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

4 years ago

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

Erqian Na, Jee Hae Kim, Lawrence Miloscio, Jason Mastaitis, Trevor Stitt, Wen Fury, Jesus Trejos, Stephen Jaspers, Ashique Rafique, Katie Cavino, Tobias Willer, Yu Bai, Esther Latres, Angelos Papatheodorou, Haruka Okamoto, George D. Yancopoulos, Jeffrey Pangilinan, Andrew J. Murphy, Jesper Gromada

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.

Publisher URL: http://www.nature.com/articles/ncomms15153

DOI: 10.1038/ncomms15153