Vlutations in either type 1 ryanodine receptor (RyR1) or the dihydropyridine receptor subunit Cav1.1 cause malignant hyperthermia susceptibility (MHS) in humans and animals. Project 2 will address key molecular events by which MHS mutations alter basal RyRI Ca2+ channel and leak and confer sensitivity to triggering agents. It is necessary to also understand how altered RyRI channel regulation influences basal changes in mitochondrial bioenergetics, produces oxidative stress, and promotes progressive muscle damage. Four interelated hypotheses are addressed in skeletal muscle and muscle cells obtained from mice and human Diopsies to understand how MHS mutations differentially alter (1) the biochemical and biophysical properties of RyRI channel regulation and their underlying posttranslational modifications, (2) adaptive changes in mitochondrial bioenergetics and whole animal energy expenditure, and (3) if RyRI channel and mitochondrial dysfunctions can be mitigated or abrogated by molecular and pharmacological interventions that reduce RyRI eak, abusive Ca2+ entry, increase SR Ca2+ load or specifically scavenge the reactive oxidized lipid product gcetoaldehyde (yKA). How RyRI channel regulation by cytoplasmic/luminal Ca2+, Mg2+ and glutathione redox potential differ among MHS mutations as a result of posttranslational modifications of RyR1 (phosphorylation, litrosylation, and formation of Lys-lactam adducts) will be investigated in four knock-in mouse models and human muscle biopsies with known MHS mutations. We will investigate the links between RyR1 dysfunction, mitochondrial matrix Ca2+, ROS production, mtDNA copy number and adaptations in Complex activities. Oxygen consumption and acidification rates will be investigated in mouse and human muscle cells under basal and after exposure to volatile anesthetics conditions. Whole body calorimetry will be used to measure resting energy expenditure and nutrient utilization rates of WT and MHS mice and how these parameters are influenced by ambient temperature, fasting and glucose challenge. The proposed studies are transformative Decause they will lead to understanding how MHS mutations produce phenotypic differences in clinical MH and progressive muscle damage, and test novel intervention strategies to mitigate these interrelated Drocesses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
2P01AR052354-06A1
Application #
8337935
Study Section
Special Emphasis Panel (ZAR1-MLB (M1))
Project Start
2012-06-01
Project End
2017-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
6
Fiscal Year
2012
Total Cost
$765,389
Indirect Cost
$179,017
Name
University of California Davis
Department
Type
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Franzini-Armstrong, Clara (2016) Can the Arrangement of RyR2 in Cardiac Muscle Be Predicted? Biophys J 110:2563-5
Polster, Alexander; Nelson, Benjamin R; Olson, Eric N et al. (2016) Stac3 has a direct role in skeletal muscle-type excitation-contraction coupling that is disrupted by a myopathy-causing mutation. Proc Natl Acad Sci U S A 113:10986-91
Bannister, Roger A; Sheridan, David C; Beam, Kurt G (2016) Distinct Components of Retrograde Ca(V)1.1-RyR1 Coupling Revealed by a Lethal Mutation in RyR1. Biophys J 110:912-21
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Franzini-Armstrong, Clara (2015) Electron Microscopy: From 2D to 3D Images with Special Reference to Muscle. Eur J Transl Myol 25:4836
Perni, Stefano; Marsden, Kurt C; Escobar, Matias et al. (2015) Structural and functional properties of ryanodine receptor type 3 in zebrafish tail muscle. J Gen Physiol 145:253
Henríquez-Olguín, Carlos; Altamirano, Francisco; Valladares, Denisse et al. (2015) Altered ROS production, NF-κB activation and interleukin-6 gene expression induced by electrical stimulation in dystrophic mdx skeletal muscle cells. Biochim Biophys Acta 1852:1410-9
Fiszer, Dorota; Shaw, Marie-Anne; Fisher, Nickla A et al. (2015) Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness. Anesthesiology 122:1033-46
Perni, Stefano; Marsden, Kurt C; Escobar, Matias et al. (2015) Structural and functional properties of ryanodine receptor type 3 in zebrafish tail muscle. J Gen Physiol 145:173-84

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