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Skeletal muscle is a robust and plastic organ which has a total protein content of over 50. Skeletal muscle is the main driving force responsible for ambulatory movements in the majority of organs(Alberts, 2002). These cells can be very large for example in adult humans some can be 2-3cm long and 100 mm in diameter (Alberts, 2002). Skeletal muscle is also known as striated muscle so named because it is transversely striped or striated. Skeletal muscle is made up of spindle shaped muscle fibres known as myoblasts, these myoblasts are the precursor cells that fuse together to form a multinucleate cell known as myotube cells. The mature skeletal muscle fibre is formed when this myoblast fusion event occurs hundreds of times. (Alberts, 2002) Differentiating myoblasts act cooperatively where differentiating myoblasts secrete factors which stimulate further myoblast differentiation. In healthy individuals, the myoblasts and muscle fibres are held in position in a meshwork of connective tissue formed by structures known as fibroblasts. This meshwork frame is the supporting control structure for the growth and development of muscle fibres. (Alberts, 2002). When viewed under a microscope cross sections of skeletal muscle fibres appear circular, within this circular outline are many nuclei just beneath the surface membrane known as the sarcolemma. The sarcolemma is the skeletal muscle cell membrane of a muscle cell consisting of a plasma cell membrane and an outer coat made of a thin polysaccharide material that contains thin collagen fibrils, the sarcolemma also plays a crucial role in skeletal muscle structure and function (Berchtold et al., 2000). There are thousands of repeating units known as sarcomeres within a single muscle cell.
The sliding filament theory
In 1954 crucial papers were published which showed for the first time the molecular basis formuscular contraction by Huxley and Hanson.
Figure 1: Shows us the differences between a relaxed state and contracted muscle fibre and the essential proteins involved.
The muscle contraction begins with the arrival of a nerve impulse at the neuromusclular junction, which causes the release of acetylcholine. Acetylcholine release causes the depolarisation of the motor end plate which travels through the muscle via the transverse tubules resulting in calcium release from the Sarcoplasmic Reticulum. The calcium released from the sarcoplasmic reticulum binds to troponin which causes a shape change in the troponin molecule which removes tropomyosin from blocking the active site of the actin molecule, allowing for the Myosin to attach to the actin molecule and form a cross bridge. ATP is then broken down which provides energy for the myosin filaments to pull the actin along its length and shorten the muscle; this occurs along the whole length of the myofibril in the muscle cells. The final step in this cycle is the detachment of the myosin head from the actin filament; this step is sped up by ATP. The ATP molecule is then broken down and the myosin head is re set ready for the next power stroke.(Huxley, 1985)
Impact of inflammation on skeletal muscle
The inflammatory response is dependent on two factors, firstly the severity of the injury and secondly the degree of muscular vascularisation at the time of the injury (Smith et al., 2008). A systemic increase in the circulating levels of cytokines can induce muscle wasting by an imbalance of protein synthesis and impaired muscle regeneration. Skeletal muscle injury due to exercise or certain disease states such as Duchenne Muscular dystrophy causes the release of inflammatory cytokines such as TNF-Î± and IL-6 and these cytokines can directly induce inflammation (Tews and Goebel, 1996). Mast cells are a primary source of cytokines and mast cells can accumulate at the site of injury to initiate an inflammatory response (Gorospe et al., 1996). The chronic presence of inflammation in muscular diseases is due to the presence of mast cells which are always present at a low level in certain disease states(Lefaucheur et al., 1996) Cachexia is the nutritionally irreversible placid loss of muscle mass which occurs via the loss of cellular fluid into the extracellular space which may result in oedema brought on in response to chronic diseases such as critical illness and sepsis. It has been shown in vivo and ex vivo in human experimental models that with chronic disease we see an underlying increase in the level of inflammatory cytokines and chemokines in the circulation which is associated with loss of muscle mass(Pedersen and Febbraio, 2008).
Systemic increases in the levels of circulating cytokines is able to induce muscle wasting by the combined effects of an imbalance in muscle protein synthesis and degradation along with impaired muscle regeneration. With increases in age we see an increase in intracellular adipose tissue and intramyocellular lipid deposits (Morley et al., 2006), studies have shown this increase can overshadow the muscle tissue and the increase may even be down to satellite cells in the elderly differentiating into adipogenic cells. (Asakura et al., 2001) Generally in the elderly we see an increase in the levels of circulating cytokines due to the release of cytokine molecule from adipocytes and fibroblasts which leads to an increased inflammatory state in skeletal muscle. Sarcopenia is the degenerative loss of muscle mass and strength with age(Payne, 2006). In sarcopenia we see a decrease in muscle mass which can be seen as a fall in the number of muscle fibres (type 1 and type 2), the size of the actual muscle fibre decreases and the sarcoplasmic reticulum and t tubular system proliferate which is related to the loss of contractile elements in the muscle.(Mitchell et al., 2012) Many factors contribute to the degeneration of muscle mass with age such as changes in the mitochondrial function, as spoken about previously the chronic elevation of cytokines in the circulation which is generally associated with ageing and can lead to increased oxidative stress. Importantly the increase in cytokines with age have been further reviewed and it has been shown that TNF-Î±, an apoptosis signalling molecule, works more effectively in elderly subjects than in young subjects, this may be due to an increase in cytokine levels (IL-6 and TGF-Î²) with age which causes a loss of muscle mass and therefore increases the sensitivity of the muscle cell to TNF-Î±(Febbraio and Pedersen, 2005). In vivo studies with TNF-Î± has shown that TNF-Î± will induce muscle wasting in healthy rodents along with rodents carrying diseases such as Cancer cachexia and sepsis (Chakravarti and Abraham, 1999). These rodent studies are supported indirectly by observations in elderly humans. (Degens, 2010). It has been shown that in age related disease states(Haddad et al., 2006)such as obesity(van Hall et al., 2008), arthritis(Bruunsgaard and Pedersen, 2003), and type 2 diabetes(Bruunsgaard and Pedersen, 2003), we see a general increase in cytokine production along with the expression of c- reactive protein. The local increase in cytokine production causes localised inflammation in vascular and synovial tissues, however recent studies have shown that there is a spill over effect, where the inflammatory cytokines from the local tissues may leak into the circulation and affect the larger tissues such as skeletal muscle. (Bruunsgaard and Pedersen, 2003)
Muscle as an endocrine organ
Skeletal muscle is an endocrine organ due to its secretion of hormone-like factors which influence metabolism in surrounding tissues and organs. (Peake et al., 2010) Myokines are a type of cytokine which are produced and released from muscle fibres and further undergo autocrine, paracrine or endocrine effects on surrounding cells. (Peake et al., 2010) Myokines play a pivotal role in muscle communication, it is thought that a contracting skeletal muscle will release myokines, which work in a hormone-like fashion to exert varying endocrine effects on surrounding organs or which act locally via smaller autocrine or paracrine mechanisms. Below I have described the cytokines released from skeletal muscle as responses to different stimuli.
Around a decade ago it became clear that prolonged skeletal muscle contraction initiated the release of IL-6 from muscle fibres into the circulation (Pedersen and Febbraio, 2008). Further research has shown IL-6 to be a crucial player in cellular metabolism. Langberg et al. performed a study which showed that IL-6 is produced by the peritendonous tissue in active muscle during exercise. Keller et al. followed up this study to investigate which muscle cells produce the cytokine IL-6. The study isolated nuclei from muscle biopsies taken before, during and after exercise and used RT-PCR to demonstrate that the nuclear transcription rate for IL-6 increases rapidly during exercise. This finding suggested a factor associated with contraction increases the rate of IL-6 transcription, most probably from the nuclei of myokines as these were the isolated cells in this case, along with the previous observation that IL-6 is expressed within muscle fibre.(Pedersen and Febbraio, 2008) Analysis of the human Vastus Lateralis which is the largest part of the quadriceps Femoris, using immunohistochemical techniques and in situ hybridization provides further evidence that contracting muscle fibres are themselves a source of IL-6 mRNA (Pedersen and Febbraio, 2008). The main source of IL-6 in the circulation is the skeletal muscle although studies have revealed skeletal muscle is not the only source of IL-6 in the circulation (Hiscock et al., 2004)IL-6 signalling in macrophages seems to be dependent upon the activation of the NFÎºÎ² signalling pathway(Febbraio and Pedersen, 2002), which can lead to an inflammatory response, whereas muscle cells can produce IL-6 without activating pro inflammatory pathways due to the intramuscular IL-6 expression being regulated by an array of interacting signalling pathways, such as Ca2+/NF of activated T cells and Glycogen/P38 mitogen activated protein kinase pathway (Febbraio and Pedersen, 2002). The fact that IL-6 has two contradicting response pathways is not due to the type or speed of activation but more to do with the environment in which the activation takes place. As mentioned previously skeletal muscle cells release IL-6 upon contraction, however IL-6 is also released due to a variety of stimulating factors such as Reactive oxygen species present in the circulation, lipopolysaccharides and presence of inflammatory cytokines (Steinberg et al., 2009). Muscle cells are known as the dominant source of IL-6 production, IL-6 is produced in different types of muscle cells such as mature myoblasts(Pedersen, 2011), cultured myotubes(Pedersen, 2011), satellite cells and murine myofibres(De Rossi et al., 2000).
