Loss of the melanocortin-4 receptor in mice causes dilated cardiomyopathy
Haploinsufficiency of the melanocortin-4 receptor, the most common monogenetic obesity syndrome in humans, is associated with a reduction in autonomic tone, bradycardia, and incidence of obesity-associated hypertension. Thus, it has been assumed that melanocortin obesity syndrome may be protective w...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/28118 |
| _version_ | 1811253028480614400 |
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| author | Michael J Litt G Donald Okoye Daniel Lark Isin Cakir Christy Moore Mary C Barber James Atkinson Josh Fessel Javid Moslehi Roger D Cone |
| author_facet | Michael J Litt G Donald Okoye Daniel Lark Isin Cakir Christy Moore Mary C Barber James Atkinson Josh Fessel Javid Moslehi Roger D Cone |
| author_sort | Michael J Litt |
| collection | DOAJ |
| description | Haploinsufficiency of the melanocortin-4 receptor, the most common monogenetic obesity syndrome in humans, is associated with a reduction in autonomic tone, bradycardia, and incidence 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 absence of the melanocortin-4 receptor (MC4R) in mice causes dilated cardiomyopathy, characterized by reduced contractility and increased left ventricular diameter. This cardiomyopathy is independent of obesity as weight matched diet induced obese mice do not display systolic dysfunction. Mc4r cardiomyopathy is characterized by ultrastructural changes in mitochondrial morphology and cardiomyocyte disorganization. Remarkably, testing of myocardial tissue from Mc4r−/− mice exhibited increased ADP stimulated respiratory capacity. However, this increase in respiration correlates with increased reactive oxygen species production – a canonical mediator of tissue damage. Together this study identifies MC4R deletion as a novel and potentially clinically important cause of heart failure. |
| first_indexed | 2024-04-12T16:44:32Z |
| format | Article |
| id | doaj.art-be1fdf60b9af4a499d962141b59a7a77 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:44:32Z |
| publishDate | 2017-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-be1fdf60b9af4a499d962141b59a7a772022-12-22T03:24:39ZengeLife Sciences Publications LtdeLife2050-084X2017-08-01610.7554/eLife.28118Loss of the melanocortin-4 receptor in mice causes dilated cardiomyopathyMichael J Litt0G Donald Okoye1https://orcid.org/0000-0003-1078-688XDaniel Lark2Isin Cakir3Christy Moore4Mary C Barber5James Atkinson6Josh Fessel7Javid Moslehi8Roger D Cone9https://orcid.org/0000-0003-3333-5651Departments of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United StatesDivision of Cardiology, Vanderbilt University, Nashville, United States; Cardio-Oncology Program, Department of Medicine, Vanderbilt University, Nashville, United StatesDepartments of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United StatesLife Sciences Institute, University of Michigan, Ann Arbor, United StatesAllergy Pulmonary and Critical Care, Vanderbilt University Department of Medicine, Nashville, United StatesDivision of Cardiology, Vanderbilt University, Nashville, United States; Cardio-Oncology Program, Department of Medicine, Vanderbilt University, Nashville, United StatesDepartment of Pathology, Vanderbilt University Medical Center, Nashville, United StatesAllergy Pulmonary and Critical Care, Vanderbilt University Department of Medicine, Nashville, United StatesDivision of Cardiology, Vanderbilt University, Nashville, United States; Cardio-Oncology Program, Department of Medicine, Vanderbilt University, Nashville, United StatesDepartments of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States; Life Sciences Institute, University of Michigan, Ann Arbor, United States; Department of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, United StatesHaploinsufficiency of the melanocortin-4 receptor, the most common monogenetic obesity syndrome in humans, is associated with a reduction in autonomic tone, bradycardia, and incidence 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 absence of the melanocortin-4 receptor (MC4R) in mice causes dilated cardiomyopathy, characterized by reduced contractility and increased left ventricular diameter. This cardiomyopathy is independent of obesity as weight matched diet induced obese mice do not display systolic dysfunction. Mc4r cardiomyopathy is characterized by ultrastructural changes in mitochondrial morphology and cardiomyocyte disorganization. Remarkably, testing of myocardial tissue from Mc4r−/− mice exhibited increased ADP stimulated respiratory capacity. However, this increase in respiration correlates with increased reactive oxygen species production – a canonical mediator of tissue damage. Together this study identifies MC4R deletion as a novel and potentially clinically important cause of heart failure.https://elifesciences.org/articles/28118heartcardiovascularcardiomyopathyMC4Rmelanocortin-4 receptorobesity |
| spellingShingle | Michael J Litt G Donald Okoye Daniel Lark Isin Cakir Christy Moore Mary C Barber James Atkinson Josh Fessel Javid Moslehi Roger D Cone Loss of the melanocortin-4 receptor in mice causes dilated cardiomyopathy eLife heart cardiovascular cardiomyopathy MC4R melanocortin-4 receptor obesity |
| title | Loss of the melanocortin-4 receptor in mice causes dilated cardiomyopathy |
| title_full | Loss of the melanocortin-4 receptor in mice causes dilated cardiomyopathy |
| title_fullStr | Loss of the melanocortin-4 receptor in mice causes dilated cardiomyopathy |
| title_full_unstemmed | Loss of the melanocortin-4 receptor in mice causes dilated cardiomyopathy |
| title_short | Loss of the melanocortin-4 receptor in mice causes dilated cardiomyopathy |
| title_sort | loss of the melanocortin 4 receptor in mice causes dilated cardiomyopathy |
| topic | heart cardiovascular cardiomyopathy MC4R melanocortin-4 receptor obesity |
| url | https://elifesciences.org/articles/28118 |
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