Short‐ and long‐term effects of ActRIIB receptor ligand trapping agents on muscle mass and downstream signaling in dystrophic (mdx) limb and respiratory musculature (1102.44)

Abstract

These studies examined the translational efficacy and the signaling consequences of in vivo treatment with two soluble ActRIIB receptor ligand trapping agents (Acceleron Pharma) in the mdx mouse model for Duchenne muscular dystrophy. A one month treatment of 30 day old mdx mice with RAP‐031 (10 mg/kg; subcutaneously, twice weekly) produced significant (p<0.05) increases in the body mass of both male (14% increase) and female (22% increase) mice. These increases were associated with proportionately larger increases in limb musculature (gastrocnemius; 30%) than in respiratory musculature (costal diaphragm; 12%). Longer periods of treatment (3 months) with RAP‐435 induced 30% increases in body mass and again produced larger proportional increases in the mass of the gastrocnemius (about 90%) than the costal diaphragm (about 43%). The 1 month RAP‐031 treatment produced relatively moderate increases in fiber density and diameter in the severely dystrophic mdx triangularis sterni (TS) muscle. However, the 3 month treatment with RAP‐435 substantially increased TS muscle mass by producing large increases in both fiber density and fiber diameter. Collagen expression and crosslinking in the mdx costal diaphragm was not influenced by treatment with RAP‐031 for periods of 1 or 3 months. The total expression of smads 2 and 3 were unaffected by RAP‐031 treatment. RAP‐031 treatment increased the expression of Smad 4 in the gastrocnemius but not in the costal diaphragm. The expression of Akt was unaffected by RAP‐031 treatment in either muscle preparation, while the proportion of phosphorylated Akt was slightly increased by RAP‐031 treatment in the gastrocnemius. These results further demonstrate the efficacy of the ActRIIB receptor ligand trapping agents in increasing dystrophic muscle mass, and suggest that muscle‐specific differences in TGF‐beta expression or smad and Akt signaling may contribute to differential effects in the limb and respiratory musculature. Grant Funding Source: Supported by NIHR15AR055360 to CGC