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.
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.
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|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|
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|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|
|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|
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