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Chronic myoplasmic calcium elevation (\u201ccalcium stress\u201d), 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 GSK3\u03b2 \u2014 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 Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.1, 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 GSK3\u03b2 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.\n                  <\/jats:p>","DOI":"10.7554\/elife.78874","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T04:15:45Z","timestamp":1673842545000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.78874","source":"Crossref","is-referenced-by-count":13,"title":["Muscle calcium stress cleaves junctophilin1, unleashing a gene regulatory program predicted to correct glucose dysregulation"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7290-9326","authenticated-orcid":true,"given":"Eshwar R","family":"Tammineni","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01k9xac83","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physiology and Biophysics, Rush University","place":["Chicago, United 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