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Regulation of muscle mass by follistatin and activins.

Myostatin is a TGF-β family member that normally acts to limit skeletal muscle mass. Follistatin is a myostatin-binding protein that can inhibit myostatin activity in vitro and promote muscle growth in vivo. Mice homozygous for a mutation in the Fst gene have been shown to die immediately after birth but have a reduced amount of muscle tissue, consistent with a role for follistatin in regulating myogenesis. Here, we show that Fst mutant mice exhibit haploinsufficiency, with muscles of Fst heterozygotes having significantly reduced size, a shift toward more oxidative fiber types, an impairment of muscle remodeling in response to cardiotoxin-induced injury, and a reduction in tetanic force production yet a maintenance of specific force. We show that the effect of heterozygous loss of Fst is at least partially retained in a Mstn-null background, implying that follistatin normally acts to inhibit other TGF-β family members in addition to myostatin to regulate muscle size. Finally, we present genetic evidence suggesting that activin A may be one of the ligands that is regulated by follistatin and that functions with myostatin to limit muscle mass. These findings potentially have important implications with respect to the development of therapeutics targeting this signaling pathway to preserve muscle mass and prevent muscle atrophy in a variety of inherited and acquired forms of muscle degeneration.

Pubmed ID: 20810712

Authors

  • Lee SJ
  • Lee YS
  • Zimmers TA
  • Soleimani A
  • Matzuk MM
  • Tsuchida K
  • Cohn RD
  • Barton ER

Journal

Molecular endocrinology (Baltimore, Md.)

Publication Data

October 29, 2010

Associated Grants

  • Agency: NIH HHS, Id: DP2OD004515
  • Agency: NINDS NIH HHS, Id: K08NS055879
  • Agency: NIA NIH HHS, Id: R01 AG037193
  • Agency: NIAMS NIH HHS, Id: R01 AR059685
  • Agency: NIAMS NIH HHS, Id: R01 AR060636
  • Agency: NCI NIH HHS, Id: R01 CA122596
  • Agency: NIGMS NIH HHS, Id: R01 GM092758
  • Agency: NICHD NIH HHS, Id: R01 HD032067
  • Agency: NIAMS NIH HHS, Id: R01AR059685
  • Agency: NIAMS NIH HHS, Id: R01AR060636
  • Agency: NICHD NIH HHS, Id: R01HD32067
  • Agency: NIAMS NIH HHS, Id: U54 AR052646
  • Agency: NIAMS NIH HHS, Id: U54AR052646

Mesh Terms

  • Activins
  • Animals
  • Follistatin
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Contraction
  • Muscle Development
  • Muscle, Skeletal
  • Myostatin
  • Organ Size