Basal Bioenergetic Abnormalities in Skeletal Muscle from Ryanodine Receptor Malignant Hyperthermia-susceptible R163C Knock-in Mice
Basal Bioenergetic Abnormalities in Skeletal Muscle from Ryanodine Receptor Malignant Hyperthermia-susceptible R163C Knock-in Mice
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DOI：
10.1074/jbc.m110.153247
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发表时间：
2011-01-07
影响因子：
4.8
通讯作者：
Pessah, Isaac N.
中科院分区：
文献类型：
--
作者：
Giulivi, Cecilia;Ross-Inta, Catherine;Pessah, Isaac N.
人类的恶性高热（MH）和中枢核心疾病与骨骼ryanodine受体（RyR1）的突变有关。表达人类MH/中央核心疾病RyR1 R163C突变的杂合小鼠在暴露于氟烷或热应激时表现出MH。考虑到许多MH症状类似于线粒体功能障碍（例如代谢性酸中毒和高热）可能引起的症状，并且MH易感小鼠或人类在静止时的细胞质Ca2+浓度高于正常水平，我们评估了R163C骨骼肌中线粒体的作用，并将其与基础（未触发）条件下的野生型小鼠进行了比较。R163C骨骼肌表现出基质Ca2+显著增加，活性氧产生增加，线粒体蛋白表达降低，mtDNA拷贝数增加。这些变化，连同较低的肌红蛋白和糖原含量、Myh4和GAPDH转录物水平、GAPDH活性和较低的葡萄糖利用率，表明一种以低氧化磷酸化和糖酵解为特征的生物能量状态的切换。生物能量状态的转变伴随着钙调磷酸酶和ERK1/2调节的Ca2+响应信号通路的失调。R163C骨骼肌中静息Ca2+的长期升高引发了快速抽搐纤维程序的维持和胰岛素抵抗样表型的发展，这是对R163C RyR1突变的代谢适应的一部分。
Malignant hyperthermia (MH) and central core disease in humans have been associated with mutations in the skeletal ryanodine receptor (RyR1). Heterozygous mice expressing the human MH/central core disease RyR1 R163C mutation exhibit MH when exposed to halothane or heat stress. Considering that many MH symptoms resemble those that could ensue from a mitochondrial dysfunction (e.g. metabolic acidosis and hyperthermia) and that MH-susceptible mice or humans have a higher than normal cytoplasmic Ca2+ concentration at rest, we evaluated the role of mitochondria in skeletal muscle from R163C compared with wild type mice under basal (untriggered) conditions. R163C skeletal muscle exhibited a significant increase in matrix Ca2+, increased reactive oxygen species production, lower expression of mitochondrial proteins, and higher mtDNA copy number. These changes, in conjunction with lower myoglobin and glycogen contents, Myh4 and GAPDH transcript levels, GAPDH activity, and lower glucose utilization suggested a switch to a compromised bioenergetic state characterized by both low oxidative phosphorylation and glycolysis. The shift in bioenergetic state was accompanied by a dysregulation of Ca2+-esponsive signaling pathways regulated by calcineurin and ERK1/2. Chronically elevated resting Ca2+ in R163C skeletal muscle elicited the maintenance of a fast-twitch fiber program and the development of insulin resistance-like phenotype as part of a metabolic adaptation to the R163C RyR1 mutation.