Coactivator-associated arginine methyltransferase 1 (
CARM1) catalyzes the methylation of
arginine residues on target
proteins critical for health and disease. The purpose of this study was to characterize the effects of short-term, pharmacological
CARM1 inhibition on skeletal muscle size, function, and
atrophy. Adult mice (n = 10 or 11/sex) were treated with either a
CARM1 inhibitor (150 mg/kg
EZM2302; EZM) or vehicle (Veh) via oral gavage for 11-13 days and muscle mass, function, and exercise capacity were assessed. In addition, we investigated the effect of
CARM1 suppression on unilateral hindlimb
denervation (DEN)-induced
muscle atrophy (n = 8/sex). We report that
CARM1 inhibition caused significant reductions in the asymmetric dimethylation of known
CARM1 substrates but no change in
CARM1 protein or
mRNA content in skeletal muscle. Reduced
CARM1 activity did not affect body or muscle mass, however, we observed a decrease in exercise capacity and muscular endurance in male mice.
CARM1 methyltransferase activity increased in the muscle of Veh-treated mice following 7 days of DEN, and this response was blunted in EZM-dosed mice. Skeletal muscle mass and myofiber cross-sectional area were significantly reduced in DEN compared with contralateral, non-DEN limbs to a similar degree in both treatment groups. Furthermore, skeletal muscle
atrophy and autophagy gene expression programs were elevated in response to DEN independent of
CARM1 suppression. Collectively, these results suggest that short-term, pharmacological
CARM1 inhibition in adult animals affects muscle performance in a sex-specific manner but does not impact the maintenance and remodeling of skeletal muscle mass during conditions of neurogenic
muscle atrophy.NEW & NOTEWORTHY Short-term pharmacological inhibition of
coactivator-associated arginine methyltransferase 1 (
CARM1) was effective at significantly reducing
CARM1 methyltransferase function in skeletal muscle.
CARM1 inhibition did not impact muscle mass, but exercise capacity was impaired, particularly in male mice, whereas morphological and molecular signatures of
denervation-induced
muscle atrophy were largely maintained in animals administered the inhibitor. Altogether, the role of
CARM1 in neuromuscular biology remains complex and requires further investigation of its therapeutic potential in muscle-wasting conditions.