Inositol trisphosphate receptor-mediated Ca2+ signalling stimulates mitochondrial function and gene expression in core myopathy patients.
Inositol trisphosphate receptor-mediated Ca2+ signalling stimulates mitochondrial function and gene expression in core myopathy patients.
复制标题
肌醇三磷酸受体介导的 Ca2 信号传导刺激核心肌病患者的线粒体功能和基因表达。
DOI：
10.1093/hmg/ddy149
复制
发表时间：
2018
影响因子：
3.5
通讯作者：
Suman M
中科院分区：
文献类型：
--
作者：
Suman M
核心肌病是由肌浆网Ca2+释放通道ryanodine受体（RyR1）突变引起的一组儿童期肌肉疾病。这些突变先前与患者骨骼肌肌管中肌醇三磷酸受体（IP3R）水平升高有关。然而，IP3R介导的Ca2+信号与疾病病理生理的功能相关性和关系尚不清楚。也有人认为，线粒体功能障碍是中心和弥漫性多微核发育的基础，缺乏线粒体活性，这是RyR1突变的关键病理后果。在这里，我们使用RyR1突变的中央核和多小核疾病患者的肌肉活检，以及该疾病的细胞和体内模型来表征与该疾病相关的整体细胞和线粒体Ca2+信号，线粒体功能和基因表达。我们发现，导致通道耗竭的RyR1突变与ip3介导的核和线粒体Ca2+信号增加以及线粒体活性增加有关。此外，western blot和芯片分析表明，在转录和蛋白质水平上，线粒体生物发生增强，并反映在线粒体DNA含量增加上。在小鼠细胞肌管模型中通过ryr1沉默重现了该表型。总之，这些数据表明，在失去功能性RyR1后，骨骼肌Ca2+信号的重塑介导了生物能量适应。
Core myopathies are a group of childhood muscle disorders caused by mutations of the ryanodine receptor (RyR1), the Ca2+release channel of the sarcoplasmic reticulum. These mutations have previously been associated with elevated inositol trisphosphate receptor (IP3R) levels in skeletal muscle myotubes derived from patients. However, the functional relevance and the relationship of IP3R mediated Ca2+signalling with the pathophysiology of the disease is unclear. It has also been suggested that mitochondrial dysfunction underlies the development of central and diffuse multi-mini-cores, devoid of mitochondrial activity, which is a key pathological consequence of RyR1 mutations. Here we used muscle biopsies of central core and multi-minicore disease patients with RyR1 mutations, as well as cellular andin vivomouse models of the disease to characterize global cellular and mitochondrial Ca2+signalling, mitochondrial function and gene expression associated with the disease. We show that RyR1 mutations that lead to the depletion of the channel are associated with increased IP3-mediated nuclear and mitochondrial Ca2+signals and increased mitochondrial activity. Moreover, western blot and microarray analysis indicated enhanced mitochondrial biogenesis at the transcriptional and protein levels and was reflected in increased mitochondrial DNA content. The phenotype was recapitulated byRYR1silencing in mouse cellular myotube models. Altogether, these data indicate that remodelling of skeletal muscle Ca2+signalling following loss of functional RyR1 mediates bioenergetic adaptation.