Gene expression profiling on innervated and denervated muscles of Smad4 KO and control mice.

To identify novel atrophy-related genes, which are controlled by BMP signaling, we performed gene expression profiling on innervated and 14 days denervated muscles of Smad4 knockout and control mice, focusing on genes that were differentially upregulated in denervated Smad4-/- muscles compared to controls. Among the different genes our attention was attracted by a gene that encodes for a novel f-box protein (Fbxo30) belonging to the SCF complex family of the ubiquitin ligases. 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 important muscle growth in animals and humans. However, the signals and pathways responsible for this hypertrophy remain largely unknown. Here we find that BMP signaling, acting through Smad1/5/8, is the fundamental hypertrophic signal. 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, that is required for muscle loss. Collectively, these data identify a critical role for the BMP pathway in adult muscle maintenance, growth and atrophy.