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Title page for ETD etd-08162017-120036


Type of Document Dissertation
Author Litt, Michael Joshua
URN etd-08162017-120036
Title Identification and Characterization of a Cardiomyopathy Syndrome Resulting from Loss of the Melanocortin 4 Receptor
Degree PhD
Department Molecular Physiology and Biophysics
Advisory Committee
Advisor Name Title
David Wasserman Committee Chair
Danny Winder Committee Member
David Weaver Committee Member
Owen Mcguiness Committee Member
Roger Cone Committee Member
Keywords
  • MC4R
  • Cardiomyopathy
  • Obesity
  • Heart
  • Free Radicals
  • Mitochondria
  • Doxorubicin
Date of Defense 2017-07-28
Availability unrestricted
Abstract
Haploinsufficiency of the melanocortin-4 receptor (MC4R) is the most common monogenetic obesity syndrome in humans. This syndrome is associated with a reduction in autonomic tone, bradycardia, hyperinsulinemia and a reduced prevalence of obesity-associated hypertension. Thus, it has been assumed that melanocortin obesity syndrome may be protective with respect to obesity-associated cardiovascular disease. We show here that deletion of the Mc4r in mice causes a dilated cardiomyopathy characterized by reduced contractility and increased left ventricular diameter. This cardiomyopathy is independent of obesity as weight matched wild type mice are spared from systolic dysfunction. Mc4r-/- heart tissue further displays ultrastructural abnormalities in mitochondrial morphology and cardiomyocyte organization. Remarkably, mitochondrial function testing of myocardial tissue from Mc4r-/- mice revealed increased ADP stimulated respiration. This is in contrast to the reduction in O2 consumption seen in other models of cardiomyopathy, as well as the reduction in whole animal energy expenditure detected in MC4R knockout animals by indirect calorimetry. However, we show that this increase in respiration correlates with increased reactive oxygen species production – a canonical mediator of tissue damage. In keeping with this hypothesis, Mc4r-/- heart tissue displays a similar transcriptional profile to that of doxorubicin treatment – a free radical generating chemotherapy. Furthermore, Mc4r+/- mice are hypersensitive to both the cachexigenic and cardiac suppressive side effects of doxorubicin treatment. Together this study identifies MC4R deletion as a novel and potentially clinically important cause of heart failure.
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