Department of Nutrition and Integrative Physiology, Florida State University, Tallahassee, Florida, United States.
Institute of Sports Sciences and Medicine, Florida State University, Tallahassee, Florida, United States.
J Appl Physiol (1985). 2023 Jul 1;135(1):183-195. doi: 10.1152/japplphysiol.00113.2023. Epub 2023 Jun 8.
Glucocorticoids induce a myopathy that includes loss of muscle mass and strength. Resistance exercise may reverse the muscle loss because it induces an anabolic response characterized by increases in muscle protein synthesis and potentially suppressing protein breakdown. Whether resistance exercise induces an anabolic response in glucocorticoid myopathic muscle is unknown, which is a problem because long-term glucocorticoid exposure alters the expression of genes that may prevent an anabolic response by limiting activation of pathways such as the mechanistic target of rapamycin in complex 1 (mTORC1). The purpose of this study was to assess whether high-force contractions initiate an anabolic response in glucocorticoid myopathic muscle. The anabolic response was analyzed by treating female mice with dexamethasone (DEX) for 7 days or 15 days. After treatment, the left tibialis anterior muscle of all mice was contracted via electrical stimulation of the sciatic nerve. Muscles were harvested 4 h after contractions. Rates of muscle protein synthesis were estimated using the SUnSET method. After 7 days of treatment, high-force contractions increased protein synthesis and mTORC1 signaling in both groups. After 15 days of treatment, high-force contractions activated mTORC1 signaling equally in both groups, but protein synthesis was only increased in control mice. The failure to increase protein synthesis may be because baseline synthetic rates were elevated in DEX-treated mice. The LC3 II/I ratio marker of autophagy was decreased by contractions regardless of treatment duration. These data show duration of glucocorticoid treatment alters the anabolic response to high-force contractions. Glucocorticoid myopathy is the most common, toxic, noninflammatory myopathy. Our work shows that high-force contractions increase protein synthesis in skeletal muscle following short-term glucocorticoid treatment. However, longer duration glucocorticoid treatment results in anabolic resistance to high-force contractions despite activation of the mechanistic target of rapamycin in complex 1 (mTORC1) signaling pathway. This work defines potential limits for high-force contractions to activate the processes that would restore lost muscle mass in glucocorticoid myopathic patients.
糖皮质激素可导致肌肉减少症和肌肉无力。阻力运动可能会逆转肌肉损失，因为它会引起合成代谢反应，表现为肌肉蛋白合成增加，潜在地抑制蛋白分解。阻力运动是否会引起糖皮质激素肌病肌肉的合成代谢反应尚不清楚，这是一个问题，因为长期糖皮质激素暴露会改变基因的表达，从而通过限制机械性靶标雷帕霉素复合物 1（mTORC1）等途径的激活来阻止合成代谢反应。本研究旨在评估高负荷收缩是否会引发糖皮质激素肌病肌肉的合成代谢反应。通过用地塞米松（DEX）治疗雌性小鼠 7 天或 15 天来分析合成代谢反应。治疗后，通过坐骨神经电刺激对所有小鼠的左胫骨前肌进行收缩。收缩后 4 小时收获肌肉。使用 SUnSET 法估计肌肉蛋白合成率。经过 7 天的治疗，高负荷收缩可增加两组的蛋白合成和 mTORC1 信号。经过 15 天的治疗，高负荷收缩在两组中同样激活了 mTORC1 信号，但仅在对照组小鼠中增加了蛋白合成。蛋白合成没有增加可能是因为 DEX 治疗小鼠的基础合成率升高。无论治疗持续时间如何，LC3 II/I 比值（自噬的标志物）都因收缩而降低。这些数据表明，糖皮质激素治疗的持续时间改变了对高负荷收缩的合成代谢反应。糖皮质激素肌病是最常见、毒性和非炎症性肌病。我们的工作表明，在短期糖皮质激素治疗后，高负荷收缩可增加骨骼肌的蛋白合成。然而，较长时间的糖皮质激素治疗会导致对高负荷收缩的合成代谢抵抗，尽管 mTORC1 信号通路的机械性靶标雷帕霉素复合物 1（mTORC1）被激活。这项工作定义了高负荷收缩激活恢复糖皮质激素肌病患者丢失肌肉质量的过程的潜在限制。
