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

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

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15153

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