Sex-specific physical activity thresholds influencing muscle function in older adults with XX genotype of ACTN3 R577X

Physical activity is widely recommended to maintain muscle health in older adults, yet its effects may vary depending on genetic background. The ACTN3 R577X polymorphism leads to α-actinin-3 deficiency in XX homozygotes and may influence skeletal muscle performance. We examined the association between physical activity and muscle mass and function in 682 community-dwelling adults aged ≥ 65 years who participated in annual health examinations between 2021 and 2024. Skeletal muscle mass index was assessed using dual-energy X-ray absorptiometry, while grip strength, gait speed, and five-time chair stand performance were evaluated according to Asian Working Group for Sarcopenia criteria. Physical activity was quantified using metabolic equivalents derived from the International Physical Activity Questionnaire. No significant association was observed between ACTN3 R577X genotype and sarcopenia components. However, in women with ACTN3 XX, physical activity exceeding 441 MET-min/week was significantly associated with poorer chair stand performance (β: 4.19, 95% CI: 0.98 ~ 7.40), revealing a U-shaped relationship between physical activity and physical performance. Sex-specific physical activity thresholds may exist in older adults with the ACTN3 XX genotype, with physical activity above 441 MET-min/week being associated with poorer muscle function in women. This specific MET value is an exploratory finding, requiring more external validation.