title: The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass.
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.
authors.affiliation: Division of Cell Signaling and Metabolism, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Winbanks
authors.forename: Justin L
authors.initials: JL
authors.lastname: Chen
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qian
authors.forename: Yingying
authors.initials: Y
authors.lastname: Liu
authors.forename: Bianca C
authors.initials: BC
authors.lastname: Bernardo
authors.forename: Claudia
authors.initials: C
authors.lastname: Beyer
authors.forename: Kevin I
authors.initials: KI
authors.lastname: Watt
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Thomson
authors.forename: Timothy
authors.initials: T
authors.lastname: Connor
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Turner
authors.forename: Julie R
authors.initials: JR
authors.lastname: McMullen
authors.forename: Lars
authors.initials: L
authors.lastname: Larsson
authors.forename: Sean L
authors.initials: SL
authors.lastname: McGee
authors.forename: Craig A
authors.initials: CA
authors.lastname: Harrison
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
mesh_terms: D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D000229:Dependovirus; D004195:Disease Models, Animal; D005260:Female; D038681:Follistatin / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006984:Hypertrophy; D051379:Mice; D008810:Mice, Inbred C57BL; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000254:growth & development / Q000294:innervation / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018008:Myogenin / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014161:Transduction, Genetic; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D055419:Bone Morphogenetic Protein 7; D038681:Follistatin; C503801:Myog protein, mouse; D018008:Myogenin; D051785:Smad Proteins; D044767:Ubiquitin-Protein Ligases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D052005:Bone Morphogenetic Protein Receptors, Type I; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases