Pretreatment with a soluble activin type IIB receptor/Fc fusion protein improves hypoxia-induced muscle dysfunction.
Hypoxia, or reduced oxygen, occurs in a variety of clinical and environmental situations. Hypoxic exposure is associated with decreased muscle mass and a concomitant reduction in exercise capacity, although the exact mechanisms are not completely understood. The activin type IIB receptor (ActRIIB) is a receptor for transforming growth factor-beta (TGFbeta) superfamily members that are involved in the negative regulation of lean tissue mass. Given that hypoxia has negative effects on muscle mass and function and that modulation of the ActRIIB has been shown to increase muscle mass, we tested the hypothesis that pharmacological targeting of the ActRIIB for 2 wk would attenuate the loss of muscle mass and function in mice after exposure to normobaric hypoxia. ActRIIB modulation was achieved using a soluble activin receptor/Fc fusion protein (sActRIIB) in mice housed in a hypoxic chamber for 1 or 2 wk. Hypoxia induced a reduction in body weight in PBS- and sActRIIB-treated mice, although sActRIIB-treated mice remained larger throughout the hypoxic exposure. The absolute forces generated by extensor digitorum longus muscles were also significantly greater in sActRIIB- than PBS-treated mice and were more resistant to eccentric contraction-induced force drop after eccentric lengthening contractions. In summary, sActRIIB pretreatment attenuated hypoxia-induced muscle dysfunction. These data suggest that targeting the ActRIIB is an effective strategy to counter hypoxia-induced muscle dysfunction and to preacclimatize to hypoxia in clinical or high-altitude settings.
Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Emidio E
EE
Pistilli
Sasha
S
Bogdanovich
Matias
M
Mosqueira
Jennifer
J
Lachey
Jasbir
J
Seehra
Tejvir S
TS
Khurana
D030301:Activin Receptors, Type II / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D030301:Activin Receptors, Type II; C425584:activin receptor type II-B