Loss of the melanocortin-4 receptor in mice causes dilated cardiomyopathy

• Published in: eLife 2017-08, Vol.6
• Main Authors: Litt, Michael J, Okoye, G Donald, Lark, Daniel, Cakir, Isin, Moore, Christy, Barber, Mary C, Atkinson, James, Fessel, Josh, Moslehi, Javid, Cone, Roger D
• Format: Article
• Language: English
• Subjects: Adenosine Diphosphate - metabolism; Age; Animal experimentation; Animals; Anthracyclines; Antineoplastic agents; Body composition; Bradycardia; Cardiac arrhythmia; Cardiomyocytes; Cardiomyopathy; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - pathology; cardiovascular; Cardiovascular disease; Cardiovascular diseases; Cell Respiration - drug effects; Child health; Childhood obesity; Congestive cardiomyopathy; Dilated cardiomyopathy; Displays (Marketing); Drug dosages; Genes; Genetic engineering; Genetically modified organisms; Glucose; Haploinsufficiency; heart; Heart cells; Heart diseases; Heart failure; Heart rate; House mouse; Human Biology and Medicine; Hypertension; MC4R; Medical research; Melanocortin; Melanocortin MC4 receptors; melanocortin-4 receptor; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondria - ultrastructure; Muscle contraction; Mutation; Myocardial diseases; Myocardium - pathology; Myocytes, Cardiac - pathology; Obesity; Peptide hormones; Physicians; Physiological aspects; Physiology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Reactive Oxygen Species - toxicity; Receptor, Melanocortin, Type 4 - deficiency; Rodents; Scientists; Software; Type 2 diabetes; Ventricle
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.28118

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. cardiomyopathy is characterized by ultrastructural changes in mitochondrial morphology and cardiomyocyte disorganization. Remarkably, testing of myocardial tissue from 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.