Functional and Molecular Characterization of Skeletal Muscle‐Specific CARM1 Knockout Mice

Coactivator‐associated arginine methyltransferase 1 [CARM1, also known as protein arginine methyltransferase 4 (PRMT4)] catalyzes the methylation of arginine residues on target proteins. Skeletal muscle CARM1 appears to have important functions during myogenesis, as well as in response to exercise and during disuse‐induced phenotypic plasticity. However, a mechanistic understanding of the role(s) of CARM1 in skeletal muscle biology is lacking. In this study, we test the hypotheses that: 1) Skeletal muscle‐specific CARM1 knockout (mKO) animals will have reduced strength, endurance, and motor function compared to their wild‐type (WT) littermates, and 2) The acute intracellular and gene expression responses in skeletal muscle to a single bout of exercise will be altered in CARM1 mKO versus WT animals. To address our first hypothesis male 12‐week‐old mKO mice and WT littermates underwent a variety of functional tests. We found that mKO mice had significantly weaker maximum grip strength, increased fatigue, and slower ambulatory activity relative to their WT counterparts. Compared to WT mice, mKO animals had altered muscle mass depending on the tissue analysed. Immunofluorescence fiber type analysis revealed significant differences between male mKO and WT mice in the soleus (SOL) muscle. Male animals were then randomly assigned to one of three experimental groups: sedentary (SED), acute exercise (0AE), or acute exercise followed by 3 hours of recovery (3AE). CARM1 mKO animals ran for significantly less time and distance (~30%) than their WT counterparts. CARM1 mRNA levels remained constant across timepoints in WT animals in both the extensor digitorum longus (EDL) and SOL. EDL muscle from WT animals displayed significantly increased (737%) exercise‐induced PGC‐1α mRNA between SED and 3AE groups, while no increase was observed in mKO animals. PGC‐1α levels were similar between all experimental groups in both WT and mKO animals in the SOL muscle. Additionally, PRMT1, PRMT5, and PRMT7 transcript expression was also consistent across timepoints, genotypes, and muscles. We observed that CARM1 protein levels were similar between experimental groups in WT animals. WT and mKO animals displayed increased phosphorylated AMPK levels at 0AE when compared to SED. Total AMPK levels were consistent across all 3 experimental groups in both WT and mKO animals, while removal of CARM1 increased AMPK content. AMPK activation status was significantly elevated from SED to 0AE, with a return to basal levels at 3AE in both the WT and mKO animals. PGC‐1α protein content was not altered by exercise or by genotype and PRMT1, PRMT5, and PRMT7 levels were also similar between groups. In conclusion, this ongoing study demonstrates that the removal of CARM1 in skeletal muscle negatively impacts measures of muscle function, as well as alters the molecular response of skeletal muscle to acute physical activity. Altogether this study serves to increase our understanding of CARM1 and its role in regulating skeletal muscle plasticity.

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