Mutations in the RYR1 gene underlie several debilitating, life-threatening muscle diseases. In this application we are proposing to use a mouse model with a knockin mutation into RyR1 (Y524S) that has features of three of these disorders: malignant hyperthermia (MH) heat/exercise-induced exertional rhabdomyolysis (ER) and central core disease (CCD). Our long term goals are to define the mechanisms that underlie the decline in muscle function associated with these diseases and to develop new interventions. Our overall working hypothesis for the current proposal the Y524S mutation in RyR1 increases the temperature sensitivity of both excitation-contraction coupling (ECC) and RyR1 Ca2+ leak, producing the MH response and driving oxidative stress and mitochondrial destruction that leads to the myopathy.
Our specific aims are to: 1) Elucidate the role of Ca2+ influx via CaV1.1 in the MH response and the development of the myopathy;2) Delineate the mechanisms of core formation in YS mice;3) Define the mechanism by which an activator (AICAR) of the energy sensing kinase AMPK prevents the MH response and evaluate AICAR's ability to slow the development of the myopathy in YS mice;and 4) Define the mechanism by which a non-immunosuppressive ligand for the protein FKBP12 prevents the MH response and evaluate SLF's effect on the myopathy in YS mice. The proposed work is highly significant because we directly couple the delineation of pathways underlying disease processes with the development of novel therapeutic interventions that have distinct mechanisms of action, allowing for some flexibility to tailor treatment strategies to different mutations associated with MH and CCD. The proposed research is innovative because of: 1) paradigm shifting hypotheses;2) unique mouse models, 3) cutting edge technologies, and 4) therapeutic interventions never previously proposed as treatments for MH or other RyR1-linked myopathies.

Public Health Relevance

This project is significant as it will advance understanding of the RyR myopathies by demonstrating that interventions designed to reduce temperature sensitive calcium release, influx and leak correct muscle function. We will also define the mechanism for core formation, as well as identify and validate new interventions and targets for the treatment of MH, CCD and potentially other RyR-related disorders.

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)
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
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
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
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
Sambuughin, Nyamkhishig; Zvaritch, Elena; Kraeva, Natasha et al. (2014) Exome analysis identifies Brody myopathy in a family diagnosed with malignant hyperthermia susceptibility. Mol Genet Genomic Med 2:472-83
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
Riazi, Sheila; Kraeva, Natalia; Muldoon, Sheila M et al. (2014) Malignant hyperthermia and the clinical significance of type-1 ryanodine receptor gene (RYR1) variants: proceedings of the 2013 MHAUS Scientific Conference. Can J Anaesth 61:1040-9
Dowling, James J; Lawlor, Michael W; Dirksen, Robert T (2014) Triadopathies: an emerging class of skeletal muscle diseases. Neurotherapeutics 11:773-85
Wagner 2nd, Larry E; Groom, Linda A; Dirksen, Robert T et al. (2014) Characterization of ryanodine receptor type 1 single channel activity using ""on-nucleus"" patch clamp. Cell Calcium 56:96-107
Rossi, Daniela; Vezzani, Bianca; Galli, Lucia et al. (2014) A mutation in the CASQ1 gene causes a vacuolar myopathy with accumulation of sarcoplasmic reticulum protein aggregates. Hum Mutat 35:1163-70
Manno, Carlo; Figueroa, Lourdes; Royer, Leandro et al. (2013) Altered Ca2+ concentration, permeability and buffering in the myofibre Ca2+ store of a mouse model of malignant hyperthermia. J Physiol 591:4439-57

Showing the most recent 10 out of 20 publications