Smad2 and 3 transcription factors control muscle mass in adulthood

Am J Physiol Cell Physiol. 2009 Jun;296(6):C1248-57. doi: 10.1152/ajpcell.00104.2009. Epub 2009 Apr 8.

Abstract

Loss of muscle mass occurs in a variety of diseases, including cancer, chronic heart failure, aquired immunodeficiency syndrome, diabetes, and renal failure, often aggravating pathological progression. Preventing muscle wasting by promoting muscle growth has been proposed as a possible therapeutic approach. Myostatin is an important negative modulator of muscle growth during myogenesis, and myostatin inhibitors are attractive drug targets. However, the role of the myostatin pathway in adulthood and the transcription factors involved in the signaling are unclear. Moreover, recent results confirm that other transforming growth factor-beta (TGF-beta) members control muscle mass. Using genetic tools, we perturbed this pathway in adult myofibers, in vivo, to characterize the downstream targets and their ability to control muscle mass. Smad2 and Smad3 are the transcription factors downstream of myostatin/TGF-beta and induce an atrophy program that is muscle RING-finger protein 1 (MuRF1) independent. Furthermore, Smad2/3 inhibition promotes muscle hypertrophy independent of satellite cells but partially dependent of mammalian target of rapamycin (mTOR) signaling. Thus myostatin and Akt pathways cross-talk at different levels. These findings point to myostatin inhibitors as good drugs to promote muscle growth during rehabilitation, especially when they are combined with IGF-1-Akt activators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Carrier Proteins / metabolism
  • Cell Differentiation
  • Cells, Cultured
  • Disease Models, Animal
  • Hypertrophy
  • Male
  • Mice
  • Mice, Transgenic
  • Muscle Denervation
  • Muscle Development*
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / innervation
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology
  • Muscular Atrophy / metabolism*
  • Muscular Atrophy / pathology
  • Muscular Atrophy / physiopathology
  • Muscular Atrophy / prevention & control
  • Mutation
  • Myostatin / metabolism
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Sciatic Nerve / surgery
  • Signal Transduction*
  • Smad2 Protein / metabolism*
  • Smad3 Protein / metabolism*
  • TOR Serine-Threonine Kinases
  • Transfection
  • Transforming Growth Factor beta / metabolism
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Carrier Proteins
  • Mstn protein, mouse
  • Muscle Proteins
  • Myostatin
  • RNA, Small Interfering
  • Receptors, Transforming Growth Factor beta
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta
  • Tripartite Motif Proteins
  • Trim63 protein, mouse
  • Ubiquitin-Protein Ligases
  • Phosphotransferases (Alcohol Group Acceptor)
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II