BMP signaling controls muscle mass.
Cell size is determined by the balance between protein synthesis and degradation. This equilibrium is affected by hormones, nutrients, energy levels, mechanical stress and cytokines. Mutations that inactivate myostatin lead to excessive muscle growth in animals and humans, but the signals and pathways responsible for this hypertrophy remain largely unknown. Here we show that bone morphogenetic protein (BMP) signaling, acting through Smad1, Smad5 and Smad8 (Smad1/5/8), is the fundamental hypertrophic signal in mice. Inhibition of BMP signaling causes muscle atrophy, abolishes the hypertrophic phenotype of myostatin-deficient mice and strongly exacerbates the effects of denervation and fasting. BMP-Smad1/5/8 signaling negatively regulates a gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1). Collectively, these data identify a critical role for the BMP pathway in adult muscle maintenance, growth and atrophy.
1] Dulbecco Telethon Institute at the Venetian Institute of Molecular Medicine, Padova, Italy. [2] Department of Biomedical Sciences, University of Padova, Padova, Italy. [3].
Roberta
R
Sartori
Elija
E
Schirwis
Bert
B
Blaauw
Sergia
S
Bortolanza
Jinghui
J
Zhao
Elena
E
Enzo
Amalia
A
Stantzou
Etienne
E
Mouisel
Luana
L
Toniolo
Arnaud
A
Ferry
Sigmar
S
Stricker
Alfred L
AL
Goldberg
Sirio
S
Dupont
Stefano
S
Piccolo
Helge
H
Amthor
Marco
M
Sandri
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000235:genetics*; D055435:Myostatin / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism; D051904:Smad8 Protein / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; C525912:Mstn protein, mouse; D055435:Myostatin; D034741:RNA, Small Interfering; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D051904:Smad8 Protein; C491621:Smad9 protein, mouse; D044767:Ubiquitin-Protein Ligases