Myofibres are basic units of skeletal muscles. They are formed of large multinucleate muscle stem cells (MuSC). There are two kinds of myofibres, fast and slow contracting. The determination of different kinds depend upon the myosin heavy chains isoforms they express.MyHC content within an individual differs because myosin are encoded by different nuclei and maintained in nuclear domain.
New muscle fibres are produced after existing ones are injured or are suffering from a disease. 'Satellite Cells' and myogenic progenitors which are present in basal lamina and muscle fibre membrane help in regeneration. The first satellite cell was determined in 1961 in the tibialis anticus muscle of the frog. They have their own membrane enclosed compartment and have more nucleus than cytoplasm. The molecular markers that are present in satellite cells are Pax7, Pax3, Myf5, M- cadherin and caveloin-1. Whenever a muscle is injured the satellite cells differentiate into myoblasts. There are several pathways which trigger the activation of satellite cells. There are several factors involved namely HGH, IGF, FGF and TGF beta family.
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ROLE OF HGF: - After injury during regeneration HGF (hepatocyte growth factors) and protein levels are increased. When c- met an HGF receptor is expressed on C2C12 cells there is a generation of muscle precursor cells .It also activates the Ras Ral pathway which in turn send the satellite cells to the site of injury.
ROLE OF FGF: - Fibroblasts growth factors (FGF) are large family of polypeptides growth factors. During muscle regeneration FGF6 expression is unregulated FGFR1 and FGFR4 are selectively expressed but when one of them is absent then muscle development is affected. For the growth of satellite cells FGFR4 is helpful while FGFR1 helps in maintaining the myoblasts which have already been formed.
ROLE OF TGF BETA FAMILY: - They are important cytokines which regulate the cell activity. Depending upon which state the satellite cells are in, the target genes are activated when TGF beta activates the phosphorylation of SMAD proteins which in turn is transferred into the nucleus. The TGF beta family has 3 members TGF beta1, TGFbeta2 and TGFbeta3.Recently a new member of the TGF beta family has been discovered which is called the myostatin (MSTN) or growth and differentiation factor 8 (GDF8). Though the functioning of MSTN is still unclear, few studies suggest that MSTN signalling can be achieved by binding of MSTN receptors to activin type 2. But a few experiments also show that when MSTN levels are high it inhibits the proliferation of C2C12 via cyclin cdk2 inactivation of retinoblastoma protein. Few studies also suggest that MSTN is mostly expressed in fast contracting muscles which contain low number of satellite cells rather than muscle mass. Thus taken together all the studies suggest that MSTN regulates myogenin by acting as an inhibitor to the satellite cell proliferation.
Yajima et al also suggest the presence of 'SIX' family genes which control the growth of muscle satellite cells. They consist of six members. During myogensis SIX1 and SIX4 are expressed in myoblasts and play important roles, removal of SIX1 and SIX4 genes lead to muscle hypoplasia. In an experiment when skeletal muscle was injured by cardio toxin SIX1 and SIX 4 positive cells were shown to be regenerating muscle. The quiescent muscle cells which have Pax7 and M - cadherin as molecular markers on them also possess SIX1 and Six4 genes. One of the interesting findings of this study is the growth of muscle satellite cells is negatively regulated when the amount of SIX proteins are above the normal level. But the presence of SIX5 protein acts as a cardinal repressor in the growth of activated satellite cells.
There are various model systems which have studied to gather information about the role of stem cells in muscle regeneration. The non mammalian models which have studied are mostly 'Jelly Fish Muscle' model and the 'Amphibian Limb regeneration' model. The most commonly used animal models are chick and mouse model systems. Figec et al describes the embryonic origin of satellite cells using chick and mouse models systems .In chick the muscle progenitors and most of the satellite cells are derived from the dermomytome. In mouse cells marked by Pax3 and Pax7 are formed in early myotome. They are maintained as growing population of cells and form the resident muscle progenitor cells. An emerging model to study muscle stem cells is 'Drosophila melanogaster'. In Drosophila the muscle stem cells are called adult muscle precursor cells (AMP) which have 'Twi' expression on them and can be easily identified. The mesoderm gives rise to the larval muscles which expresses the helix loop helix transcription factor (Twi factor). The body wall muscles arise from the mesodermal cells which have high levels of 'Twi'. At the end of larval life the AMP's grow and give rise to the adult fly musculature.
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Nicholas et al recently found and suggested that absence of CD34 on skeletal muscle satellite cells marks a reversible state of activation during injury.[ ].CD34 is found as a receptor on satellite cells of skeletal muscles . After injury CD34+ cells are activated to maintain a reserve during the course of regeneration , but the absence of Cd34 also shows a state of activation which is reversible .Cd34+/- equally take part in myogensis but CD34- cells show lower expression of Pax7, Pax3, Myf5, MyoD and c-met. Although the actual function of CD 34 is still unclear, it is a highly glycosylated siaolmucin receptor which plays a role in signalling, cellular adhesion and repulsion.
Filippin et al reviewed the role nitric oxide and repair of skeletal muscle injury. [ ].Skeletal muscle undergoes a lot of injuries such as crush, cuts, bruises, freezing etc. These have profound effects on the normal functioning of the muscle. The repair of muscle takes place in three stages 1) degeneration and inflammation 2) regeneration of the muscle 3) fibrosis. After an injury the myogenic satellite cells are activated. They proliferate and differentiate and repair the damaged muscle fibres. Nitric oxide (NO) , metalloproteinase (MMP) and hepatocyte growth factor (HGF) play an important role in the repair of skeletal muscle. During the release HGF from the extracellular matrix NO's role in it can be determined by administering l- NAME (an inhibitor of NO) before stretch treatment. In vivo the activation of satellite cells were prevented by l- NAME. This indicates that when muscle fibres are stretched it liberates HGF in an NO dependent manner. The release of No dependent HGF matrix is mediated by MMP which is a large family of zinc dependent endopeptidases and degrade several extracellular matrix proteins.??
Chen et al has also proposed that that the growth of skeletal muscle satellite cells and myogenic progenitors cells are repressed by micro RNA1 and micro RNA206.During satellite cell differentiation micro RNA1 and micro RNA 206 are up regulated while during skeletal muscle regeneration they are down regulated . Over expression of micro RNA1 and micro RNA 206 prohibits the growth of potential satellite cells. They showed that Pax7 was one of the regulatory targets of micro RNA 1 and micro RNA206 during satellite cells proliferation and differentiation. During the progression from cell proliferation to differentiation the micro RNA play an important role by limiting Pax7 expression. All satellite cells express Pax7 and it initially activates Myf5 and MyoD for the satellite cells to differentiate and become myogenic progenitor cells. The activated MyoD in satellite cells up regulates micro RNA1 and micro RNA206 which in turn repress Pax7 post transcriptionally. Thus the repression of Pax7 protein levels is one of the mechanisms by micro RNA's regulate satellite cell activity.
Urish et al suggested that antioxidant levels represent a major determinant in the regenerative capacity of muscle stem cells. [ ].Muscle derived stem cells (MDSC) during regeneration show a high resistance to oxidative stress. When muscle derive stem cells were exposed to hydrogen peroxide and TNF alpha they showed a greater rate of differentiation than the myoblasts. This shows that the muscle derived stem cells have a better ability to cope with oxidative stress. When myogenic cells are introduced to TNF alpha or IL 1 their differentiation is inhibited by activation of nuclear factor kappa B pathway. But the inhibition causes the muscle progenitor cells to repair the damaged muscle fibres. This proves that the muscle derived stem cells can differentiate even if they are exposed to oxidative stress by modifying nuclear factor kappa B pathway activation.