Protein Arginine Methyltransferase Expression During An Acute Time Course Of Denervation‐Induced Skeletal Muscle Plasticity

Protein arginine methyltransferase 1 (PRMT1) and co‐activator‐associated arginine methyltransferase 1 (CARM1) are critical components of a diverse set of intracellular functions including cell signaling and transcriptional regulation. Despite the limited number of studies investigating PRMT biology in muscle, evidence strongly suggests that PRMT1 and CARM1 are important players in the regulation of skeletal muscle plasticity. However, their role in disuse‐induced muscle remodeling is unknown. Thus, our study objective was to determine whether denervation‐induced muscle disuse alters PRMT expression and activity in skeletal muscle and to contextualize PRMT biology within the early disuse‐evoked signaling events that precede muscle atrophy. After unilateral sectioning of the sciatic nerve, mice were subjected to 6 (n = 7), 12 (n = 7), 24 (n = 6), 72 (n = 5), or 168 (n = 4) hours of denervation. The contralateral limb served as an internal control. Western blot analyses were employed to determine protein expression levels in the denervated tibialis anterior (TA) muscle, relative to the contralateral, non‐denervated, control TA muscle across the experimental time course. A ~25% reduction (p < 0.05) in TA muscle mass was observed in the denervated hind limb after 168 hours. PRMT1 and CARM1 protein expression were significantly increased by 3‐ and 1.3‐fold, respectively, in the denervated hind limb, as compared to the control limb after 72 and 168 hours of inactivity. This differential response to denervation‐induced muscle disuse suggests a unique sensitivity to, or regulation by, potential upstream signaling and transcriptional pathways. These denervation‐induced increases in PRMT expression were accompanied by a ~15–25% elevation in cellular mono‐methyl arginine content at 72 and 168 hours, a marker of global PRMT methyltransferase activity. Muscle RING‐finger protein‐1 (MuRF1) protein expression was also significantly elevated 2.5–3‐fold after 72 and 168 hours of denervation, suggesting that PRMT expression may be mediated by factors governing the muscle atrophy program. Peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α) protein expression was diminished by ~40% (p < 0.05) in the denervated limb after 6 hours and remained depressed throughout the time course. In contrast, p38 mitogen‐activated protein kinase (MAPK) phosphorylation status (phosphorylated/total) tended to be elevated by ~10–50% in the denervated muscle throughout the experimental time course. AMP‐activated protein kinase (AMPK) phosphorylation status was lowered by ~40% (p < 0.05) after 6 and 12 hours of denervation. By 168 hours, AMPK phosphorylation status was 50% greater in the denervated limb than in the control limb. Our data suggest that alterations in AMPK, p38 MAPK, and PGC‐1α signaling are among the earliest signals that precede the induction of the atrophy program in response to neurogenic muscle disuse. Furthermore, PRMT1 and CARM1 may contribute to the remodeling of muscle during denervation‐induced atrophy. Support or Funding Information Natural Sciences and Engineering Research Council of Canada and Canada Research Chairs

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