Ligands for FKBP12 increase Ca2+influx and protein synthesis to improve skeletal muscle function

Chang Seok Lee, Dimitra K. Georgiou, Adan Dagnino-Acosta, Jianjun Xu, Iskander I. Ismailov, Mark Knoblauch, Tanner O. Monroe, Rui Rui Ji, Amy D. Hanna, Aditya D. Joshi, Cheng Long, Joshua Oakes, Ted Tran, Benjamin T. Corona, Sabina Lorca, Christopher P. Ingalls, Vihang A. Narkar, Johanna T. Lanner, J. Henri Bayle, William J. DurhamSusan L. Hamilton

Research output: Contribution to journalArticle

13 Scopus citations

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 Ca2+influx to enhance refilling of sarcoplasmic reticulum Ca2+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.

Original languageEnglish (US)
Pages (from-to)25556-25570
Number of pages15
JournalJournal of Biological Chemistry
Volume289
Issue number37
DOIs
StatePublished - Sep 12 2014

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Lee, C. S., Georgiou, D. K., Dagnino-Acosta, A., Xu, J., Ismailov, I. I., Knoblauch, M., Monroe, T. O., Ji, R. R., Hanna, A. D., Joshi, A. D., Long, C., Oakes, J., Tran, T., Corona, B. T., Lorca, S., Ingalls, C. P., Narkar, V. A., Lanner, J. T., Bayle, J. H., ... Hamilton, S. L. (2014). Ligands for FKBP12 increase Ca2+influx and protein synthesis to improve skeletal muscle function. Journal of Biological Chemistry, 289(37), 25556-25570. https://doi.org/10.1074/jbc.M114.586289