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 â a canonical mediator of tissue damage. In keeping with this hypothesis, Mc4r-/- heart tissue displays a similar transcriptional profile to that of doxorubicin treatment â 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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-08162017-120036 |
| Date | 26 August 2017 |
| Creators | Litt, Michael Joshua |
| Contributors | Roger Cone, David Wasserman, Owen Mcguiness, Danny Winder, David Weaver |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-08162017-120036/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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