The skeletal muscle ryanodine receptor (RYR1) regulates Ca2+ release from the sarcoplasmic reticulum (SR) stores and is mutated in human central core disease (CCD) and in the pharmacogenetic syndrome, malignant hyperthermia (MH). Although MH and CCD mutations in RyR1 are thought to alter SR Ca2+ release channel function and muscle excitation-contraction (EC) coupling, the mechanisms by which these effects result in phenotypic changes in muscle characteristic of these disorders are unknown. This project will use transgenic MH and CCD knock-in mice to provide detailed analyses of the fundamental mechanisms by which RYR1 disease mutations alter in vivo muscle function. The long-term goal of this project is to define the cellular/molecular mechanisms and principles by which MH/CCD mutations alter Ca2+ homeostasis and excitation-contraction (EC) coupling in intact muscle. Our overall hypothesis is: MH and CCD mutations in MH/CCD regions 1 and 2 enhance voltage- and Ca2+-gated SR release by altering crucial intra and intermolecular interactions within RYR1 and between RYR1 and the voltage dependent Ca2+ channel in the t-tubule membrane, while CCD-selective mutations in the region 3 pore region of RyR1 disrupt Ca2+ permeation through the channel. To test this hypothesis, we propose to: 1. Create three new MH/CCD mouse lines and analyze the effects of the mutations on muscle contractile properties in response to caffeine and temperature, 2. Analyze the effects of the mutations on RYR1 structure, S.Assess the effects of MH/CCD mutations in RyR1 on Ca2+ homeostasis and bi-directional DHPR-RyR1 coupling in myotubes and adult muscle fibers obtained from MH/CCD knock-in mice, and 4 Evaluate the effects of MH/CCD mutations on in situ release channel sensitivity to activation by RyR1 ligands and local increases in junctional Ca2+. This application brings together two collaborators, both highly committed to elucidating fundamental mechanisms of MH and CCD pathophysiology, but who approach the problems in very different, but complimentary ways. This union will result in a uniquely interdisciplinary project that will determine the mechanisms by which MH/CCD disease mutations alter RyR1 structure and regulation, subcellular Ca2+ transport/handling mechanisms, muscle EC coupling, and SR Ca2+ storage/sequestration. Results will have broad implications for other disorders of Ca2+ dysregulation in

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MOSS-E (02))
Program Officer
Boyce, Amanda T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Schools of Medicine
United States
Zip Code
Michelucci, Antonio; Paolini, Cecilia; Boncompagni, Simona et al. (2017) Strenuous exercise triggers a life-threatening response in mice susceptible to malignant hyperthermia. FASEB J 31:3649-3662
Lee, Chang Seok; Hanna, Amy D; Wang, Hui et al. (2017) A chemical chaperone improves muscle function in mice with a RyR1 mutation. Nat Commun 8:14659
Michelucci, Antonio; De Marco, Alessandro; Guarnier, Flavia A et al. (2017) Antioxidant Treatment Reduces Formation of Structural Cores and Improves Muscle Function in RYR1Y522S/WT Mice. Oxid Med Cell Longev 2017:6792694
Jarrett, Kelsey E; Lee, Ciaran M; Yeh, Yi-Hsien et al. (2017) Somatic genome editing with CRISPR/Cas9 generates and corrects a metabolic disease. Sci Rep 7:44624
Linsley, Jeremy W; Hsu, I-Uen; Groom, Linda et al. (2017) Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3. Proc Natl Acad Sci U S A 114:E228-E236
Georgiou, Dimitra K; Dagnino-Acosta, Adan; Lee, Chang Seok et al. (2015) Ca2+ Binding/Permeation via Calcium Channel, CaV1.1, Regulates the Intracellular Distribution of the Fatty Acid Transport Protein, CD36, and Fatty Acid Metabolism. J Biol Chem 290:23751-65
Paolini, Cecilia; Quarta, Marco; Wei-LaPierre, Lan et al. (2015) Oxidative stress, mitochondrial damage, and cores in muscle from calsequestrin-1 knockout mice. Skelet Muscle 5:10
Michelucci, Antonio; Paolini, Cecilia; Canato, Marta et al. (2015) Antioxidants protect calsequestrin-1 knockout mice from halothane- and heat-induced sudden death. Anesthesiology 123:603-17
Pedrotti, Simona; Giudice, Jimena; Dagnino-Acosta, Adan et al. (2015) The RNA-binding protein Rbfox1 regulates splicing required for skeletal muscle structure and function. Hum Mol Genet 24:2360-74
Lee, Chang Seok; Georgiou, Dimitra K; Dagnino-Acosta, Adan et al. (2014) Ligands for FKBP12 increase Ca2+ influx and protein synthesis to improve skeletal muscle function. J Biol Chem 289:25556-70

Showing the most recent 10 out of 26 publications