Activin IIB receptor blockade attenuates dystrophic pathology in a mouse model of Duchenne muscular dystrophy.
Modulation of transforming growth factor-β (TGF-β) signaling to promote muscle growth holds tremendous promise for the muscular dystrophies and other disorders involving the loss of functional muscle mass. Previous studies have focused on the TGF-β family member myostatin and demonstrated that inhibition of myostatin leads to muscle growth in normal and dystrophic mice. We describe a unique method of systemic inhibition of activin IIB receptor signaling via adeno-associated virus (AAV)-mediated gene transfer of a soluble form of the extracellular domain of the activin IIB receptor to the liver. Treatment of mdx mice with activin IIB receptor blockade led to increased skeletal muscle mass, increased force production in the extensor digitorum longus (EDL), and reduced serum creatine kinase. No effect on heart mass or function was observed. Our results indicate that activin IIB receptor blockade represents a novel and effective therapeutic strategy for the muscular dystrophies.
Morine
Kevin J
KJ
Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. km446@drexel.edu
Bish
Lawrence T
LT
Selsby
Joshua T
JT
Gazzara
Jeffery A
JA
Pendrak
Klara
K
Sleeper
Meg M
MM
Barton
Elisabeth R
ER
Lee
Se-Jin
SJ
Sweeney
H Lee
HL
D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors*; D000818:Animals; D015153:Blotting, Western; D003001:Cloning, Molecular; D003401:Creatine / Q000097:blood; D003402:Creatine Kinase / Q000097:blood; D000229:Dependovirus / Q000235:genetics; D004452:Echocardiography; D006334:Heart Function Tests; D051379:Mice; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000254:growth & development / Q000473:pathology* / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D055435:Myostatin / Q000502:physiology; D009929:Organ Size / Q000187:drug effects; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology
D055435:Myostatin; D016212:Transforming Growth Factor beta; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B; D003402:Creatine Kinase; D003401:Creatine