Galanin Is a Checkpoint Regulator of Mitochondrial Biogenesis Coordinating a Pro-Survival Phenotype in Post-Infarct Myocardial Remodeling

Background: Myocardial infarction due to ischemia-reperfusion (I/R) results in aberrant cell fate decisions leading to metabolic, inflammatory and fibrotic reprogramming of the myocardium and loss of cardiac function. However, molecular underpinnings of post-infarct-remodelled heart remain largely incomplete. The present study addresses the role of galanin, a pleiotropic endogenous peptide, in the regulation of cell death-associated acute and chronic myocardial remodeling after cardiac I/R injury. Methods: C57Bl/6J mice were subjected to 24h and 14 days of mycardial I/R and were post-treated with galanin. Cell death assessments, cardiac metabolism, mitochondrial damage and histological analysis were performed to evaluate cardiac remodeling. Real-time mitochondrial respiration was monitored in living cardiomyoblasts using the Seahorse technology. Findings: In the acute phase of I/R injury, galanin preserves cardiac mitochondrial integrity and reactivates fetal-like metabolic program characterized by depressed fatty acid (FA) oxidation and increased glucose metabolism resulting in infarct size reduction. In progressive post-infarct remodeling, galanin counteracts inflammation-associated cardiac fibrosis translating in a pro-survival phenotype in mice. In vitro, galanin prevents oxidative stress-mediated apoptotic cell death and promotes mitochondrial biogenesis and respiration. Mechanistically, galanin reprograms cell death decisions through Forkhead box protein O1 (FoxO1) pathway. Interpretation: These findings uncover galanin as a key checkpoint regulator of mitochondrial biogenesis in cell death-associated myocardial metabolic remodeling and offer a promising strategy for the treatment of post-infarct heart failure. Funding: This work was supported by the INSERM, Region Midi-Pyrenees and ERASMUS MUNDUS MEDEA project, INSERM. Declaration of Interest: None. Ethical Approval: The investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985) and was performed in accordance with the recommendations of the French Accreditation of the Laboratory Animal Care (approved by the local Centre National de la RechercheScientifique ethics committee).