Activin A more prominently regulates muscle mass in primates than does GDF8

Abstract

Growth and differentiation factor 8 (GDF8) is a TGF-β superfamily member, and negative regulator of skeletal muscle mass. GDF8 inhibition results in prominent muscle growth in mice, but less impressive hypertrophy in primates, including man. Broad TGF-β inhibition suggests another family member negatively regulates muscle mass, and its blockade enhances muscle growth seen with GDF8-specific inhibition. Here we show that activin A is the long-sought second negative muscle regulator. Activin A specific inhibition, on top of GDF8 inhibition, leads to pronounced muscle hypertrophy and force production in mice and monkeys. Inhibition of these two ligands mimics the hypertrophy seen with broad TGF-β blockers, while avoiding the adverse effects due to inhibition of multiple family members. Altogether, we identify activin A as a second negative regulator of muscle mass, and suggest that inhibition of both ligands provides a preferred therapeutic approach, which maximizes the benefit:risk ratio for muscle diseases in man.

Osteogenesis Imperfecta: New Perspectives From Clinical and Translational Research

“…Given the close correlation between muscle and bone, this led to the hypothesis that treatments targeting muscle could be beneficial for both muscle and bone in OI. Myostatin and activin A are two members of the TGFβ family that inhibit muscle growth by signaling through the activin receptor 2B . A soluble activin receptor 2B that inhibits both myostatin and activin A led to a marked increase in muscle and bone mass in oim mice .…”

“…Myostatin and activin A are two members of the TGFb family that inhibit muscle growth by signaling through the activin receptor 2B. (123) A soluble activin receptor 2B that inhibits both myostatin and activin A led to a marked increase in muscle and bone mass in oim mice. (124) A slightly different soluble activin receptor 2B had similarly beneficial effects on muscles and bones in oim and G610C mice.…”

Emerging Interventions for Elderly Patients—The Promise of Regenerative Medicine

“…A recent phase I study (NCT02943239) compared the effect the antimyostatin antibody (REGN1033) with an antiactivin antibody (REGN2477) in 48 healthy postmenopausal women. Activin A is another ligand that signals through the ActRII receptor pathway and has been found to have a greater effect on muscle mass in primates than myostatin . Study participants received a single dose of either placebo or one of three dose levels of the combination of the two antibodies.…”

“…Activin A is another ligand that signals through the ActRII receptor pathway and has been found to have a greater effect on muscle mass in primates than myostatin. 33 Study participants received a single dose of either placebo or one of three dose levels of the combination of the two antibodies. At 8 weeks, participants who received the highest dose of REGN2477 along with the antimyostatin antibody REGN1033 showed the greatest increases in thigh muscle volume, as measured by magnetic resonance imaging: 7.7% compared with 0.88% in placebo (P < 0.001).…”

Detection of the myostatin‐neutralizing antibody Domagrozumab in serum by means of Western blotting and LC‐HRMS

“…Skeletal muscle mass and function are negatively regulated by cytokines of the transforming growth factor beta (TGF‐β) superfamily such as myostatin (growth differentiation factor‐8, GDF‐8) and activin A . Especially the regulative role of myostatin has been extensively studied in the past and the knockout of the corresponding gene in mice (Mstn −/− ) resulted in a significantly increased muscle mass due to an elevated muscle fiber number and size .…”