title: Mitochondrial and energetic cardiac phenotype in hypothyroid rat. Relevance to heart failure.
abstract: Changes in thyroid status are associated with profound alterations in biochemical and physiological functioning of cardiac muscle, although its impact on cardiac energy metabolism is still debated. Similarities between the changes in cardiac gene expression in pathological hypertrophy leading to heart failure and hypothyroidism prompted scientists to suggest a role for thyroid hormone status in the development of metabolic and functional alterations in this disease. We thus investigated the effects of hypothyroidism on cardiac energy metabolism. Hypothyroid state (HYPO) was induced by thyroidectomy and propyl-thio-uracyl in male rats for 3 weeks. We examined the effects of hypothyroid state on oxidative capacity and mitochondrial substrate utilization by measuring oxygen consumption of saponin permeabilized cardiac fibers, mitochondrial biogenesis by reverse transcription polymerase chain reaction and energy metabolism, and energy transfer enzymes by spectrophotometry. The results show that maximal oxidative capacity of the myocardium was decreased from 24.9 +/- 0.9 in control (CT) to 19.3 +/- 0.7 micromol O(2) min(-1) g dry weight(-1) in HYPO. However, protein content and messenger RNA (mRNA) of PGC-1alpha and mRNA of its transcription cascade that is thought to control mitochondrial content in normal myocardium and heart failure, were unchanged in HYPO. Mitochondrial utilization of glycerol-3P (-70%), malate (-45%), and octanoate (-24%) but not pyruvate was decreased in HYPO. Moreover, the creatine kinase system and energy transfer were hardly affected in HYPO. Besides, hypothyroidism decreased the activation of other signaling pathways like p38 mitogen-activated protein kinases, AMP-activated protein kinase, and calcineurin. These results show that cellular hypothyroidism can hardly account for the specific energetic alterations of heart failure.
authors.affiliation: INSERM, U769, Université Paris-Sud, Châtenay-Malabry, France.
authors.forename: Yoni
authors.initials: Y
authors.lastname: Athéa
authors.forename: Anne
authors.initials: A
authors.lastname: Garnier
authors.forename: Dominique
authors.initials: D
authors.lastname: Fortin
authors.forename: Lahoucine
authors.initials: L
authors.lastname: Bahi
authors.forename: Vladimir
authors.initials: V
authors.lastname: Veksler
authors.forename: Renée
authors.initials: R
authors.lastname: Ventura-Clapier
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D019703:Calcineurin / Q000502:physiology; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D004735:Energy Transfer / Q000502:physiology; D006333:Heart Failure / Q000503:physiopathology*; D007037:Hypothyroidism / Q000139:chemically induced / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008929:Mitochondria, Heart / Q000502:physiology*; D009097:Multienzyme Complexes / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010641:Phenotype; D011441:Propylthiouracil; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D013963:Thyroid Hormones / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; C548050:RCAN1 protein, rat; D013963:Thyroid Hormones; D014157:Transcription Factors; D011441:Propylthiouracil; D003576:Electron Transport Complex IV; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D019703:Calcineurin