Sex-Specific Effect of CARM1 in Skeletal Muscle Adaptations to Exercise

Abstract

Purpose The purpose of this study was to determine how the intersection of coactivator-associated arginine methyltransferase 1 (CARM1) and biological sex impacts skeletal muscle adaptations to chronic physical activity. Methods 12-week-old female (F) and male (M) wild-type (WT) and CARM1 skeletal muscle-specific knockout mice (mKO) were randomly assigned to sedentary (SED) or voluntary wheel running (VWR) experimental groups. For 8 weeks, the animals in the VWR cohort had volitional access to running wheels. Subsequently, we performed whole-body functional tests, and 48 hours later muscles were harvested for molecular analysis. Western blotting, enzyme activity assays, as well as confocal and transmission electron microscopy (TEM) were used to examine skeletal muscle biology. Results Our data reveal a sex-dependent reduction in VWR volume caused by muscle-specific ablation of CARM1, as F CARM1 mKO mice performed less chronic, volitional exercise than their WT counterparts. Regardless of VWR output, exercise-induced adaptations in physiological function were similar between experimental groups. A broad panel of protein arginine methyltransferase (PRMT) biology measurements, including markers of arginine methyltransferase expression and activity, were unaffected by VWR, except for CARM1 and PRMT7 protein levels, which decreased and increased with VWR, respectively. Changes in myofiber morphology and mitochondrial protein content showed similar trends among animals. However, a closer examination of TEM images revealed contrasting responses to VWR in CARM1 mKO mice compared to WT littermates, particularly in mitochondrial size and fractional area. Conclusions The present findings demonstrate that CARM1 mKO reduces daily running volume in F mice, as well as exercise-evoked skeletal muscle mitochondrial plasticity, which indicates that this enzyme plays an essential role in sex-dependent differences in exercise performance and mitochondrial health.