Humans with function-disrupting variants in the myostatin gene (MSTN) have increased skeletal muscle mass and strength, and less adiposity.
Authors
Affiliations (13)
Affiliations (13)
- Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA.
- Aging and Age-Related Disorders, Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA.
- Regeneron Imaging Center, Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA.
- Obesity, Muscle and Metabolism, Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA.
- Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
- Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
- Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA. [email protected].
- Aging and Age-Related Disorders, Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA. [email protected].
- Regeneron Imaging Center, Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA. [email protected].
- Obesity, Muscle and Metabolism, Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA. [email protected].
- Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA. [email protected].
- Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA. [email protected].
- Aging and Age-Related Disorders, Regeneron Pharmaceuticals, Tarrytown, New York, NY, USA. [email protected].
Abstract
Myostatin negatively regulates skeletal muscle size in multiple species, and therefore, myostatin blockade has been therapeutically explored to promote muscle growth in humans, including to counter the muscle loss seen in obese humans using GLP1R agonists. In this study, we present results from a large multi-cohort genetic association analysis, using data from 1.1 million individuals to examine the effects of function-disrupting mutations in the myostatin gene (MSTN) on traits relevant to body composition and cardiometabolic health. Carriers of function-disrupting variants display decreased adiposity, an increase in lean mass, and increased grip strength and creatinine levels. We further characterize the effects of these variants on body composition using whole-body MRI data from UK Biobank, leveraging deep learning models to perform automated image segmentation for 77,572 individuals. Among mutation carriers increased muscle mass is observed across multiple muscle groups, with heterozygote carriers of loss-of-function-like mutations exhibiting increases in excess of 10%. Our findings demonstrate that lifelong reduction in myostatin function enhances muscle size and strength in humans while decreasing body adiposity, providing insights into the potential benefits and safety of long-term therapeutic blockade of myostatin signaling.