Targeting the Activin Type IIB Receptor to Improve Muscle Mass and Function in the mdx Mouse Model of Duchenne Muscular Dystrophy

Abstract

The activin receptor type IIB (ActRIIB) is a transmembrane receptor for transforming growth factor-␤ 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.

Effects of muscular dystrophy, exercise and blocking activin receptor IIB ligands on the unfolded protein response and oxidative stress

“…Blockade of AcvR2B ligands can be achieved, e.g. by using the soluble ligand binding domain of type IIb activin receptor fused to the Fc domain (sAcvR2B-Fc) to effectively increase muscle size [18][19][20][21]. Blocking these proteins using various strategies has been shown to attenuate dystrophic pathology of the mdx mouse in some [18,22], but not in all studies [20,23].…”

Co-Administration of Myostatin-Targeting siRNA and ActRIIB-Fc Fusion Protein Increases Masseter Muscle Mass and Fiber Size

“…It is also reported that the potent cell surface receptor ActRIIB binds and inhibits myostatin, leading to dramatic muscle growth (24)(25)(26). Based on this background, we hypothesized that the combination of these two agents would have a therapeutic advantage.…”

“…Ligands, including myostatin and growth differentiation factor-11 (GDF-11), bind to the ActRIIB, leading to phosphorylation and nuclear translocation of Smad2/3, which mediates muscle atrophy (20). Interestingly, the soluble ligandbinding domain of ActRIIB fused to the Fc domain of IgG (ActRIIB-Fc) potently binds and inhibits TGF-␤ family members in muscle, leading to rapid and dramatic muscle growth both in vitro and in vivo (21)(22)(23)(24).…”

Genetic Therapy for Duchenne Muscular Dystrophy: Principles and Progress

“…Another study explored the possibility of inhibiting myostatin by using RNAi against ActRIIb and restore quasi dystrophin by AAV-U7 mediated exon skipping in a mouse model of muscular dystrophy (Dumonceaux et al, 2010). Recently in the same animal model the use of soluble ligands of ActRIIb as peptides, including the extracellular portion of the ActRIIb fused to the Fc portion of murine IgG (sActRIIb), has been shown to improve skeletal muscle mass and functional strength (Pistilli et al, 2011).…”