Skeletal muscle is usually a highly specialized tissue composed of non-dividing
Skeletal muscle is usually a highly specialized tissue composed of non-dividing multi-nucleated muscle fibres that contract to generate force in a controlled and directed manner. and such failures become increasingly prominent in cases of progressive muscle disease and in old age. Recent progress in the isolation of muscle satellite cells and elucidation of the cellular and molecular mediators controlling their activity indicate that these cells represent promising therapeutic targets. Such satellite cell-based therapies may involve either direct cell replacement or development of drugs that enhance endogenous Vatiquinone muscle repair mechanisms. Here we discuss recent breakthroughs in understanding both the cell intrinsic and extrinsic regulators that determine the formation and function of muscle satellite cells as well as promising paths forward to realizing their full therapeutic potential. ) flow cytometric quantification of the muscle stem cell pool indicated an approximately threefold decrease in the frequency of these cells in young animals when compared with age-matched wild-type controls . The underlying mechanisms responsible for these changes in the satellite cell pool in diseased muscle have yet to be fully elucidated but may relate to intrinsic alterations introduced by the proliferative stress associated with the necessity for repeated bouts of muscle regeneration in response to a chronic degenerative condition. Such repeated cycles of satellite cell activation may lead to telomere shortening  or accumulation of mutations in key satellite cell regulatory genes resulting in a loss of satellite cell self-renewal activity and impaired myogenic capacity. Consistent with this notion a recent report noted that the severity and progression of muscular dystrophy were substantially enhanced in mice with short telomeres owing to dysfunctional telomerase activity . This exacerbated dystrophic phenotype which was associated with impaired proliferation and deficient regenerative potential of satellite cells could be partially corrected by transplantation of unaffected satellite cells implying a cell-autonomous contribution of satellite cell dysfunction to muscle degenerative Rabbit Polyclonal to HNRNPUL2. disease . Yet in addition to intrinsic deficits disease-associated alterations in muscle satellite cell function also may reflect changes in the dystrophic environment which may act to suppress the myogenic activity of these cells. Several non-myogenic cell types normally found within the skeletal muscle have been suggested to contribute directly to failed muscle regeneration. For example fibroblasts in dystrophic patients have been shown to secrete increased levels of insulin-like growth factor (IGF)-1 binding proteins which may sequester IGF-1 away from myogenic cells . Likewise secreted factors including proliferation- and migration-inducing cytokines like the CXCR4 ligand SDF-1α are induced in injured and regenerating muscle and may help to regulate and topographically organize post-natal skeletal myogenesis [28 Vatiquinone 29 Together these observations suggest a critical role for the satellite cell microenvironment in modulating myogenic precursor cell activity a hypothesis that could Vatiquinone have important implications for muscle therapeutic strategies aimed at stimulating endogenous satellite cell activity as well as for enhancing muscle fibre engraftment in transplantation-based approaches (see below). In conclusion though often unaffected Vatiquinone by the primary genetic lesion that gives rise to muscular dystrophy disease-related effects on satellite cells may nonetheless contribute to progressive muscle degeneration. Reduced satellite cell numbers arising from chronic proliferative engagement coupled with a potentially suppressive microenvironment may hasten failure of muscle homeostasis in diseased or dystrophic tissue. 4 avenues: transplantation of muscle satellite cells supports muscle repair As noted above many different forms of degenerative muscle disease exist many of which are caused by an inherited deficiency or mutation of crucial muscle structural or regulatory proteins. DMD for example is an X-linked disease that results from the loss of expression of the protein dystrophin which normally serves to link the myofibre cytoskeleton to the extracellular matrix. DMD affects one in every approximately 3000 male births annually causes severe muscle wasting and weakness and.