Backgroundα-Melanocyte-stimulating hormone (α-MSH) regulates diverse physiological functions by activating melanocortin receptors (MC-R). α-MSH is predominantly expressed in the pituitary gland, but it is also found in several peripheral tissues such as the skin and heart. However, the role of α-MSH and its possible target receptors in the heart remain completely unknown. Therefore, we sought to investigate whether α-MSH could be involved in the regulation of pathological cardiac remodeling.MethodsTissue α-MSH concentrations and the effects of chronic α-MSH administration were investigated in mice subjected to transverse aortic constriction (TAC). Rat H9c2 cells, neonatal mouse ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) were used to study the effects of α-MSH and selective MC-R agonists. Inducible cardiomyocyte-specific melanocortin 5 receptor (MC5-R) knockout mouse model was engineered to investigate the role of MC5-R in cardiac hypertrophy.Resultsα-MSH was highly expressed in the mouse heart, particularly in the ventricles, and its level was reduced in the left ventricles of TAC-operated mice. Administration of a stable α-MSH analogue protected mice against TAC-induced cardiac hypertrophy and systolic dysfunction.In vitroexperiments revealed that cardiomyocytes serve as effector cells for the α-MSH mediated antihypertrophic signaling and that selective activation of MC5-R mimics the actions of α-MSH. In keeping with these findings, MC5-R was downregulated in the failing mouse heart and stressed hiPSC-CMs. Silencing of MC5-R in mouse cardiomyocytes induced hypertrophy and fibrosis markersin vitroand aggravated TAC-induced cardiac hypertrophy and fibrosisin vivo. Conversely, pharmacological activation of MC5-R improved systolic function and reduced cardiac fibrosis in TAC-operated mice.Conclusionsα-MSH is expressed in the heart and protects against pathological cardiac remodeling by activating MC5-R in cardiomyocytes. These results suggest that analogues of naturally occurring α-MSH, that have been recently approved for clinical use and have agonistic activity at MC5-R, may be of benefit in treating heart failure.