Skeletal muscle-specific Prmt1 deletion causes muscle atrophy via deregulation of the PRMT6-FOXO3 axis.

ABSTRACT

Protein arginine methyltransferases (PRMTs) have emerged as important regulators of skeletal muscle metabolism and regeneration. However, the direct roles of the various PRMTs during skeletal muscle remodeling remain unclear. Using skeletal muscle-specific prmt1 knockout mice, we examined the function and downstream targets of PRMT1 in muscle homeostasis. We found that muscle-specific PRMT1 deficiency led to muscle atrophy. PRMT1-deficient muscles exhibited enhanced expression of a macroautophagic/autophagic marker LC3-II, FOXO3 and muscle-specific ubiquitin ligases, TRIM63/MURF-1 and FBXO32, likely contributing to muscle atrophy. 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 the PRMT6-FOXO3 axis in the control of autophagy and protein degradation underlying muscle maintenance. Abbreviations Ad-RNAi adenovirus-delivered small interfering RNA; AKT thymoma viral proto-oncogene; AMPK AMP-activated protein kinase; Baf A1 bafilomycin A1; CSA cross-sectional area; EDL extensor digitorum longus; FBXO32 F-box protein 32; FOXO forkhead box O; GAS gatrocnemieus; HDAC histone deacetylase; IGF insulin-like growth factor; LAMP lysosomal-associated membrane protein; MAP1LC3B/LC3B microtubule-associated protein 1 light chain 3 beta; mKO Mice with skeletal muscle-specific deletion of Prmt1; MTOR mechanistic target of rapamycin kinase; MYH myosin heavy chain; MYL1/MLC1f myosin, light polypeptide 1; PRMT protein arginine N-methyltransferase; sgRNA single guide RNA; SQSTM1 sequestosome 1; SOL soleus; TA tibialis anterior; TRIM63/MURF-1 tripartite motif-containing 63; YY1 YY1 transcription factor.