Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA; Division of Cardiology, Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA; Division of Cardiology, Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
Mol Metab. 2019 May;23:88-97. doi: 10.1016/j.molmet.2019.02.009. Epub 2019 Feb 27.
Endurance exercise training remodels skeletal muscle, leading to increased mitochondrial content and oxidative capacity. How exercise entrains skeletal muscle signaling pathways to induce adaptive responses remains unclear. In past studies, we identified Perm1 (PGC-1 and ERR induced regulator, muscle 1) as an exercise-induced gene and showed that Perm1 overexpression elicits similar muscle adaptations as endurance exercise training. The mechanism of action and the role of Perm1 in exercise-induced responses are not known. In this study, we aimed to determine the pathway by which Perm1 acts as well as the importance of Perm1 for acute and long-term responses to exercise.
We performed immunoprecipitation and mass spectrometry to identify Perm1 associated proteins, and validated Perm1 interactions with the Ca/calmodulin-dependent protein kinase II (CaMKII). We also knocked down Perm1 expression in gastrocnemius muscles of mice via AAV-mediated delivery of shRNA and assessed the impact of reduced Perm1 expression on both acute molecular responses to a single treadmill exercise bout and long-term adaptive responses to four weeks of voluntary wheel running training. Finally, we asked whether Perm1 levels are modulated by diet or diseases affecting skeletal muscle function.
We show that Perm1 associates with skeletal muscle CaMKII and promotes CaMKII activation. In response to an acute exercise bout, muscles with a knock down of Perm1 showed defects in the activation of CaMKII and p38 MAPK and blunted induction of regulators of oxidative metabolism. Following four weeks of voluntary training, Perm1 knockdown muscles had attenuated mitochondrial biogenesis. Finally, we found that Perm1 expression is reduced in diet-induced obese mice and in muscular dystrophy patients and mouse models.
Our findings identify Perm1 as a muscle-specific regulator of exercise-induced signaling and Perm1 levels as tuners of the skeletal muscle response to exercise. The decreased Perm1 levels in states of obesity or muscle disease suggest that Perm1 may link pathological states to inefficient exercise responses.
耐力运动训练重塑骨骼肌，导致线粒体含量和氧化能力增加。运动如何使骨骼肌信号通路感应，从而引起适应性反应尚不清楚。在过去的研究中，我们发现 Perm1（PGC-1 和 ERR 诱导调节因子，肌肉 1）是一种运动诱导基因，并表明 Perm1 过表达会引起与耐力运动训练相似的肌肉适应性变化。Perm1 的作用机制及其在运动诱导反应中的作用尚不清楚。在这项研究中，我们旨在确定 Perm1 发挥作用的途径，以及 Perm1 对运动的急性和长期反应的重要性。
我们进行免疫沉淀和质谱分析以鉴定与 Perm1 相关的蛋白，并验证 Perm1 与钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）的相互作用。我们还通过 AAV 介导的 shRNA 传递在小鼠的比目鱼肌中敲低 Perm1 表达，并评估减少 Perm1 表达对单次跑步机运动急性分子反应和对四周自愿轮跑训练的长期适应反应的影响。最后，我们询问 Perm1 水平是否受饮食或影响骨骼肌功能的疾病调节。
我们表明 Perm1 与骨骼肌 CaMKII 相关，并促进 CaMKII 激活。在急性运动发作时，敲低 Perm1 的肌肉中 CaMKII 和 p38 MAPK 的激活存在缺陷，氧化代谢调节因子的诱导也减弱。在四周的自愿训练后，Perm1 敲低肌肉的线粒体生物发生减弱。最后，我们发现饮食诱导肥胖的小鼠和肌肉疾病患者以及小鼠模型中的 Perm1 表达减少。
我们的研究结果将 Perm1 确定为运动诱导信号的肌肉特异性调节因子，Perm1 水平是骨骼肌对运动反应的调节因子。肥胖或肌肉疾病状态下 Perm1 水平降低表明 Perm1 可能将病理状态与低效的运动反应联系起来。