TNF-Î± is a cytokine whose catabolic activity in skeletal muscle may depend on the presence of other inflammatory cytokines such as IL-1, IL-6 and IFN-Î³. (Pedersen, 2011) TNF-Î± circulates through the body, responding to certain stimuli such as disease or injury and regulates metabolic tissue activity. A combination of IFN-Î³ and TNF-Î± is known to cause a down regulation of the muscular protein MyoD in muscle cells (Figarella-Branger et al., 2006). As well as this down regulation of muscular protein, TNF-Î± is the most potent stimulus contributing to muscle wastage and can inhibit lipoprotein lipase activity resulting in cachexia(147).
IL-10 is known as the human cytokine synthesis inhibitory factor. Although IL-10 has pro inflammatory effects, it has also been shown that co-treatment with IL-6 can have anti-inflammatory effects on the muscle fibres.(151)Il-10 has pleitropic effects with regard to inflammation. It has the ability to down regulate the expression of Th 1 cytokines, MHC class 2 antigens and co stimulatory molecules on macrophages and enhance Î² cell survival, proliferation and antibody production. IL-10 can block NF-ÐºB activity in the inflammatory pathway and reduces JaK-STAT signalling.
Rantes also known as CCL-5 is released by many cell types including skeletal muscle cells, this chemokine interacts with G Protein Coupled Receptors(GPCR) to regulate angiogenic processes.(153)The GPCR constitutes a large protein family of receptors that sense molecules outside of the cells and activate inside signal transduction pathways and cellular inflammatory responses.
CXCL-1 expression is induced upon exercise; this increased expression of CXCL-1 is coupled with increased muscle mRNA expression of VEGF and CD31 which suggests a role for CXCL-1 in muscle angiogenesis. (154) CXCL-1 as well ha having mitogenic properties can also decrease the severity of Multiple Sclerosis and may offer a neuro-protective function.
IFN-Î³ causes a dose dependant increase in proliferation of myoblasts in skeletal muscle of certain test subjects (155). IFN-Î³ is an important activator of macrophages; it is also secreted by T helper cells, cytotoxic T cells and NK cells. IFN-Î³ is important for cell self activation during the onset of infection. (156)
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)
Perspective of inflammation towards ageing
It is not unusual to see two to four fold increases in the levels of cytokines such as IL-6 and TNF-Î± in the circulation of an ageing individual (90). The increases in cytokine levels occurs naturally even in the absence of disease states, but due to an increase in the basal level of circulating cytokines and therefore a decrease in the immune function we may see an increase in the incidence of disease with age(91). It must be stressed that the increased low grade level of cytokines in the elderly is clearly a consequence of age related disease (92). There is a clear association with both increases in the production of reactive oxygen species and decreases in antioxidant capacity with age. Recent studies have suggested that Reactive Oxygen Species can activate receptors known as toll like receptors which are a specific class of proteins that are involved in the innate immune response. The activation of these receptors is essential to the control of the bodies' inflammatory response. Therefore we can see that we have a clear association between the increase In Reactive Oxygen Species and a decrease in the antioxidant capacity which favours the loss of muscle mass with age (93). Short term inflammation is crucial for the recovery of muscle cells from injury, it has been suggested that the low grade increase in inflammation we see with ageing may be caused by a larger immediate release of cytokines upon muscle damage and a longer recovery phase, which may again lead to an increase in the basal level of cytokines in the circulation.(95) This hypothesis may suggest that the elderly are capable of implementing an adequate immune response however the inflammatory components are not removed in the normal time frame that is expressed in the young and so the extended presence of cytokines in the circulation of the elderly cause further muscle damage(96). This extended recovery phase seen in the elderly may also be the cause of the increase in chronic low grade inflammation we associate with ageing (97). The stable low level of cytokines in the circulation may be present to enable the body to mount a greater response than normal towards infection to eradicate the damage there and then.
