Intracellular calcium leak lowers glucose storage in human muscle, promoting hyperglycemia and diabetes
- Rush University, United States
- University of Toronto, Canada
- Toronto General Hospital, Canada
- The Hospital for Sick Children, Canada
Abstract
Most glucose is processed in muscle, for energy or glycogen stores. Malignant Hyperthermia Susceptibility (MHS) exemplifies muscle conditions that increase [Ca2+]cytosol. 42% of MHS patients have hyperglycemia. We show that phosphorylated glycogen phosphorylase (GPa), glycogen synthase (GSa) – respectively activated and inactivated by phosphorylation – and their Ca2+-dependent kinase (PhK), are elevated in microsomal extracts from MHS patients' muscle. Glycogen and glucose transporter GLUT4 are decreased. [Ca2+]cytosol, increased to MHS levels, promoted GP phosphorylation. Imaging at ~100 nm resolution located GPa at sarcoplasmic reticulum (SR) junctional cisternae, and apo-GP at Z disk. MHS muscle therefore has a wide-ranging alteration in glucose metabolism: high [Ca2+]cytosol activates PhK, which inhibits GS, activates GP and moves it toward the SR, favoring glycogenolysis. The alterations probably cause these patients' hyperglycemia. For basic studies, MHS emerges as a variable stressor, which forces glucose pathways from the normal to the diseased range, thereby exposing novel metabolic links.
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All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures and tables in a multi-sheet Excel file
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Funding
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR071381)
- Sheila Riazi
- Eduardo Rios
National Institute of Advanced Industrial Science and Technology (R01AR072602)
- Eduardo Rios
National Institute of General Medical Sciences (R01GM111254)
- Eduardo Rios
National Center for Research Resources
- Eduardo Rios
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of Rush University (# 17-035, 16-091 and 18-065). All surgery was carried out on animals previously euthanized by methods approved under said protocols. Every effort was made to minimize stress and suffering.
Human subjects: Following approval by the institutional Research Ethics Board of Toronto General Hospital (TGH), informed consents were obtained from all patients who underwent the CHCT. The consent, also approved by the Institutional Review Board of Rush University, included use of biopsies for functional studies, imaging and cell culture.
Copyright
© 2020, Tammineni et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Intracellular calcium leak lowers glucose storage in human muscle, promoting hyperglycemia and diabetes
eLife 9:e53999.
https://doi.org/10.7554/eLife.53999
