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.

中文翻译：

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CARM1 对骨骼肌运动适应的性别特异性影响。

目的本研究的目的是确定共激活剂相关精氨酸甲基转移酶 1 (CARM1) 和生物性别的交叉如何影响骨骼肌对长期体力活动的适应。方法 将 12 周龄雌性 (F) 和雄性 (M) 野生型 (WT) 和 CARM1 骨骼肌特异性敲除小鼠 (mKO) 随机分配到久坐 (SED) 或自愿轮跑 (VWR) 实验组。在 8 周的时间里，VWR 组中的动物可以自主使用跑轮。随后，我们进行了全身功能测试，48小时后收获肌肉进行分子分析。使用蛋白质印迹、酶活性测定以及共聚焦和透射电子显微镜（TEM）来检查骨骼肌生物学。结果我们的数据揭示了 CARM1 肌肉特异性消融引起的 VWR 体积的性别依赖性减少，因为 F CARM1 mKO 小鼠比 WT 小鼠进行的慢性意志运动较少。无论 VWR 输出如何，运动引起的生理功能适应在实验组之间是相似的。广泛的蛋白质精氨酸甲基转移酶 (PRMT) 生物学测量，包括精氨酸甲基转移酶表达和活性的标记物，不受 VWR 的影响，但 CARM1 和 PRMT7 蛋白质水平除外，它们分别随 VWR 降低和升高。动物中肌纤维形态和线粒体蛋白质含量的变化显示出相似的趋势。然而，对 TEM 图像的仔细检查显示，与 WT 同窝小鼠相比，CARM1 mKO 小鼠对 VWR 的反应不同，特别是在线粒体大小和分数面积方面。结论 目前的研究结果表明，CARM1 mKO 降低了 F 小鼠的每日跑步量，以及运动引起的骨骼肌线粒体可塑性，这表明该酶在运动表现和线粒体健康的性别依赖性差异中发挥着重要作用。