title: Thyroid Hormone Stimulation of Autophagy Is Essential for Mitochondrial Biogenesis and Activity in Skeletal Muscle.
abstract: Thyroid hormone (TH) and autophagy share similar functions in regulating skeletal muscle growth, regeneration, and differentiation. Although TH recently has been shown to increase autophagy in liver, the regulation and role of autophagy by this hormone in skeletal muscle is not known. Here, using both in vitro and in vivo models, we demonstrated that TH induces autophagy in a dose- and time-dependent manner in skeletal muscle. TH induction of autophagy involved reactive oxygen species (ROS) stimulation of 5'adenosine monophosphate-activated protein kinase (AMPK)-Mammalian target of rapamycin (mTOR)-Unc-51-like kinase 1 (Ulk1) signaling. TH also increased mRNA and protein expression of key autophagy genes, microtubule-associated protein light chain 3 (LC3), Sequestosome 1 (p62), and Ulk1, as well as genes that modulated autophagy and Forkhead box O (FOXO) 1/3a. TH increased mitochondrial protein synthesis and number as well as basal mitochondrial O2 consumption, ATP turnover, and maximal respiratory capacity. Surprisingly, mitochondrial activity and biogenesis were blunted when autophagy was blocked in muscle cells by Autophagy-related gene (Atg)5 short hairpin RNA (shRNA). Induction of ROS and 5'adenosine monophosphate-activated protein kinase (AMPK) by TH played a significant role in the up-regulation of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A), the key regulator of mitochondrial synthesis. In summary, our findings showed that TH-mediated autophagy was essential for stimulation of mitochondrial biogenesis and activity in skeletal muscle. Moreover, autophagy and mitochondrial biogenesis were coupled in skeletal muscle via TH induction of mitochondrial activity and ROS generation.
authors.affiliation: Laboratory of Hormonal Regulation (R.L., R.A.S., B.K.S., J.Z., K.O., W.WY.Y., P.M.Y.), Program of Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore 169857; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung 45363, Indonesia; Department of Anatomy (Y.W., B.-H.B.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599; and Duke Molecular Physiology Institute and Department of Medicine (P.M.Y.), Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Ronny
authors.initials: R
authors.lastname: Lesmana
authors.affiliation: Laboratory of Hormonal Regulation (R.L., R.A.S., B.K.S., J.Z., K.O., W.WY.Y., P.M.Y.), Program of Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore 169857; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung 45363, Indonesia; Department of Anatomy (Y.W., B.-H.B.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599; and Duke Molecular Physiology Institute and Department of Medicine (P.M.Y.), Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Rohit A
authors.initials: RA
authors.lastname: Sinha
authors.affiliation: Laboratory of Hormonal Regulation (R.L., R.A.S., B.K.S., J.Z., K.O., W.WY.Y., P.M.Y.), Program of Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore 169857; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung 45363, Indonesia; Department of Anatomy (Y.W., B.-H.B.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599; and Duke Molecular Physiology Institute and Department of Medicine (P.M.Y.), Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Brijesh K
authors.initials: BK
authors.lastname: Singh
authors.affiliation: Laboratory of Hormonal Regulation (R.L., R.A.S., B.K.S., J.Z., K.O., W.WY.Y., P.M.Y.), Program of Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore 169857; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung 45363, Indonesia; Department of Anatomy (Y.W., B.-H.B.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599; and Duke Molecular Physiology Institute and Department of Medicine (P.M.Y.), Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Laboratory of Hormonal Regulation (R.L., R.A.S., B.K.S., J.Z., K.O., W.WY.Y., P.M.Y.), Program of Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore 169857; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung 45363, Indonesia; Department of Anatomy (Y.W., B.-H.B.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599; and Duke Molecular Physiology Institute and Department of Medicine (P.M.Y.), Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ohba
authors.affiliation: Laboratory of Hormonal Regulation (R.L., R.A.S., B.K.S., J.Z., K.O., W.WY.Y., P.M.Y.), Program of Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore 169857; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung 45363, Indonesia; Department of Anatomy (Y.W., B.-H.B.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599; and Duke Molecular Physiology Institute and Department of Medicine (P.M.Y.), Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Laboratory of Hormonal Regulation (R.L., R.A.S., B.K.S., J.Z., K.O., W.WY.Y., P.M.Y.), Program of Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore 169857; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung 45363, Indonesia; Department of Anatomy (Y.W., B.-H.B.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599; and Duke Molecular Physiology Institute and Department of Medicine (P.M.Y.), Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Winifred W Y
authors.initials: WW
authors.lastname: Yau
authors.affiliation: Laboratory of Hormonal Regulation (R.L., R.A.S., B.K.S., J.Z., K.O., W.WY.Y., P.M.Y.), Program of Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore 169857; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung 45363, Indonesia; Department of Anatomy (Y.W., B.-H.B.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599; and Duke Molecular Physiology Institute and Department of Medicine (P.M.Y.), Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Boon-Huat
authors.initials: BH
authors.lastname: Bay
authors.affiliation: Laboratory of Hormonal Regulation (R.L., R.A.S., B.K.S., J.Z., K.O., W.WY.Y., P.M.Y.), Program of Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore 169857; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung 45363, Indonesia; Department of Anatomy (Y.W., B.-H.B.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599; and Duke Molecular Physiology Institute and Department of Medicine (P.M.Y.), Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Yen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071187:Autophagy-Related Protein 5; D000071189:Autophagy-Related Protein-1 Homolog; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D007700:Kinetics; D008297:Male; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000187:drug effects; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D010101:Oxygen Consumption / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013974:Thyroxine / Q000378:metabolism / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D014284:Triiodothyronine; C546843:mTOR protein, mouse; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C112444:Ulk1 protein, mouse; D055372:AMP-Activated Protein Kinases; D013974:Thyroxine