Hanson M Gartz, Wilde Jonathan J, Moreno Rosa L, Minic Angela D, Niswander Lee
Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, United States.
Department of Physiology, University of Colorado, Anschutz Medical Campus, Aurora, United States.
Elife. 2015 Jan 7;4:e02923. doi: 10.7554/eLife.02923.
Myopathies decrease muscle functionality. Mutations in ryanodine receptor 1 (RyR1) are often associated with myopathies with microscopic core-like structures in the muscle fiber. In this study, we identify a mouse RyR1 model in which heterozygous animals display clinical and pathological hallmarks of myopathy with core-like structures. The RyR1 mutation decreases sensitivity to activated calcium release and myoplasmic calcium levels, subsequently affecting mitochondrial calcium and ATP production. Mutant muscle shows a persistent potassium leak and disrupted expression of regulators of potassium homeostasis. Inhibition of KATP channels or increasing interstitial potassium by diet or FDA-approved drugs can reverse the muscle weakness, fatigue-like physiology and pathology. We identify regulators of potassium homeostasis as biomarkers of disease that may reveal therapeutic targets in human patients with myopathy of central core disease (CCD). Altogether, our results suggest that amelioration of potassium leaks through potassium homeostasis mechanisms may minimize muscle damage of myopathies due to certain RyR1 mutations.
肌病会降低肌肉功能。兰尼碱受体1（RyR1）的突变通常与肌肉纤维中具有微观核心样结构的肌病相关。在本研究中，我们鉴定出一种小鼠RyR1模型，其中杂合动物表现出具有核心样结构的肌病的临床和病理特征。RyR1突变降低了对激活的钙释放和肌浆钙水平的敏感性，随后影响线粒体钙和ATP的产生。突变肌肉表现出持续的钾泄漏以及钾稳态调节因子的表达紊乱。抑制KATP通道或通过饮食或FDA批准的药物增加细胞外钾可以逆转肌肉无力、疲劳样生理和病理状态。我们将钾稳态调节因子鉴定为疾病生物标志物，这可能揭示患有中央核心疾病（CCD）肌病的人类患者的治疗靶点。总之，我们的结果表明，通过钾稳态机制改善钾泄漏可能会将某些RyR1突变导致的肌病的肌肉损伤降至最低。
