Skeletal muscle wasting is caused by physical disuse, aging and chronic diseases and it is detrimental for the metabolic health and aggravates other chronic diseases, leading to increased morbidity and mortality. In atrophying muscles, FOXO transcription factors are activated which in turn regulate multiple components of the ubiquitin-proteasome pathway, such as the muscle-specific ubiquitin ligases muscle RING-finger (MuRF1) and Atrogin1/MAFbx, leading to accelerated proteolysis and atrophy. Thus, the mechanism by which FOXO transcription factors are regulated in skeletal muscle needs to be investigated to better understand muscle homeostasis and dysfunction. Protein arginine methyltransferases (PRMTs) have emerged as important regulators of skeletal muscle metabolism and regeneration. However, their function in skeletal muscle remodeling and homeostasis remains unclear.
In this study, we investigated the role of PRMT1 in skeletal muscle by utilizing skeletal muscle-specific PRMT1 knockout mice. We found that muscle-specific PRMT1 deficiency leads to muscle atrophy. PRMT1 level is decreased in the fasted state of skeletal muscle while increased in the refed condition. Consistently, PRMT1-deficient muscles exhibit enhanced levels of FoxO3a and muscle-specific ubiquitin ligases, MuRF1 and Atrogin1 that are associated with protein degradation. The mechanistic study reveals that PRMT1 regulates FOXO3 through PRMT6 modulation. In the absence of PRMT1, increased PRMT6 specifically methylates FOXO3 at arginine 188 and 249, leading to its activation. Finally, we demonstrate that PRMT1 deficiency triggers FOXO3 hyperactivation, which is abrogated by PRMT6 depletion. Taken together, PRMT1 is a key regulator for PRMT6/ FOXO3 axis in the control of skeletal muscle maintenance. Thus, PRMT1 may be a target to prevent muscle wasting under specific pathological conditions and related metabolic diseases.
This research was conducted as a joint research of researchers from SKKU and Korea University. It was posted on the online version of the Autophagy journal on January 2019.