Regulation of Muscle Mass by Follistatin and Activins
- 1 October 2010
- journal article
- other
- Published by The Endocrine Society in Molecular Endocrinology
- Vol. 24 (10), 1998-2008
- https://doi.org/10.1210/me.2010-0127
Abstract
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.Keywords
This publication has 65 references indexed in Scilit:
- Administration of a soluble activin type IIB receptor promotes skeletal muscle growth independent of fiber typeJournal of Applied Physiology, 2010
- Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube sizeAmerican Journal of Physiology-Cell Physiology, 2009
- Redundancy of myostatin and growth/differentiation factor 11 functionBMC Developmental Biology, 2009
- Inhibition of myostatin with emphasis on follistatin as a therapy for muscle diseaseMuscle & Nerve, 2009
- Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitorsProceedings of the National Academy of Sciences of the United States of America, 2008
- Lack of myostatin results in excessive muscle growth but impaired force generationProceedings of the National Academy of Sciences of the United States of America, 2007
- FSTL3 deletion reveals roles for TGF-β family ligands in glucose and fat homeostasis in adultsProceedings of the National Academy of Sciences of the United States of America, 2007
- A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheepNature Genetics, 2006
- A deletion in the bovine myostatin gene causes the double–muscled phenotype in cattleNature Genetics, 1997
- Functional analysis of activins during mammalian developmentNature, 1995