Intracellular calcium leak lowers glucose storage in human muscle, promoting hyperglycemia and diabetes
Eshwar R Tammineni,
Natalia Kraeva,
Lourdes Figueroa,
Carlo Manno,
Carlos A Ibarra,
Amira Klip,
Sheila Riazi,
Eduardo Rios
Affiliations
Eshwar R Tammineni
Department of Physiology and Biophysics, Rush University Medical Center, Chicago, United States
Natalia Kraeva
Malignant Hyperthermia Investigation Unit (MHIU) of the University Health Network (Canada), Toronto, Canada; Department of Anaesthesia & Pain Management, Toronto General Hospital, UHN, University of Toronto, Toronto, Canada
Lourdes Figueroa
Department of Physiology and Biophysics, Rush University Medical Center, Chicago, United States
Carlo Manno
Department of Physiology and Biophysics, Rush University Medical Center, Chicago, United States
Malignant Hyperthermia Investigation Unit (MHIU) of the University Health Network (Canada), Toronto, Canada; Department of Anaesthesia & Pain Management, Toronto General Hospital, UHN, University of Toronto, Toronto, Canada
Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
Sheila Riazi
Malignant Hyperthermia Investigation Unit (MHIU) of the University Health Network (Canada), Toronto, Canada; Department of Anaesthesia & Pain Management, Toronto General Hospital, UHN, University of Toronto, Toronto, Canada
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.