Previous studies have suggested that we see an increase in the cytokine levels with age, however more recently studies have shown that the levels of IL-6 and TGF-Î² which is a cytokine that can control cell proliferation and differentiation remain the same in young and old subjects. This study showed that the reason for the measured increase in cytokine levels was due to the increase of the IL-6 and TGF-Î² receptors in the mRNA with age not the cytokines themselves (97). The increase in TGF-Î² receptor may have a functional importance as TGF-Î² receptors inhibit the myogenic activity of satellite cells (105) which are muscle precursor cells. In addition to TGF-Î², IFN-Î³ regulates the growth and differentiation of muscle cells (106). There are drugs that target this increase with age. One pharmacological intervention is the use of medication such as Angiotensin Converting Enzymes and non-steroidal anti-inflammatory drugs among others which play a clinical role in reducing inflammation (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).
Perspective of inflammation towards critical illness
Critical illness in the muscle cells resulting in severe muscle weakness is strongly associated with inflammatory diseases such as sepsis. Critical illnesses can produce microorganism-associated toxins which can lead to severe muscle inflammation and injury. The incidence of muscular dysfunction due to critical illness is unknown although one study has suggested that skeletal muscle is commonly damaged as a consequence of severe sepsis (121). Muscle disease due to critical illness myopathy is characterized by the loss of the contractile proteins Myosin and Actin, muscle fibre atrophy and disorganization of the myofibrils which collectively results in loss of muscle mass(122). Muscle wasting in critical illness is said to be related to the activation of the protein Calpain, the Ub proteasome system and the autophagy lysosomal pathway(124). Skeletal muscle of critically ill patients shows expression of apoptotic myonuclei and pro apoptotic proteases, the presence of these cascade acting molecules may suggest fibre atrophy and myosin loss is due to an apoptotic cascade (125).
Cancer cachexia is associated with progressive weight loss and depletion of host reserves of adipose tissue and skeletal muscle which leads to muscle weakness and contributes to the weight loss associated with cancer patients (126). TNF-Î± or other host derived cytokines are signal molecules in cachexia and skeletal muscle wasting. These TNF signals seem to be produced through single nucleotide polymorphisms along with IL-1 and IL-6. These findings in turn suggest the immune system plays a key role in the unpredictable presentation of cancer cachexia (127). In cancer cachexia pro inflammatory cytokines such as TNF-Î± are synthesised and secreted, these pro inflammatory cytokines are known to help the cancer calls grow and survive through angiogenic and apoptotic signalling(128). The TNF-Î± cytokine stimulates muscle atrophy by expression of the E3-ligases, ATROGIN-1 and MURF-1 and a homolog of TNF-Î± known as TWEAK can also induce MURF-1 which helps to degrade myosin heavy chains resulting in loss of skeletal muscle mass. IL-6s role in regulating cancer cachexia has been shown to be positive, where patients with lung cancer who have shown symptoms of weight loss were given a monoclonal antibody IL-6 dose, upon treatment the patients reported reversal of the anorexia and fatigue although there was little change in lean body mass however this may be due to the passiveness of the patients due to the critical illness (129). Pain is associated with advanced cancers, the pain response is the release of glucocorticoids through the neuroendocrine stress response (130). The release of glucocorticoids can mediate the inflammatory response by suppressing the protein PGC-1Î² which usually leads to the expression of the MURF-2 and ATROGIN-1 E3 ligase atrophy markers (131). The suppression of the PGC-1Î² protein is seen in many skeletal muscle models and when over expressed the PGC-1Î± can prevent muscle fibre loss by inhibiting the FOXO-3 protein which is a likely trigger for apoptosis (132). Currently there is no treatment for critical illness myopathy although electrical muscle stimulation has been shown to reduce the incidence of the illness (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).
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