1. Ligands for FKBP12 increase Ca2+ influx and protein synthesis to improve skeletal muscle function.
- Author
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Lee CS, Georgiou DK, Dagnino-Acosta A, Xu J, Ismailov II, Knoblauch M, Monroe TO, Ji R, Hanna AD, Joshi AD, Long C, Oakes J, Tran T, Corona BT, Lorca S, Ingalls CP, Narkar VA, Lanner JT, Bayle JH, Durham WJ, and Hamilton SL
- Subjects
- Animals, Calcium Signaling drug effects, Dose-Response Relationship, Drug, Mechanistic Target of Rapamycin Complex 1, Mice, Multiprotein Complexes, Muscle Contraction drug effects, Muscle, Skeletal metabolism, Protein Binding, Protein Biosynthesis drug effects, Sarcoplasmic Reticulum drug effects, Sarcoplasmic Reticulum metabolism, TOR Serine-Threonine Kinases, Tacrolimus Binding Protein 1A chemistry, Tacrolimus Binding Protein 1A genetics, Ligands, Muscle, Skeletal growth & development, Sirolimus administration & dosage, Tacrolimus Binding Protein 1A metabolism
- 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., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2014
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