TY - JOUR
T1 - Targeting the activin type IIB receptor to improve muscle mass and function in the mdx mouse model of Duchenne muscular dystrophy
AU - Pistilli, Emidio E.
AU - Bogdanovich, Sasha
AU - Goncalves, Marcus D.
AU - Ahima, Rexford S.
AU - Lachey, Jennifer
AU - Seehra, Jasbir
AU - Khurana, Tejvir S.
N1 - Funding Information:
Supported by a research grant from the World Anti-Doping Agency (WADA) (T.K.) and a National Institutes of Health Training Grant in Muscle Biology ( AR053461 to E.E.P.) through the Pennsylvania Muscle Institute.
PY - 2011/3
Y1 - 2011/3
N2 - The activin receptor type IIB (ActRIIB) is a transmembrane receptor for transforming growth factor-β superfamily members, including myostatin, that are involved in the negative regulation of skeletal muscle mass. We tested the translational hypothesis that blocking ligand binding to ActRIIB for 12 weeks would stimulate skeletal muscle growth and improve muscle function in the mdx mouse. ActRIIB was targeted using a novel inhibitor comprised of the extracellular portion of the ActRIIB fused to the Fc portion of murine IgG (sActRIIB), at concentrations of 1.0 and 10.0 mg/kg-1 body weight. After 12 weeks of treatment, the 10.0 mg/kg-1 dose caused a 27% increase in body weight with a concomitant 33% increase in lean muscle mass. Absolute force production of the extensor digitorum longus muscle ex vivo was higher in mice after treatment with either dose of sActRIIB, and the specific force was significantly higher after the lower dose (1.0 mg/kg-1), indicating functional improvement in the muscle. Circulating creatine kinase levels were significantly lower in mice treated with sActRIIB, compared with control mice. These data show that targeting the ActRIIB improves skeletal muscle mass and functional strength in the mdx mouse model of DMD, providing a therapeutic rationale for use of this molecule in treating skeletal myopathies.
AB - The activin receptor type IIB (ActRIIB) is a transmembrane receptor for transforming growth factor-β superfamily members, including myostatin, that are involved in the negative regulation of skeletal muscle mass. We tested the translational hypothesis that blocking ligand binding to ActRIIB for 12 weeks would stimulate skeletal muscle growth and improve muscle function in the mdx mouse. ActRIIB was targeted using a novel inhibitor comprised of the extracellular portion of the ActRIIB fused to the Fc portion of murine IgG (sActRIIB), at concentrations of 1.0 and 10.0 mg/kg-1 body weight. After 12 weeks of treatment, the 10.0 mg/kg-1 dose caused a 27% increase in body weight with a concomitant 33% increase in lean muscle mass. Absolute force production of the extensor digitorum longus muscle ex vivo was higher in mice after treatment with either dose of sActRIIB, and the specific force was significantly higher after the lower dose (1.0 mg/kg-1), indicating functional improvement in the muscle. Circulating creatine kinase levels were significantly lower in mice treated with sActRIIB, compared with control mice. These data show that targeting the ActRIIB improves skeletal muscle mass and functional strength in the mdx mouse model of DMD, providing a therapeutic rationale for use of this molecule in treating skeletal myopathies.
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U2 - 10.1016/j.ajpath.2010.11.071
DO - 10.1016/j.ajpath.2010.11.071
M3 - Article
C2 - 21356379
AN - SCOPUS:79952764909
SN - 0002-9440
VL - 178
SP - 1287
EP - 1297
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -