PRMT Biology in Skeletal Muscle During Acute and Chronic Exercise

Abstract

Protein arginine methyltransferases (PRMTs) play an important role in muscle. Using three unique but complementary approaches across human and mouse models, we examined PRMT biology during conditions of exercise-induced skeletal muscle plasticity. In response to acute and chronic cues for muscle plasticity in human muscle, an array of PRMT-specific increases and reductions in expression and activity were observed. Following this we generated coactivator-associated arginine methyltransferase 1 (CARM1) skeletal muscle-specific knockout (mKO) mice to further examine the role of this enzyme. We discovered that the rate of arginine methylation is equivalent to that of phosphorylation and ubiquitination in healthy muscle. CARM1 mKO displayed altered transcriptome and arginine methylproteomic signatures, confirming remodelled muscle contractile and neuromuscular junction characteristics, which foreshadowed the animal’s decreased acute exercise tolerance. Removal of CARM1 reduced voluntary wheel running (VWR) performance in a sex-dependent manner and eliminated the strong, positive correlation between VWR distance and mitochondrial number observed in WT mice. While CARM1 was shown to regulate AMPK-PGC-1α signaling during acute conditions of activity-induced muscle plasticity, molecular measures of PRMT biology were mostly unaffected by VWR and the removal of this enzyme. In conclusion, these results indicate that changes to expression and activity are PRMT-specific and reveal the broad impact of CARM1 in the maintenance and remodelling of skeletal muscle biology.