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. Durham & 1 others Susan L. Hamilton

Research output: Contribution to journalArticle

13 Citations (Scopus)

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

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Tacrolimus Binding Protein 1A
Muscle
Skeletal Muscle
Sirolimus
Ligands
Proteins
TOR Serine-Threonine Kinases
Fatigue of materials
Muscle Fatigue
Sarcoplasmic Reticulum
Fatigue
Durability
Body Weight
Muscles
Fibers
mechanistic target of rapamycin complex 1

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., ... 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

Ligands for FKBP12 increase Ca2+influx and protein synthesis to improve skeletal muscle function. / Lee, Chang Seok; Georgiou, Dimitra K.; Dagnino-Acosta, Adan; Xu, Jianjun; Ismailov, Iskander I.; Knoblauch, Mark; Monroe, Tanner O.; Ji, Rui Rui; Hanna, Amy D.; Joshi, Aditya D.; Long, Cheng; Oakes, Joshua; Tran, Ted; Corona, Benjamin T.; Lorca, Sabina; Ingalls, Christopher P.; Narkar, Vihang A.; Lanner, Johanna T.; Bayle, J. Henri; Durham, William J.; Hamilton, Susan L.

In: Journal of Biological Chemistry, Vol. 289, No. 37, 12.09.2014, p. 25556-25570.

Research output: Contribution to journalArticle

Lee, CS, Georgiou, DK, Dagnino-Acosta, A, Xu, J, Ismailov, II, Knoblauch, M, Monroe, TO, Ji, RR, Hanna, AD, Joshi, AD, Long, C, Oakes, J, Tran, T, Corona, BT, Lorca, S, Ingalls, CP, Narkar, VA, Lanner, JT, Bayle, JH, Durham, WJ & Hamilton, SL 2014, 'Ligands for FKBP12 increase Ca2+influx and protein synthesis to improve skeletal muscle function', Journal of Biological Chemistry, vol. 289, no. 37, pp. 25556-25570. https://doi.org/10.1074/jbc.M114.586289
Lee CS, Georgiou DK, Dagnino-Acosta A, Xu J, Ismailov II, Knoblauch M et al. Ligands for FKBP12 increase Ca2+influx and protein synthesis to improve skeletal muscle function. Journal of Biological Chemistry. 2014 Sep 12;289(37):25556-25570. https://doi.org/10.1074/jbc.M114.586289
Lee, Chang Seok ; Georgiou, Dimitra K. ; Dagnino-Acosta, Adan ; Xu, Jianjun ; Ismailov, Iskander I. ; Knoblauch, Mark ; Monroe, Tanner O. ; Ji, Rui Rui ; Hanna, Amy D. ; Joshi, Aditya D. ; Long, Cheng ; Oakes, Joshua ; Tran, Ted ; Corona, Benjamin T. ; Lorca, Sabina ; Ingalls, Christopher P. ; Narkar, Vihang A. ; Lanner, Johanna T. ; Bayle, J. Henri ; Durham, William J. ; Hamilton, Susan L. / Ligands for FKBP12 increase Ca2+influx and protein synthesis to improve skeletal muscle function. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 37. pp. 25556-25570.
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