Single-nucleus profiling unveils a geroprotective role of the FOXO3 in primate skeletal muscle aging

Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia, and increases the risk of many aging-related metabolic diseases. Here, we report phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging. A higher transcriptional fluctuation was observed in myonuclei relative to other interstitial cell types, indicating a higher susceptibility of skeletal muscle fiber to aging. We found a downregulation of FOXO3 in aged primate skeletal muscle, and identified FOXO3 as a hub transcription factor maintaining skeletal muscle homeostasis. Through the establishment of a complementary experimental pipeline based on a human pluripotent stem cell-derived myotube model, we revealed that silence of FOXO3 accelerates human myotube senescence, whereas genetic activation of endogenous FOXO3 alleviates human myotube aging. Altogether, based on a combination of monkey skeletal muscle and human myotube aging research models, we unraveled the pivotal role of the FOXO3 in safeguarding primate skeletal muscle from aging, providing a comprehensive resource for the development of clinical diagnosis and targeted therapeutic interventions against human skeletal muscle aging and the onset of sarcopenia along with aging-related disorders.

Automated summary

In this study, the authors conducted phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging. They found that myonuclei had higher transcriptional fluctuation compared to other interstitial cell types, suggesting a greater susceptibility of skeletal muscle fiber to aging. The downregulation of FOXO3 in aged primate skeletal muscle was identified, and it was revealed to be a hub transcription factor maintaining skeletal muscle homeostasis. Using a human pluripotent stem cell-derived myotube model, they showed that silence of FOXO3 accelerated human myotube senescence, while genetic activation of endogenous FOXO3 alleviated human myotube aging. Overall, this study unraveled the pivotal role of FOXO3 in safeguarding primate skeletal muscle from aging, providing insights for clinical diagnosis and targeted therapeutic interventions against human skeletal muscle aging and sarcopenia.