muscle group or several muscles throughout the body. Muscle inflammation itself is not uncommon. We are constantly using our muscles on a day to day basis and sometimes our muscles are put under strain. As part of the bodies protective mechanism muscles may also experience injury from an external force. Upon muscle injury there is usually no other clinical features or disturbances of other organs and systems. Some causes of myositis may be more complex however and can have a long term effect which can cause permanent damage and compromise muscle function. This may include autoimmune disease, infections, toxicity of certain drugs and substances. Most chronic forms of myositis appear to be associated more often with autoimmune diseases. There are several types of myositis which can be broadly divided into the infectious and non-infectious causes. Infectious myositis is inflammation of the muscle cell due to an acute, subacute, or chronic infection. Bacterial infection is a severe often acute infection that arises when bacteria spread to the muscles from another site of infection, either superficial or deep. Bacterial myositis can at times be associated with an insect bite, where the insects act as carriers and reservoirs of the bacteria that can cause infection. Non infectious myositis is largely due to autoimmune mechanisms where the body attacks its own muscle cells. The exact cause of the autoimmune mechanism is largely unknown although it may be associated with familial history, environmental factors or be related to systemic autoimmune diseases. Dermatomyositis causes inflammation on both the skin and the skeletal muscle cells. The skin inflammation is often seen as a dry rash on knuckles, elbows and knees, and if the rash occurs without muscle weakness then the muscle inflammation is known as amyopathis dermatomyositis. The muscle weakness affects the proximal muscles and the inflammation progresses slowly throughout the body. The muscle weakness is not only isolated to the skeletal muscles of the limbs but can affect even smooth muscles and cardiac muscle. Similar to dermatomyositis, polymyositis also causes the progression of muscle weakness and distribution, as well as the involvement of areas other than the skeletal muscle, although in polymyositis there is no sign of a skin rash. The early stages of inclusion body mysositis are associated with the distal muscles and the myositis has a preference to spread towards the flexor muscles of the wrist and fingers and the extensor muscles of the knee(138). Dominant manifestations of myositis as well as leading to muscle weakness also show raised creatine kinase levels. Enhanced expression of Interferons, interleukins and Tumour necrosis factor has been demonstrated in muscle tissue from patients suffering from myositis(139). An increase in expression of intercellular adhesion molecule -1 and vascular cell adhesion molecule-1 in muscle and serum samples is seen from experimental myositis(140), however it seems some drugs do have an effect on myositis states as serum levels of these adhesion molecules are responsive to corticosteroid treatment.(141) In addition to VCAM-1, sE-selectin levels are also elevated in polymyositis and dermatomyositis(142). Moreover, polymyositis and dermatomyositis have distinct serum adhesion molecule profiles, with enhanced expression of platelet endothelial cell adhesion molecule-1 and Intercellular cell adhesion molecule-1 being common to both (143).