Basal Bioenergetic Abnormalities in Skeletal Muscle from Ryanodine Receptor Malignant Hyperthermia-susceptible R163C Knock-in Mice

Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2010; 286(1):99-113. DOI: 10.1074/jbc.M110.153247
Source: PubMed


Malignant hyperthermia (MH) and central core disease in humans have been associated with mutations in the skeletal ryanodine
receptor (RyR1). Heterozygous mice expressing the human MH/central core disease RyR1 R163C mutation exhibit MH when exposed
to halothane or heat stress. Considering that many MH symptoms resemble those that could ensue from a mitochondrial dysfunction
(e.g. metabolic acidosis and hyperthermia) and that MH-susceptible mice or humans have a higher than normal cytoplasmic Ca2+ concentration at rest, we evaluated the role of mitochondria in skeletal muscle from R163C compared with wild type mice under
basal (untriggered) conditions. R163C skeletal muscle exhibited a significant increase in matrix Ca2+, increased reactive oxygen species production, lower expression of mitochondrial proteins, and higher mtDNA copy number.
These changes, in conjunction with lower myoglobin and glycogen contents, Myh4 and GAPDH transcript levels, GAPDH activity, and lower glucose utilization suggested a switch to a compromised bioenergetic state characterized
by both low oxidative phosphorylation and glycolysis. The shift in bioenergetic state was accompanied by a dysregulation of
Ca2+-responsive signaling pathways regulated by calcineurin and ERK1/2. Chronically elevated resting Ca2+ in R163C skeletal muscle elicited the maintenance of a fast-twitch fiber program and the development of insulin resistance-like
phenotype as part of a metabolic adaptation to the R163C RyR1 mutation.

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Available from: Eleonora Napoli
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