Perm1 regulates CaMKII activation and shapes skeletal muscle responses to endurance exercise training
Perm1 regulates CaMKII activation and shapes skeletal muscle responses to endurance exercise training
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DOI：
10.1016/j.molmet.2019.02.009
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发表时间：
2019-05-01
影响因子：
8.1
通讯作者：
Kralli, Anastasia
中科院分区：
文献类型：
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作者：
Cho, Yoshitake;Tachibana, Shizuko;Kralli, Anastasia
目的：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。运动如何影响骨骼肌信号通路以诱导适应性反应仍不清楚。在过去的研究中，我们确定Perm 1（PGC-1和ERR诱导的调节因子，肌肉1）作为一个运动诱导的基因，并表明Perm 1过表达引起类似的肌肉适应耐力运动训练。Perm 1在运动诱导反应中的作用机制和作用尚不清楚。在这项研究中，我们的目的是确定的途径，Perm 1的行为以及Perm 1的重要性，为急性和长期的responses to exercise.Methods：我们进行了免疫沉淀和质谱鉴定Perm 1相关蛋白，并验证Perm 1与钙离子/钙调素依赖性蛋白激酶II（CaMKII）的相互作用。我们还通过AAV介导的shRNA递送敲低了小鼠腓肠肌中的Perm 1表达，并评估了减少Perm 1表达对单次跑步机运动回合的急性分子反应和对四周自愿轮跑训练的长期适应性反应的影响。最后，我们问是否Perm 1水平调节饮食或疾病影响骨骼肌functions.Results：我们表明，Perm 1协会与骨骼肌CaMKII和促进CaMKII激活。在一个急性运动回合，肌肉与击倒Perm 1显示缺陷的激活CaMKII和p38 MAPK和钝化诱导的调节剂的氧化代谢。经过四周的自愿训练，Perm 1敲除肌肉的线粒体生物合成减弱。最后，我们发现，Perm 1的表达减少饮食诱导的肥胖小鼠和肌肉萎缩症患者和小鼠models.Conclusions：我们的研究结果确定Perm 1作为肌肉特异性调节运动诱导的信号和Perm 1水平的骨骼肌运动反应的调谐器。肥胖或肌肉疾病状态下Perm 1水平的降低表明Perm 1可能将病理状态与低效的运动反应联系起来。(C)2019作者由爱思唯尔有限公司出版。
Objective: 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.Methods: We performed immunoprecipitation and mass spectrometry to identify Perm1 associated proteins, and validated Perm1 interactions with the Ca2+/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.Results: 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.Conclusions: 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. (C) 2019 The Authors. Published by Elsevier GmbH.