P2.55 Mstn/Dysf double knockout mice gain muscle mass but no strength

Abstract

Mutations in myostatin lead to a massive increase in muscle mass suggesting potential relevance of myostatin inhibition for therapeutic treatment of muscle wasting. Contradictory data in mdx and laminin a2 deficient mice have been published debating on the effect of myostatin inhibition in case of muscular dystrophies. Mutations in dysferlin cause limb girdle muscular dystrophy 2B due to defects in muscle membrane repair. We asked whether myostatin knock-out in a dysferlin deficient mouse model leads to improved muscle performance and a decrease in histopathological alterations. We crossed myostatin null mutant mice with the dysferlin deficient mouse model B6.A/J-Dysfprmd. Mstn −/−/ B6.A/J-Dysfprmd (DKO) were compared to Mstn−/−, B6.A/J-Dysfprmd and C57BL/6 mice (n = 8/group). Individual muscle mass was determined and body composition was performed. Treadmill performance was assessed for three weeks and grip strength was tested. We histologically analyzed Quadriceps and Tibialis muscle of untrained and trained mice at three months of age. Mstn−/− and DKO mice equally gained muscle mass but differed significantly in physiological muscle function. In treadmill analysis B6.A/J-Dysfprmd slowly worsened over time (weeks) compared to WT and Mstn−/− while DKO already showed a significantly reduced running distance and a higher rate of drop backs during the first training days. Grip strength was mostly reduced in DKO, but was also significantly diminished in B6.A/J-Dysfprmd and Mstn−/− compared to WT. The histological analysis reflects the impaired muscle function of B6.A/J-Dysfprmd and especially DKO mice with significantly increased numbers of central nucleated, necrotic and regenerating fibers. Like in Mstn−/− mice muscle fiber diameter was increased in DKO mice but showing additional atrophic fibers. These results indicate that permanent myostatin knock-out aggravates the course of disease in dysferlinopathy and that this is not a promising therapeutic option.