title: Thyroid hormone reverses aging-induced myocardial fatty acid oxidation defects and improves the response to acutely increased afterload.
abstract: BACKGROUND
  Subclinical hypothyroidism occurs during aging in humans and mice and may contribute to the development of heart failure. Aging also impairs myocardial fatty acid oxidation, causing increased reliance on flux through pyruvate dehydrogenase (PDH) to maintain function. We hypothesize that the metabolic changes in aged hearts make them less tolerant to acutely increased work and that thyroid hormone supplementation reverses these defects.
  
  
  METHODS
  Studies were performed on young (Young, 4-6 months) and aged (Old, 22-24 months) C57/BL6 mice at standard (50 mmHg) and high afterload (80 mmHg). Another aged group received thyroid hormone for 3 weeks (Old-TH, high afterload only). Function was measured in isolated working hearts along with substrate fractional contributions (Fc) to the citric acid cycle (CAC) using perfusate with (13)C labeled lactate, pyruvate, glucose and unlabeled palmitate and insulin.
  
  
  RESULTS
  Old mice maintained cardiac function under standard workload conditions, despite a marked decrease in unlabeled (presumably palmitate) Fc and relatively similar individual carbohydrate contributions. However, old mice exhibited reduced palmitate oxidation with diastolic dysfunction exemplified by lower -dP/dT. Thyroid hormone abrogated the functional and substrate flux abnormalities in aged mice.
  
  
  CONCLUSIONS
  The aged heart shows diminished ability to increase cardiac work due to substrate limitations, primarily impaired fatty acid oxidation. The heart accommodates slightly by increasing efficiency through oxidation of carbohydrate substrates. Thyroid hormone supplementation in aged mice significantly improves cardiac function potentially through restoration of fatty acid oxidation.
authors.affiliation: Seattle Children's Research Institute, Seattle, Washington, United States of America.
authors.forename: Dolena
authors.initials: D
authors.lastname: Ledee
authors.forename: Michael A
authors.initials: MA
authors.lastname: Portman
authors.forename: Masaki
authors.initials: M
authors.lastname: Kajimoto
authors.forename: Nancy
authors.initials: N
authors.lastname: Isern
authors.forename: Aaron K
authors.initials: AK
authors.lastname: Olson
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002952:Citric Acid Cycle / Q000187:drug effects; D005227:Fatty Acids / Q000097:blood / Q000378:metabolism*; D006334:Heart Function Tests; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D010084:Oxidation-Reduction / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013379:Substrate Specificity / Q000187:drug effects; D013963:Thyroid Hormones / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D014463:Ultrasonography
chemical_list: D005227:Fatty Acids; D012333:RNA, Messenger; D013963:Thyroid Hormones; D000105:Acetyl Coenzyme A