Division of Cardiology, Vanderbilt University, Nashville, United States; Cardio-Oncology Program, Department of Medicine, Vanderbilt University, Nashville, United States
Daniel Lark
Departments of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States
Isin Cakir
Life Sciences Institute, University of Michigan, Ann Arbor, United States
Christy Moore
Allergy Pulmonary and Critical Care, Vanderbilt University Department of Medicine, Nashville, United States
Mary C Barber
Division of Cardiology, Vanderbilt University, Nashville, United States; Cardio-Oncology Program, Department of Medicine, Vanderbilt University, Nashville, United States
James Atkinson
Department of Pathology, Vanderbilt University Medical Center, Nashville, United States
Josh Fessel
Allergy Pulmonary and Critical Care, Vanderbilt University Department of Medicine, Nashville, United States
Javid Moslehi
Division of Cardiology, Vanderbilt University, Nashville, United States; Cardio-Oncology Program, Department of Medicine, Vanderbilt University, Nashville, United States
Departments 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 States
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.
