title: Thyroid Hormone Receptor α Plays an Essential Role in Male Skeletal Muscle Myoblast Proliferation, Differentiation, and Response to Injury.
abstract: Thyroid hormone plays an essential role in myogenesis, the process required for skeletal muscle development and repair, although the mechanisms have not been established. Skeletal muscle develops from the fusion of precursor myoblasts into myofibers. We have used the C2C12 skeletal muscle myoblast cell line, primary myoblasts, and mouse models of resistance to thyroid hormone (RTH) α and β, to determine the role of thyroid hormone in the regulation of myoblast differentiation. T3, which activates thyroid hormone receptor (TR) α and β, increased myoblast differentiation whereas GC1, a selective TRβ agonist, was minimally effective. Genetic approaches confirmed that TRα plays an important role in normal myoblast proliferation and differentiation and acts through the Wnt/β-catenin signaling pathway. Myoblasts with TRα knockdown, or derived from RTH-TRα PV (a frame-shift mutation) mice, displayed reduced proliferation and myogenic differentiation. Moreover, skeletal muscle from the TRα1PV mutant mouse had impaired in vivo regeneration after injury. RTH-TRβ PV mutant mouse model skeletal muscle and derived primary myoblasts did not have altered proliferation, myogenic differentiation, or response to injury when compared with control. In conclusion, TRα plays an essential role in myoblast homeostasis and provides a potential therapeutic target to enhance skeletal muscle regeneration.
authors.affiliation: Department of Medicine (A.M., Y.-Y.L., A.Y., G.A.B.), Veterans Affairs Greater Los Angeles Healthcare System, and Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California 90073; Department of Neurosurgery (J.-W.L., N.-H.K., A.K., V.C.), Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Urology (S.S., N.T., L.P.), Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027; and National Cancer Institute (S.C.), Bethesda, Maryland 20892.
authors.forename: Anna
authors.initials: A
authors.lastname: Milanesi
authors.affiliation: Department of Medicine (A.M., Y.-Y.L., A.Y., G.A.B.), Veterans Affairs Greater Los Angeles Healthcare System, and Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California 90073; Department of Neurosurgery (J.-W.L., N.-H.K., A.K., V.C.), Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Urology (S.S., N.T., L.P.), Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027; and National Cancer Institute (S.C.), Bethesda, Maryland 20892.
authors.forename: Jang-Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Medicine (A.M., Y.-Y.L., A.Y., G.A.B.), Veterans Affairs Greater Los Angeles Healthcare System, and Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California 90073; Department of Neurosurgery (J.-W.L., N.-H.K., A.K., V.C.), Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Urology (S.S., N.T., L.P.), Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027; and National Cancer Institute (S.C.), Bethesda, Maryland 20892.
authors.forename: Nam-Ho
authors.initials: NH
authors.lastname: Kim
authors.affiliation: Department of Medicine (A.M., Y.-Y.L., A.Y., G.A.B.), Veterans Affairs Greater Los Angeles Healthcare System, and Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California 90073; Department of Neurosurgery (J.-W.L., N.-H.K., A.K., V.C.), Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Urology (S.S., N.T., L.P.), Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027; and National Cancer Institute (S.C.), Bethesda, Maryland 20892.
authors.forename: Yan-Yun
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Department of Medicine (A.M., Y.-Y.L., A.Y., G.A.B.), Veterans Affairs Greater Los Angeles Healthcare System, and Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California 90073; Department of Neurosurgery (J.-W.L., N.-H.K., A.K., V.C.), Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Urology (S.S., N.T., L.P.), Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027; and National Cancer Institute (S.C.), Bethesda, Maryland 20892.
authors.forename: An
authors.initials: A
authors.lastname: Yang
authors.affiliation: Department of Medicine (A.M., Y.-Y.L., A.Y., G.A.B.), Veterans Affairs Greater Los Angeles Healthcare System, and Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California 90073; Department of Neurosurgery (J.-W.L., N.-H.K., A.K., V.C.), Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Urology (S.S., N.T., L.P.), Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027; and National Cancer Institute (S.C.), Bethesda, Maryland 20892.
authors.forename: Sargis
authors.initials: S
authors.lastname: Sedrakyan
authors.affiliation: Department of Medicine (A.M., Y.-Y.L., A.Y., G.A.B.), Veterans Affairs Greater Los Angeles Healthcare System, and Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California 90073; Department of Neurosurgery (J.-W.L., N.-H.K., A.K., V.C.), Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Urology (S.S., N.T., L.P.), Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027; and National Cancer Institute (S.C.), Bethesda, Maryland 20892.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kahng
authors.affiliation: Department of Medicine (A.M., Y.-Y.L., A.Y., G.A.B.), Veterans Affairs Greater Los Angeles Healthcare System, and Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California 90073; Department of Neurosurgery (J.-W.L., N.-H.K., A.K., V.C.), Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Urology (S.S., N.T., L.P.), Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027; and National Cancer Institute (S.C.), Bethesda, Maryland 20892.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Cervantes
authors.affiliation: Department of Medicine (A.M., Y.-Y.L., A.Y., G.A.B.), Veterans Affairs Greater Los Angeles Healthcare System, and Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California 90073; Department of Neurosurgery (J.-W.L., N.-H.K., A.K., V.C.), Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Urology (S.S., N.T., L.P.), Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027; and National Cancer Institute (S.C.), Bethesda, Maryland 20892.
authors.forename: Nikita
authors.initials: N
authors.lastname: Tripuraneni
authors.affiliation: Department of Medicine (A.M., Y.-Y.L., A.Y., G.A.B.), Veterans Affairs Greater Los Angeles Healthcare System, and Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California 90073; Department of Neurosurgery (J.-W.L., N.-H.K., A.K., V.C.), Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Urology (S.S., N.T., L.P.), Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027; and National Cancer Institute (S.C.), Bethesda, Maryland 20892.
authors.forename: Sheue-yann
authors.initials: SY
authors.lastname: Cheng
authors.affiliation: Department of Medicine (A.M., Y.-Y.L., A.Y., G.A.B.), Veterans Affairs Greater Los Angeles Healthcare System, and Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California 90073; Department of Neurosurgery (J.-W.L., N.-H.K., A.K., V.C.), Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Urology (S.S., N.T., L.P.), Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027; and National Cancer Institute (S.C.), Bethesda, Maryland 20892.
authors.forename: Laura
authors.initials: L
authors.lastname: Perin
authors.affiliation: Department of Medicine (A.M., Y.-Y.L., A.Y., G.A.B.), Veterans Affairs Greater Los Angeles Healthcare System, and Departments of Medicine and Physiology, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California 90073; Department of Neurosurgery (J.-W.L., N.-H.K., A.K., V.C.), Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Urology (S.S., N.T., L.P.), Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027; and National Cancer Institute (S.C.), Bethesda, Maryland 20892.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Brent
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004351:Drug Resistance; D016368:Frameshift Mutation; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D024510:Muscle Development / Q000187:drug effects; D018482:Muscle, Skeletal / Q000166:cytology / Q000293:injuries / Q000502:physiology*; D032448:Myoblasts, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D034622:RNA Interference; D012038:Regeneration; D037021:Thyroid Hormone Receptors alpha / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D014284:Triiodothyronine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D000085:Acetates; C413355:GC 1 compound; D010636:Phenols; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine