Lifespan analysis of dystrophic mdx fast-twitch muscle morphology and its impact on contractile function

Duchenne muscular dystrophy is caused by the absence of the protein dystrophin from skeletal muscle and is characterized by progressive cycles of necrosis/regeneration. Using the dystrophin deficient mdx mouse model we studied the morphological and contractile chronology of dystrophic skeletal muscle pathology in fast twitch EDL muscles from animals 4-22 months of age containing 100% regenerated muscle fibers. Catastrophically, the older age groups lost [~]80% of their maximum force after one eccentric contraction of 20% strain, with the greatest loss [~]93% recorded in senescent 22 month old mdx mice. In old age groups there was minimal force recovery [~]24% after 120 minutes, correlated with a dramatic increase in the number and complexity of branched fibers. This data supports our two-stage model where a "tipping point" is reached when branched fibers rupture irrevocably on eccentric contraction. These findings have important implications for pre-clinical drug studies and genetic rescue strategies.