SB431542 treatment promotes the hypertrophy of skeletal muscle fibers but decreases specific force.
The small molecule inhibitor SB431542 inhibits activin type I receptors. The muscle growth-inhibitor myostatin binds to and signals via these receptors. The aim of this study was to test the hypothesis that SB431542 can inhibit myostatin-related Smad signaling and induce muscle growth in cultured C2C12 myotubes and increase growth and specific force in cultured Xenopus muscle fibers. The effect of SB431542 was assessed in vitro on C2C12 myotubes and ex vivo using mature Xenopus muscle fibers. SB431542 treatment reduced myostatin-induced C-terminal Smad2 phosphorylation and resulted in the formation of enlarged myotubes. However myogenin expression was unchanged, while p70 S6k phosphorylation at Thr389, total myosin heavy chain, and the rate of protein synthesis were all reduced. Mature Xenopus muscle fibers that were treated with SB431542 had a higher fiber cross-sectional area but decreased specific force production than control. SB431542 can initially antagonize myostatin signaling, but long-term unexpected signaling effects occur. Muscle fibers hypertrophy, but their specific force decreases compared to control.
Institute of Medical Sciences, School of Medicine and Dentistry, University of Aberdeen, Foresterhill, Aberdeen AB252ZD, Scotland, United Kingdom. r01kiw6@abdn.ac.uk
Kevin I
KI
Watt
Richard T
RT
Jaspers
Phillip
P
Atherton
Ken
K
Smith
Michael J
MJ
Rennie
Aivaras
A
Ratkevicius
Henning
H
Wackerhage
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002460:Cell Line; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D004149:Dioxoles / Q000494:pharmacology*; D006984:Hypertrophy / Q000139:chemically induced* / Q000378:metabolism; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053580:Muscle Strength / Q000187:drug effects* / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000187:drug effects / Q000378:metabolism; D055435:Myostatin / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051899:Smad2 Protein / Q000378:metabolism; D014982:Xenopus laevis
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D055435:Myostatin; D051899:Smad2 Protein; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D018995:Myosin Heavy Chains