Genetic evidence in the mouse solidifies the calcium hypothesis of myofiber death in muscular dystrophy.
Genetic evidence in the mouse solidifies the calcium hypothesis of myofiber death in muscular dystrophy.
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DOI：
10.1038/cdd.2015.65
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发表时间：
2015-09
影响因子：
12.4
通讯作者：
Molkentin JD
中科院分区：
文献类型：
--
作者：
Burr AR;Molkentin JD
肌营养不良症（MD）是指一组临床和遗传上异质性的退行性肌肉疾病，其特征是进行性肌肉萎缩，并且常常过早死亡。尽管大多数MD形式的主要缺陷通常是由于肌膜完整性丧失造成的，但导致肌肉变性和肌纤维坏死的次要分子机制仍存在争议。一种假设表明，胞浆钙升高或失调是常见的转导事件，导致 MD 中的肌纤维坏死。先前对营养不良动物模型或人类肌纤维中静息钙水平的测量产生了模棱两可的结果。然而，最近对基因改造小鼠模型的研究在很大程度上证实了MD的钙假说，例如骨骼肌中人为升高钙的模型表现出暴发性营养不良样疾病，而钙清除率增强或钙流入受抑制的模型对肌纤维死亡和MD具有抵抗力。在这里，我们将回顾该领域和来自基因改造小鼠模型的最新数据，我们认为这些数据共同证明了钙是MD肌纤维坏死的主要效应物的假设。这一关于钙的新共识应该指导未来在临床试验以及基于基因治疗的方法中评估的药物的选择。
Muscular dystrophy (MD) refers to a clinically and genetically heterogeneous group of degenerative muscle disorders characterized by progressive muscle wasting and often premature death. Although the primary defect underlying most forms of MD typically results from a loss of sarcolemmal integrity, the secondary molecular mechanisms leading to muscle degeneration and myofiber necrosis is debated. One hypothesis suggests that elevated or dysregulated cytosolic calcium is the common transducing event, resulting in myofiber necrosis in MD. Previous measurements of resting calcium levels in myofibers from dystrophic animal models or humans produced equivocal results. However, recent studies in genetically altered mouse models have largely solidified the calcium hypothesis of MD, such that models with artificially elevated calcium in skeletal muscle manifest fulminant dystrophic-like disease, whereas models with enhanced calcium clearance or inhibited calcium influx are resistant to myofiber death and MD. Here, we will review the field and the recent cadre of data from genetically altered mouse models, which we propose have collectively mostly proven the hypothesis that calcium is the primary effector of myofiber necrosis in MD. This new consensus on calcium should guide future selection of drugs to be evaluated in clinical trials as well as gene therapy-based approaches.