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.
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.
|Peter, Angela K; Miller, Gaynor; Capote, Joana et al. (2017) Nanospan, an alternatively spliced isoform of sarcospan, localizes to the sarcoplasmic reticulum in skeletal muscle and is absent in limb girdle muscular dystrophy 2F. Skelet Muscle 7:11|
|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|
|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|
|DiFranco, Marino; Yu, Carl; Quiñonez, Marbella et al. (2015) Inward rectifier potassium currents in mammalian skeletal muscle fibres. J Physiol 593:1213-38|
|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|
|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|
|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; 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|
|Lalani, Seema R; Ware, Stephanie M; Wang, Xueqing et al. (2013) MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development. Hum Mol Genet 22:4339-48|
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