ACTN3 R577X and human androgen biology: A critical mini review of androgen exposure and skeletal muscle responsiveness

ACTN3 R577X may contribute to variation in skeletal-muscle adaptation to androgens. This narrative mini-review distinguishes circulating androgen exposure, androgen receptor (AR) measurements, and physiological responsiveness across human and experimental studies. Small human studies report heterogeneous associations between genotype and resting or exercise-associated testosterone. One investigation reported lower AR protein in alpha-actinin-3-deficient muscle in small human cohorts and genotype-dependent responses to androgen perturbation in mice, with developmental and muscle-specific restrictions. Human training studies report inconsistent relationships between AR measurements and hypertrophy, while cell-specific mouse experiments demonstrate context-dependent roles for myofiber and mesenchymal-progenitor AR. One ACTN3 restoration experiment did not increase muscle mass or fast-fiber size. Together, these findings support testing whether ACTN3 modifies the relationship between androgen exposure and muscle growth, but they do not establish this effect in adult humans or identify AR as its mediator. AR could contribute causally, mark another relevant muscle characteristic, or accompany adaptation through alternative pathways. Human studies should distinguish genotype-associated growth at comparable exposure from differences in exposure-response slopes, using a prespecified genetic model and longitudinal exposure measurements. Illustrative interaction-power scenarios emphasize the need for adequately sized cohorts. AR CAG-repeat analyses remain exploratory, and female-inclusive studies are necessary for generalizability. The reviewed evidence motivates direct testing but does not support genotype-guided testosterone treatment.