The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass

Winbanks, CE; Watt, KI; Connor, T; Qian, H; McGee, SL; Larsson, L; Gregorevic, P; Liu, Y; Bernardo, BC; Chen, JL; Beyer, C; Harrison, CA; Turner, BJ; Thomson, RE; McMullen, JR
Abstract
Although the canonical transforming growth factor β signaling pathway represses skeletal muscle growth and promotes muscle wasting, a role in muscle for the parallel bone morphogenetic protein (BMP) signaling pathway has not been defined. We report, for the first time, that the BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling. In agreement, we observed that BMP signaling is augmented in models of muscle growth. Importantly, stimulation of BMP signaling is essential for conservation of muscle mass after disruption of the neuromuscular junction. Inhibiting the phosphorylation of Smad1/5 exacerbated denervation-induced muscle atrophy via an HDAC4-myogenin-dependent process, whereas increased BMP-Smad1/5 activity protected muscles from denervation-induced wasting. Our studies highlight a novel role for the BMP signaling pathway in promoting muscle growth and inhibiting muscle wasting, which may have significant implications for the development of therapeutics for neuromuscular disorders.
Journal J CELL BIOL
ISSN 0021-9525
Published 28 Oct 2013
Volume 203
Issue 2
Pages 345-57
DOI 10.1083/jcb.201211134
Type Journal Article
Sponsorship
NHMRC: 526648, 1008910, 1006488, 1046782, 1013533, 1030474; ARC: FT0001657