BMP signaling controls muscle mass

Nat Genet. 2013 Nov;45(11):1309-18. doi: 10.1038/ng.2772. Epub 2013 Sep 29.

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 excessive muscle growth in animals and humans, but the signals and pathways responsible for this hypertrophy remain largely unknown. Here we show that bone morphogenetic protein (BMP) signaling, acting through Smad1, Smad5 and Smad8 (Smad1/5/8), is the fundamental hypertrophic signal in mice. Inhibition of BMP signaling causes muscle atrophy, abolishes the hypertrophic phenotype of myostatin-deficient mice and strongly exacerbates the effects of denervation and fasting. BMP-Smad1/5/8 signaling negatively regulates a gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1). Collectively, these data identify a critical role for the BMP pathway in adult muscle maintenance, growth and atrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / metabolism*
  • Cell Line
  • Enzyme Activation
  • Gene Expression Profiling
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Skeletal / metabolism*
  • Muscular Atrophy / genetics*
  • Myostatin / genetics
  • RNA Interference
  • RNA, Small Interfering
  • Signal Transduction
  • Smad1 Protein / genetics
  • Smad1 Protein / metabolism
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism*
  • Smad5 Protein / genetics
  • Smad5 Protein / metabolism
  • Smad8 Protein / genetics
  • Smad8 Protein / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Bone Morphogenetic Proteins
  • Mstn protein, mouse
  • Myostatin
  • RNA, Small Interfering
  • Smad1 Protein
  • Smad1 protein, mouse
  • Smad4 Protein
  • Smad4 protein, mouse
  • Smad5 Protein
  • Smad5 protein, mouse
  • Smad8 Protein
  • Smad9 protein, mouse
  • Ubiquitin-Protein Ligases

Associated data

  • GEO/GSE49826