Lacking a common protein may affect how muscles respond to testosterone, potentially affecting athletic performance and age-related muscle loss, according to a new study. 

The research, led by Murdoch Children’s Research Institute (MCRI), has uncovered a surprising link between ACTN3, the gene for speed, and the body’s response to testosterone, the hormone that helps maintain muscle mass.

The α-actinin-3 proteinis found in muscles important for explosive activities. About one in five people lack this proteindue to a variation in the ACTN3 gene. 

MCRI’s Dr Jane Seto said the research showed this genetic variation reduced levels of the androgen receptor in muscle tissue in both men and women, impacting how muscles grow or shrink in response to testosterone.

“This gene has long been associated with elite sprinting ability, but we’re now seeing it plays a much broader role in muscle biology,” she said. “It’s not just about speed but about how your muscles respond to testosterone.”

Published in Science Advances, the study using both mouse models and human samples, found that missing this protein worsened muscle loss in male mice when testosterone was blocked, and blunted muscle growth in female mice treated with supplementary testosterone during puberty.

The study also identified seven key genes that appear to drive this effect, as they are sensitive to testosterone and depend on the α-actinin-3 protein for proper expression. These specific genes influence important cell processes such as breaking down amino acids, cleaning out damaged cells and regenerating newer, healthier ones and producing energy in mitochondria.

“This could help explain why some people lose muscle more rapidly with age or illness, and why others respond differently to testosterone-based therapies,” Dr Seto said.

“The findings support this protein as a potential target for future treatments aimed at preserving muscle mass, especially in older adults or those undergoing testosterone-related therapies.”

Publication

Kelly N. Roeszler, Michael See, Lyra R. Meehan, Giscard Lima, Alexander Kolliari-Turner, Sarah E. Alexander, Shanie Landen, Harrison D. Wood, Chrystal F. Tiong, Weiyi Chen, Tomris Mustafa, Peter J. Houweling, Nir Eynon, Severine Lamon, Yannis Pitsiladis, David J. Handelsman, Fernando J. Rossello, Mirana Ramialison, Kathryn N. North and Jane T. Seto. ‘ACTN3 genotype influences androgen response in developing murine skeletal muscle,’ Sciences Advances.  DOI: 10.1126/sciadv.adw1059 

*The content of this communication is the sole responsibility of MCRI and does not reflect the views of the NHMRC. 

Funding

The study was supported by the Australian National Health and Medical Research Council (NHMRC) project grant APP1130215 (JTS, KNN), World Anti-Doping Agency 16E11FP (YP), NHMRC Dora Lush Postgraduate Scholarship GNT1114935 (KNR), Australian Research Council Future Fellowship FT210100278 (SeL), NHMRC L3 Investigator Grant #1197361 (DJH) and the Novo Nordisk Foundation NNF21CC0073729 (MS, FJR, MR). 

*All experiments were approved but MCRI’s Animal Ethics Committee and adhered to the principles of refinement, reducement and replacement.