Does the Pathogenic Sequence of Skeletal Muscle Degeneration in Duchenne Muscular Dystrophy Begin and End with Unrestrained Satellite Cell Activation?

Abstract

A recent study describing unique effects of myostatin inhibition on a severely dystrophic (mdx) muscle, and independent experiments showing that branched fibers are uniquely sensitive to activity-induced membrane rupture, have led to a new hypothesis of dystrophic pathogenesis. This hypothesis states that the absence of dystrophin directly results in some degree of unrestrained satellite cell activation that is not dependent upon prior fiber injury. The hypothesis further states that dystrophin promotes satellite cell quiescence, and that its absence directly results in a lack of control over the mechanism(s) by which muscle activity regulates satellite cell activation and fiber growth during passive stretch and concentric and eccentric exercise. The ultimate consequence of this lack of control is to produce branched, weak, and fragile fibers that accumulate at a rate dependent upon the history of activation for each dystrophic muscle. The purpose of this opinion paper is to summarize the results in support of this new hypothesis in an attempt to stimulate further research on the regulation of satellite cell activity in dystrophic muscle.