Abstract
Cell size is determined by the balance between protein synthesis and degradation. This equilibrium is affected by hormones, nutrients, energy levels, mechanical stress and cytokines. Mutations that inactivate Myostatin lead to increased muscle growth in animals and humans. However, the signals and pathways responsible for this hypertrophy remain largely unknown. Here we find that signaling by Bone morphogenetic proteins (BMP), acting through Smad1/5/8, is the fundamental hypertrophic signal and dominates Myostatin signaling. Inhibition of BMP signaling causes muscle atrophy, abolishes the hypertrophic phenotype of Myostatin knockout and strongly exacerbates the effects of denervation and fasting. BMP-Smad1/5/8 negatively regulates a novel gene (Fbxo30) that encodes an ubiquitin ligase, which we named Muscle Ubiquitin-ligase of SCF complex in Atrophy-1 (MUSA1), that is required for muscle loss. Collectively, these data identify a critical role for the BMP pathway in adult muscle maintenance, and uncover the regulation of BMP signaling as the rate-limiting step of muscle growth and atrophy.
Published Version
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