| Literature DB >> 25053409 |
Chang Seok Lee1, Dimitra K Georgiou1, Adan Dagnino-Acosta1, Jianjun Xu1, Iskander I Ismailov1, Mark Knoblauch1, Tanner O Monroe1, RuiRui Ji1, Amy D Hanna1, Aditya D Joshi1, Cheng Long1, Joshua Oakes1, Ted Tran1, Benjamin T Corona2, Sabina Lorca3, Christopher P Ingalls2, Vihang A Narkar3, Johanna T Lanner1, J Henri Bayle1, William J Durham4, Susan L Hamilton5.
Abstract
Rapamycin at high doses (2-10 mg/kg body weight) inhibits mammalian target of rapamycin complex 1 (mTORC1) and protein synthesis in mice. In contrast, low doses of rapamycin (10 μg/kg) increase mTORC1 activity and protein synthesis in skeletal muscle. Similar changes are found with SLF (synthetic ligand for FKBP12, which does not inhibit mTORC1) and in mice with a skeletal muscle-specific FKBP12 deficiency. These interventions also increase Ca(2+) influx to enhance refilling of sarcoplasmic reticulum Ca(2+) stores, slow muscle fatigue, and increase running endurance without negatively impacting cardiac function. FKBP12 deficiency or longer treatments with low dose rapamycin or SLF increase the percentage of type I fibers, further adding to fatigue resistance. We demonstrate that FKBP12 and its ligands impact multiple aspects of muscle function.Entities:
Keywords: Calcium; Excitation-Contraction Coupling (E-C Coupling); Fatigue; Protein Synthesis; RyR1; Ryanodine Receptor; Skeletal Muscle; mTORC1
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Year: 2014 PMID： 25053409 PMCID： PMC4162161 DOI： 10.1074/jbc.M114.586289
Source DB: PubMed Journal: J Biol Chem ISSN： 0021-9258 Impact factor: 5.157