Improvement of Dystrophic Muscle Fragility by Short-Term Voluntary Exercise through Activation of Calcineurin Pathway in mdx Mice
Improvement of Dystrophic Muscle Fragility by Short-Term Voluntary Exercise through Activation of Calcineurin Pathway in mdx Mice
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DOI：
10.1016/j.ajpath.2018.07.015
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发表时间：
2018-11-01
影响因子：
6
通讯作者：
Ferry, Arnaud
中科院分区：
文献类型：
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作者：
Delacroix, Clement;Hyzewicz, Janek;Ferry, Arnaud
mdx 小鼠（杜氏肌营养不良症模型）中的抗肌营养不良蛋白缺乏会导致肌肉无力，表现为特定最大力量降低以及脆性（即，更容易受到收缩引起的损伤，如延长收缩后力量下降幅度更大所示）。这两种症状都可以通过基于肌营养不良蛋白恢复的疗法和长期（数月）自愿锻炼得到改善。在此，我们评估了短期（1周）自愿轮跑的效果。我们发现跑步改善了胫骨前肌 (TA) 的脆弱性，但没有改善跖肌的脆弱性，与肌营养蛋白的上调无关，且不会影响无力。此外，跑步也保留了 TA 肌肉的兴奋性，如延长收缩后复合肌肉动作电位测量结果所示。有趣的是，钙调神经磷酸酶抑制剂环孢菌素 A 可以防止跑步对肌肉脆性和兴奋性的影响。环孢素还可以防止跑步引起的 TA 肌肉兴奋性（Scn4a 和 Cacna1s）和较慢收缩表型（Myh2 和 Tnni1）相关基因的表达变化。总之，短期自愿运动可以改善 mdx 小鼠的 TA 肌肉脆性，而不会使虚弱情况恶化。其作用与兴奋性的保留、钙调磷酸酶途径的激活以及涉及兴奋性和较慢收缩表型的基因程序的变化有关。因此，通过适当的运动训练来修复杜氏肌营养不良症患者的肌肉脆性值得更详细地探讨。
Dystrophin deficiency in mdx mice, a model for Duchenne muscular dystrophy, leads to muscle weakness revealed by a reduced specific maximal force as well as fragility (ie, higher susceptibility to contraction induced injury, as shown by a greater force decrease after lengthening contractions). Both symptoms could be improved with dystrophin restoration-based therapies and long-term (months) voluntary exercise. Herein, we evaluated the effect of short-term (1-week) voluntary wheel running. We found that running improved fragility of tibialis anterior muscle (TA), but not plantaris muscle, independently of utrophin up-regulation, without affecting weakness. Moreover, TA muscle excitability was also preserved by running, as shown by compound muscle action potential measurements after lengthening contractions. Of interest, the calcineurin inhibitor cyclosporin A prevented the effect of running on both muscle fragility and excitability. Cyclosporin also prevented the running-induced changes in expression of genes involved in excitability (Scn4a and Cacna1s) and slower contractile phenotype (Myh2 and Tnni1) in TA muscle. In conclusion, short-term voluntary exercise improves TA muscle fragility in mdx mice, without worsening weakness. Its effect was related to preserved excitability, calcineurin pathway activation, and changes in the program of genes involved in excitability and slower contractile phenotype. Thus, remediation of muscle fragility of Duchenne muscular dystrophy patients through appropriate exercise training deserves to be explored in more detail.