Abstract
Duchenne muscular dystrophy is an inherited disorder that is characterized by progressive skeletal muscle weakness and wasting, with a failure of muscle maintenance/repair mediated by satellite cells (muscle stem cells). The function of skeletal muscle stem cells resident in dystrophic muscle may be perturbed by being in an increasing pathogenic environment, coupled with constant demands for repairing muscle. To investigate the contribution of satellite cell exhaustion to this process, we tested the functionality of satellite cells isolated from the mdx mouse model of Duchenne muscular dystrophy. We found that satellite cells derived from young mdx mice contributed efficiently to muscle regeneration within our in vivo mouse model. To then test the effects of long-term residence in a dystrophic environment, satellite cells were isolated from aged mdx muscle. Surprisingly, they were as functional as those derived from young or aged wild type donors. Removing satellite cells from a dystrophic milieu reveals that their regenerative capacity remains both intact and similar to satellite cells derived from healthy muscle, indicating that the host environment is critical for controlling satellite cell function.
Highlights
Skeletal muscle maintenance, repair, and regeneration are mediated by skeletal muscle stem cells
Duchenne muscular dystrophy (DMD) is a chronic and debilitating genetic disorder in which muscle regeneration fails to compensate for the loss of muscle tissue (Emery, 2002)
It has been suggested that inadequate muscle regeneration in muscular dystrophies may be due to loss of satellite cells, which after many rounds of muscle degeneration and regeneration, become ‘exhausted’ (Morgan and Zammit, 2010)
Summary
Repair, and regeneration are mediated by skeletal muscle stem cells. The lack of dystrophin in DMD will have only an indirect effect on satellite cell function, as it leads to chronic fiber necrosis and consequent activation, proliferation and differentiation of nearby satellite cells in an increasing hostile dystrophic microenvironment (Morgan and Zammit 2010). In DMD, satellite cell function may be indirectly affected, through constant recruitment to muscle repair and regeneration and so their regenerative capacity may become exhausted by the progression of the dystrophy with time This may synergise with the increasing hostile microenvironment of the dystrophic muscle to prevent effective repair (Morgan and Zammit 2010). We isolated satellite cells from aged mdx mice to test their capacity to regenerate muscle after long-term residence in a dystrophic environment and found that they too were able to regenerate muscle as efficiently as satellite cells derived from young or aged wild type donors. Our data imply that the impaired muscle regeneration observed in this model of DMD arises mainly from the pathological environment, rather than from endogenous defects in the regenerative capacity of satellite cells
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