Opposing effects of calcium stress in human muscle: defective glucose utilization leading to diabetes vs. stress-adaptive effects of a junctophilin fragment

Calcium ion movements between cellular stores and the cytosol govern muscle contraction, the most energy-consuming function in mammals, which confers striated myocytes a pivotal role in glycemia regulation. Chronic myoplasmic calcium elevation, found in malignant hyperthermia-susceptible (MHS) patients and in other myopathies, has been suggested to underlie the progression from hyperglycemia to insulin resistance. However, what drives such progression remains elusive. We find that muscle cells derived from MHS patients have decreased content of junctophilin1, a protein that colocalizes in the couplon with both the calcium channel RyR1 and calpain1, accompanied by an increase in a 44 kDa junctophilin1 fragment (JPh44) that localizes in the nuclei. We also find increased an activated fragment of GSK3, a specialized kinase that inhibits glycogen synthase, which favors glycogenolysis. 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 myotubes, including decreased translation of GSK3b. These effects reveal a stress-adaptive response, similar to that of a junctophilin 2 fragment described in heart failure, mediated by the novel regulator of transcription JPh44. ### Competing Interest Statement The authors have declared no competing interest.