Pediatric and adult muscular dystrophies share a common characteristic of progressive weakness and wasting. Therapies aiming to increase muscle growth would not cure the underlying pathophysiology of these disorders but potentially improve function. IGF-1 is a potent inducer of muscle growth and myostatin is a specific inhibitor of muscle growth. Stimulating IGF-1 and inhibiting myostatin pathways induces muscle growth and regeneration and improves several features of the mdx mouse model of muscular dystrophy. The goal of this revised project is to evaluate the potential synergistic actions of these modulators of muscle growth and to evaluate the potential convergence of these signaling pathways.
The specific aims are: 1) To determine if there are additive effects on muscle growth in mice genetically lacking myostatin and also constitutively overexpressing IGF-1. 2) To determine if the mdx mouse has a milder muscular dystrophy in the absence of myostatin and the constitutive overexpression of IGF-1 than with either modification alone. 3) To determine if postnatal IGF-1 stimulation and postnatal myostatin inhibition have additive effects in normal and utr/mdx mice and 4) To evaluate the potential convergence of IGF-1 and myostatin signaling pathways through Akt. The results from these experiments will provide important preclinical data on whether these strategies of enhancing muscle growth and regeneration can be successfully used in combination for the treatment of muscular dystrophies. Lay summary: Muscle size and strength are influenced by growth factors including myostatin which inhibits muscle growth and IGF-1 which stimulated muscle growth. Recently, clinical trials began in muscular dystrophy patients with study drugs that affect the action of these growth factors. This project will provide preclinical data on the potential benefits or toxicity of regulating both myostatin and IGF-1 simultaneously.
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