title: Ligands for FKBP12 increase Ca2+ influx and protein synthesis to improve skeletal muscle function.
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.
authors: From the Baylor College of Medicine, Houston, Texas 77030.
authors: Chang Seok
authors: CS
authors: Lee
authors: From the Baylor College of Medicine, Houston, Texas 77030.
authors: Dimitra K
authors: DK
authors: Georgiou
authors: From the Baylor College of Medicine, Houston, Texas 77030.
authors: Adan
authors: A
authors: Dagnino-Acosta
authors: From the Baylor College of Medicine, Houston, Texas 77030.
authors: Jianjun
authors: J
authors: Xu
authors: From the Baylor College of Medicine, Houston, Texas 77030.
authors: Iskander I
authors: II
authors: Ismailov
authors: From the Baylor College of Medicine, Houston, Texas 77030.
authors: Mark
authors: M
authors: Knoblauch
authors: From the Baylor College of Medicine, Houston, Texas 77030.
authors: Tanner O
authors: TO
authors: Monroe
authors: From the Baylor College of Medicine, Houston, Texas 77030.
authors: RuiRui
authors: R
authors: Ji
authors: From the Baylor College of Medicine, Houston, Texas 77030.
authors: Amy D
authors: AD
authors: Hanna
authors: From the Baylor College of Medicine, Houston, Texas 77030.
authors: Aditya D
authors: AD
authors: Joshi
authors: From the Baylor College of Medicine, Houston, Texas 77030.
authors: Cheng
authors: C
authors: Long
authors: From the Baylor College of Medicine, Houston, Texas 77030.
authors: Joshua
authors: J
authors: Oakes
authors: From the Baylor College of Medicine, Houston, Texas 77030.
authors: Ted
authors: T
authors: Tran
authors: the Muscle Biology Laboratory, Department of Kinesiology and Health, Georgia State University, Atlanta, Georgia 30302.
authors: Benjamin T
authors: BT
authors: Corona
authors: the Center for Metabolic and Degenerative Disease, University of Texas Health Science Center, Houston, Texas 77030, and.
authors: Sabina
authors: S
authors: Lorca
authors: the Muscle Biology Laboratory, Department of Kinesiology and Health, Georgia State University, Atlanta, Georgia 30302.
authors: Christopher P
authors: CP
authors: Ingalls
authors: the Center for Metabolic and Degenerative Disease, University of Texas Health Science Center, Houston, Texas 77030, and.
authors: Vihang A
authors: VA
authors: Narkar
authors: From the Baylor College of Medicine, Houston, Texas 77030.
authors: Johanna T
authors: JT
authors: Lanner
authors: From the Baylor College of Medicine, Houston, Texas 77030.
authors: J Henri
authors: JH
authors: Bayle
authors: the Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555-1041.
authors: William J
authors: WJ
authors: Durham
authors: From the Baylor College of Medicine, Houston, Texas 77030, susanh@bcm.tmc.edu.
authors: Susan L
authors: SL
authors: Hamilton
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000187:drug effects; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D008024:Ligands; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D022061:Tacrolimus Binding Protein 1A; D020123:Sirolimus
keywords: Calcium; Excitation-Contraction Coupling (E-C Coupling); Fatigue; Protein Synthesis; RyR1; Ryanodine Receptor; Skeletal Muscle; mTORC1