AAV-mediated delivery of a mutated myostatin propeptide ameliorates calpain 3 but not a-sarcoglycan deficiency

Myostatin is a negative regulator of muscle mass whose inhibition has been proposed as a therapeutic strategy for muscle-wasting conditions. Indeed, blocking myostatin action through different strategies has proved beneficial for the pathophysiology of the dystrophin-deficient mdx mouse. In this report, we tested the inhibition of myo- statin by AAV-mediated expression of a mutated pro- peptide in animal models of two limb-girdle muscular dystrophies: LGMD2A caused by mutations in the calpain 3 (CAPN3) gene and LGMD2D caused by mutations in the

a-sarcoglycan gene (SGCA). In the highly regenerative Sgca-null mice, survival of the a-sarcoglycan-deficient muscle fibers did not improve after transfer of the myo- statin propeptide. In calpain 3-deficient mice, a boost in muscle mass and an increase in absolute force were obtained, suggesting that myostatin inhibition could consti- tute a therapeutic strategy in this predominantly atrophic disorder.

AAV-mediated delivery of a mutated myostatin propeptide ameliorates calpain 3 but not a-sarcoglycan deficiency