FKBP12 is a small immunophilin that binds with high affinity to sarcoplasmic reticulum Ca2+ release channels (ryanodine receptors, RyRs) and transforming growth factor ?1 receptors (T?I RI). In this application we are going to test the hypothesis that the gain of E-C coupling is regulated in a biphasic manner by FKBP concentration. Specifically we will: 1) Demonstrate that FKBP12 binding to RyR1 controls the gain of E-C coupling in a biphasic manner, thereby, modulating Ca2+ stores, force production, fatigue, and recovery from injury;2) Evaluate the ability T?RI activation to increase the gain of E-C coupling via FKBP12;3) Evaluate the ability of drugs that decrease FKBP12 binding to RyR1 to slow the development of fatigue and enhance recovery from injury and 4) Identify the amino acids on RyR1 that contribute to FKBP12 binding. The research described in this application will clarify the role of FKBP12 in skeletal muscle function and lay the groundwork for the development of new therapeutic interventions to slow diaphragm fatigue and enhance recovery from injury.

Public Health Relevance

The research in this application will investigate the role of small immunophilins (FKBPs) in muscle Ca2+ homeostasis, fatigue, and recovery from injury. Diaphragm fatigue is a serious medical problem that contributes to respiratory failure in patients with skeletal muscle, cardiovascular and pulmonary diseases and to failure to wean patients from ventilators. Also, the rate of recovery of skeletal muscle from injury has profound effects on rehabilitation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR041802-17
Application #
8197354
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (03))
Program Officer
Boyce, Amanda T
Project Start
1993-08-01
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
17
Fiscal Year
2012
Total Cost
$460,301
Indirect Cost
$118,971
Name
Baylor College of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
DiFranco, Marino; Kramerova, Irina; Vergara, Julio L et al. (2016) Attenuated Ca(2+) release in a mouse model of limb girdle muscular dystrophy 2A. Skelet Muscle 6:11
DiFranco, Marino; Yu, Carl; Quiñonez, Marbella et al. (2015) Inward rectifier potassium currents in mammalian skeletal muscle fibres. J Physiol 593:1213-38
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
DiFranco, Marino; Quiñonez, Marbella; Shieh, Perry et al. (2014) Action potential-evoked calcium release is impaired in single skeletal muscle fibers from heart failure patients. PLoS One 9:e109309
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
Zampighi, Guido A; Serrano, Raul; Vergara, Julio L (2014) A novel synaptic vesicle fusion path in the rat cerebral cortex: the ""saddle"" point hypothesis. PLoS One 9:e100710
DiFranco, Marino; Yu, Carl; Quiñonez, Marbella et al. (2013) Age-dependent chloride channel expression in skeletal muscle fibres of normal and HSA(LR) myotonic mice. J Physiol 591:1347-71
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

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