ACTN3 genotype influences androgen response in skeletal muscle

Androgens act through androgen receptor (AR) to maintain muscle mass. Evidence suggests that this pathway is influenced by ACTN3 (α-actinin-3) - “the Gene for Speed”. Given that one in 5 people worldwide lack α-actinin-3, it is possible they may respond to androgens differently. In this study, we show that α-actinin-3 deficiency decreases AR in skeletal muscles of mice and humans (in males and females), and that AR levels positively correlate with α-actinin-3 expression in a dosage dependent manner. α-Actinin-3 deficiency exacerbates gastrocnemius muscle mass loss with androgen deprivation in male mice, and stunts the muscle growth response to dihydrotestosterone at the onset of puberty in female mice. This is mediated by differential activation of pathways regulating amino acid metabolism, intracellular transport, autophagy, mitochondrial activity, MAPK and calcineurin signalling, which may be driven by 7 key genes that are both androgen sensitive and α-actinin-3-dependent in expression. Our results highlight a role for α-actinin-3 in the regulation of muscle mass and suggest that ACTN3 is a genetic modifier of androgen action in skeletal muscle.