Muscle calcium stress cleaves junctophilin1, unleashing a gene regulatory program predicted to correct glucose dysregulation.

Calcium ion movements between cellular stores and the cytosol govern muscle contraction, the most energy-consuming function in mammals, which confers skeletal myofibers a pivotal role in glycemia regulation. Chronic myoplasmic calcium elevation (“calcium stress”), found in malignant hyperthermia-susceptible (MHS) patients and multiple myopathies, has been suggested to underlie the progression from hyperglycemia to insulin resistance. What drives such progression remains elusive. We find that muscle cells derived from MHS patients have increased content of an activated fragment of GSK3β — a specialized kinase that inhibits glycogen synthase, impairing glucose utilization and delineating a path to hyperglycemia. We also find decreased content of junctophilin1, an essential structural protein that colocalizes in the couplon with the voltage-sensing CaV1.1, the calcium channel RyR1 and calpain1, accompanied by an increase in a 44 kDa junctophilin1 fragment (JPh44) that moves into nuclei. We trace these changes to activated proteolysis by calpain1, secondary to increased myoplasmic calcium. We demonstrate that a JPh44-like construct induces transcriptional changes predictive of increased glucose utilization in myoblasts, including less transcription and translation of GSK3β and decreased transcription of proteins that reduce utilization of glucose. These effects reveal a stress-adaptive response, mediated by the novel regulator of transcription JPh44.

细胞内储存库与细胞质之间的钙离子运动控制着肌肉收缩，这是哺乳动物中最耗能的功能，使得骨骼肌纤维在血糖调节中具有关键作用。在恶性高热易感（MHS）患者和多种肌病中发现的慢性肌浆钙升高（“钙应激”），被认为是从高血糖发展到胰岛素抵抗的基础。是什么推动了这种进展仍然不清楚。我们发现，来自MHS患者的肌肉细胞中，一种抑制糖原合酶的特异性激酶GSK3β的活化片段含量增加，这会损害葡萄糖利用并描绘出一条通往高血糖的路径。我们还发现junctophilin1的含量降低，junctophilin1是一种必需的结构蛋白，它与电压敏感的CaV1.1、钙通道RyR1和钙蛋白酶1共定位在偶联子中，同时伴有一个进入细胞核的44 kDa junctophilin1片段（JPh44）增加。我们将这些变化归因于钙蛋白酶1的活化蛋白水解作用，这是肌浆钙增加的继发结果。我们证明，一种类似JPh44的构建体在成肌细胞中诱导转录变化，预示着葡萄糖利用增加，包括GSK3β的转录和翻译减少以及降低葡萄糖利用的蛋白质转录减少。这些效应揭示了一种由新型转录调节因子JPh44介导的应激适应性反应。