Intracellular calcium leak lowers glucose storage in human muscle, promoting hyperglycemia and diabetes

  1. Eshwar R Tammineni
  2. Natalia Kraeva
  3. Lourdes Figueroa
  4. Carlo Manno
  5. Carlos A Ibarra
  6. Amira Klip
  7. Sheila Riazi
  8. Eduardo Rios  Is a corresponding author
  1. Rush University, United States
  2. University of Toronto, Canada
  3. Toronto General Hospital, Canada
  4. 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.

Data availability

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

Article and author information

Author details

  1. Eshwar R Tammineni

    Physiology and Biophysics, Rush University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Natalia Kraeva

    Anaesthesia and Pain Management, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Lourdes Figueroa

    Physiology and Biophysics, Rush University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Carlo Manno

    Physiology and Biophysics, Rush University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Carlos A Ibarra

    Anaesthesia and Pain Management, Toronto General Hospital, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8898-6772
  6. Amira Klip

    Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7906-0302
  7. Sheila Riazi

    Anaesthesia and Pain Management, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Eduardo Rios

    Physiology and Biophysics, Rush University, Chicago, United States
    For correspondence
    erios@rush.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0985-8997

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.

Reviewing Editor

  1. Mark T Nelson, University of Vermont, United States

Publication history

  1. Received: November 27, 2019
  2. Accepted: May 4, 2020
  3. Accepted Manuscript published: May 4, 2020 (version 1)
  4. Version of Record published: June 9, 2020 (version 2)

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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  1. Eshwar R Tammineni
  2. Natalia Kraeva
  3. Lourdes Figueroa
  4. Carlo Manno
  5. Carlos A Ibarra
  6. Amira Klip
  7. Sheila Riazi
  8. Eduardo Rios
(2020)
Intracellular calcium leak lowers glucose storage in human muscle, promoting hyperglycemia and diabetes
eLife 9:e53999.
https://doi.org/10.7554/eLife.53999

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