Role of Chaperone-Mediated Autophagy in heart regeneration
Rôle de l'Autophagie Médiée par les Chaperonnes dans la régénération du cœur
Résumé
Myocardial infarction (MI), a coronary heart disease, is a leading cause of death worldwide. Following such an injury, the damaged tissue is replaced by a noncontractile fibrotic scar, causing pathological tissue restructuring and ultimately heart failure. Current medical treatments can delay post-infarction pathophysiological remodeling but fail to re-establish new functional myocardium. Adult zebrafish have the unique ability to regenerate their heart after different insults, including cryoinjury - a method that recapitulates key post-infarction events including tissue death, fibrosis, and scarring in a localized manner. Recent data emphasize the importance of metabolic reprogramming to support regeneration. After cardiac damage, the cellular metabolism switches from oxidative to glycolytic which is critical to support endothelial cell (EC) and cardiomyocyte (CM) regeneration. Late studies show that manipulation of metabolic enzymes to enhance glycolysis is sufficient to promote adult CM proliferation in zebrafish and mice. Chaperone-mediated Autophagy (CMA), a major pathway of lysosomal proteolysis, is critical for cellular homeostasis and metabolism. It targets a specific amino acid sequence within proteins (KFERQ motif), thereby selectively remodeling the proteome. Targets include key carbohydrate and lipid metabolism enzymes. My pioneering PhD work was one of the first to identify CMA in fish, revealing its role in metabolic processes. Here we hypothesize that CMA activation plays a key role during heart regeneration by regulating the cardiac metabolic switch after injury Firstly, we focused on assessing CMA status in heart regeneration. To this end, we measured lamp2a expression, the rate-limiting factor of CMA, in zebrafish heart at different timepoints after cardiac cryoinjury. Our results indicate a gradual activation of lamp2a, with a peak at 4 days post-cryoinjury. We confirmed this upregulation by high resolution in situ hybridization for lamp2a . Our current efforts are focused on investigating the impact of CMA loss- and gain-of-function on heart regeneration using new genetic models. Overall, this study will help understand the role of CMA in metabolic reprograming during heart regeneration, having the potential to inform new MI therapies.