Estrogen Receptor-β Prevents Cardiac Fibrosis

摘要

Elisabeth R. Barton Myostatin is a TGF-B 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 re- duced amount of muscle tissue, consistent with a role for fol- listatin in regulating myogenesis. Here, we show that Fst mutant mice exhibit haploinsufficiency, with muscles of Fst heterozy- gotes having significantly reduced size, a shift toward more ox- idative fiber types, an impairment of muscle remodeling in re- sponse 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 nor- mally acts to inhibit other TGF-B 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 im- plications with respect to the development of therapeutics tar- geting this signaling pathway to preserve muscle mass and pre- vent muscle atrophy in a variety of inherited and acquired forms of muscle degeneration.