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-sus...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/78874 |
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| author | Eshwar R Tammineni Lourdes Figueroa Carlo Manno Disha Varma Natalia Kraeva Carlos A Ibarra Amira Klip Sheila Riazi Eduardo Rios |
| author_facet | Eshwar R Tammineni Lourdes Figueroa Carlo Manno Disha Varma Natalia Kraeva Carlos A Ibarra Amira Klip Sheila Riazi Eduardo Rios |
| author_sort | Eshwar R Tammineni |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T18:39:28Z |
| format | Article |
| id | doaj.art-5333c0d70b9d492dab05f804a377068f |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-10T18:39:28Z |
| publishDate | 2023-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-5333c0d70b9d492dab05f804a377068f2023-02-01T17:12:39ZengeLife Sciences Publications LtdeLife2050-084X2023-02-011210.7554/eLife.78874Muscle calcium stress cleaves junctophilin1, unleashing a gene regulatory program predicted to correct glucose dysregulationEshwar R Tammineni0https://orcid.org/0000-0001-7290-9326Lourdes Figueroa1Carlo Manno2Disha Varma3Natalia Kraeva4Carlos A Ibarra5https://orcid.org/0000-0001-8898-6772Amira Klip6https://orcid.org/0000-0001-7906-0302Sheila Riazi7Eduardo Rios8https://orcid.org/0000-0003-0985-8997Department of Physiology and Biophysics, Rush University, Chicago, United StatesDepartment of Physiology and Biophysics, Rush University, Chicago, United StatesDepartment of Physiology and Biophysics, Rush University, Chicago, United StatesDepartment of Internal Medicine, Division of Nephrology, Rush University, Chicago, United StatesDepartment of Anesthesia & Pain Management, University of Toronto, Toronto, CanadaDepartment of Anesthesia & Pain Management, University of Toronto, Toronto, CanadaCell Biology Program, The Hospital for Sick Children, Toronto, CanadaDepartment of Anesthesia & Pain Management, University of Toronto, Toronto, CanadaDepartment of Physiology and Biophysics, Rush University, Chicago, United StatesCalcium 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.https://elifesciences.org/articles/78874transcription factorsphosphorylationprotein kinaseglucose transportimmunocytochemistry |
| spellingShingle | Eshwar R Tammineni Lourdes Figueroa Carlo Manno Disha Varma Natalia Kraeva Carlos A Ibarra Amira Klip Sheila Riazi Eduardo Rios Muscle calcium stress cleaves junctophilin1, unleashing a gene regulatory program predicted to correct glucose dysregulation eLife transcription factors phosphorylation protein kinase glucose transport immunocytochemistry |
| title | Muscle calcium stress cleaves junctophilin1, unleashing a gene regulatory program predicted to correct glucose dysregulation |
| title_full | Muscle calcium stress cleaves junctophilin1, unleashing a gene regulatory program predicted to correct glucose dysregulation |
| title_fullStr | Muscle calcium stress cleaves junctophilin1, unleashing a gene regulatory program predicted to correct glucose dysregulation |
| title_full_unstemmed | Muscle calcium stress cleaves junctophilin1, unleashing a gene regulatory program predicted to correct glucose dysregulation |
| title_short | Muscle calcium stress cleaves junctophilin1, unleashing a gene regulatory program predicted to correct glucose dysregulation |
| title_sort | muscle calcium stress cleaves junctophilin1 unleashing a gene regulatory program predicted to correct glucose dysregulation |
| topic | transcription factors phosphorylation protein kinase glucose transport immunocytochemistry |
| url | https://elifesciences.org/articles/78874 |
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