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.
Key Findings
Results
No significant association was observed between ACTN3 R577X genotype and sarcopenia components in community-dwelling older adults.
Study included 682 community-dwelling adults aged ≥65 years
Participants underwent annual health examinations between 2021 and 2024
Sarcopenia components assessed included skeletal muscle mass index, grip strength, gait speed, and five-time chair stand performance
Skeletal muscle mass index was assessed using dual-energy X-ray absorptiometry (DXA)
Assessment followed Asian Working Group for Sarcopenia criteria
Results
In women with the ACTN3 XX genotype, physical activity exceeding 441 MET-min/week was significantly associated with poorer chair stand performance.
The association had a beta coefficient of 4.19 (95% CI: 0.98 ~ 7.40)
Physical activity was quantified using metabolic equivalents (METs) derived from the International Physical Activity Questionnaire (IPAQ)
The threshold of 441 MET-min/week is described as an exploratory finding requiring external validation
The finding revealed a U-shaped relationship between physical activity and physical performance in this subgroup
The association was specific to women with the XX genotype, indicating a sex-specific effect
Results
The relationship between physical activity and muscle function in older women with ACTN3 XX genotype follows a U-shaped pattern.
The U-shaped relationship suggests that both insufficient and excessive physical activity (above 441 MET-min/week) may be associated with poorer muscle function
This pattern was observed specifically in women with the ACTN3 XX homozygous genotype
The ACTN3 R577X XX genotype leads to α-actinin-3 deficiency in homozygotes
The sex-specific nature of this threshold implies that men with the XX genotype did not show the same association
Background
The ACTN3 R577X polymorphism leads to α-actinin-3 deficiency in XX homozygotes, which was the genetic basis for investigating differential responses to physical activity.
XX homozygotes lack α-actinin-3, a protein relevant to skeletal muscle performance
The study examined whether this genetic background modifies the association between physical activity and muscle mass and function
682 community-dwelling adults aged ≥65 years were included in the analysis
Physical activity effects were hypothesized to vary depending on genetic background
What This Means
This research examined how a specific gene variant affects the relationship between exercise and muscle health in older adults. The gene in question, ACTN3, has a variant (called XX) that causes people to lack a muscle protein called α-actinin-3. The study followed 682 community-dwelling adults aged 65 and older, measuring their physical activity levels alongside several indicators of muscle health including grip strength, walking speed, and the ability to rise from a chair repeatedly.
The most notable finding was that older women who carry two copies of the XX variant of ACTN3 showed worse performance on the chair-stand test when their weekly physical activity exceeded approximately 441 MET-minutes per week — a moderate level of activity. This created a U-shaped pattern, meaning that performance was poorer both at very low activity levels and above this threshold. This relationship was not seen in men with the same genetic variant, suggesting that the effect is sex-specific. Importantly, the overall presence of the XX genotype alone was not linked to worse muscle health across the whole group.
This research suggests that older women with the ACTN3 XX genotype may respond differently to physical activity than others, and that exceeding a certain activity threshold could be associated with reduced muscle function in this group. However, the authors themselves caution that the specific threshold of 441 MET-min/week is an exploratory finding that needs to be confirmed in other studies before drawing firm conclusions. The findings highlight the potential importance of considering both genetic background and sex when thinking about exercise recommendations for older adults.
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Hsu H, Fang W, Lee M, Chen W, Chen Y, Lin H, et al.. (2026). Sex-specific physical activity thresholds influencing muscle function in older adults with XX genotype of ACTN3 R577X.. Scientific reports. https://doi.org/10.1038/s41598-026-57340-5