Heart failure (HF) with reduced ejection fraction is prevalent in leading to reduced life expectancy, poor quality of life and is responsible for a large proportion of healthcare costs. Dilated cardiomyopathy (DCM) is one of the main etiologies responsible for HF, especially in young and middle-aged patients. DCM is defined by ventricular chamber enlargement and systolic impairment leading to progressive HF. Nowadays, there is a lack of specific therapies for DCM able to reverse this condition. Our group has been a pioneer in demonstrating that imbalanced mitochondrial dynamics in cardiomyocytes results in an overt DCM phenotype. We generated a mouse with genetic ablation of the mitochondrial protease YME1L in cardiomyocytes (cYKO), which results in incorrect OPA1 processing and ultra-fragmented mitochondria in the heart in adulthood. These mice display normal cardiac function until week 30 of age, where a progressive DCM phenotype with reduced lifespan is shown. Moreover, cardiomyocytes display a metabolic switch characterized by preferential use of glucose as a metabolic substrate. This thesis project focusses firstly on the causality of the protease YME1L during DCM development. Unexpectedly, we found mitochondrial abnormalities (larger size and increased respiration) in a subclinical stage of the disease, when no macroscopic cardiac phenotype is apparent. We demonstrate an autophagy impairment underlying Yme1l cardiac-genetic ablation. This is accompanied by increased ER stress, apparently mediated by dysregulation of Ca2+ handling. Interestingly, these defects are seen in animals before onset of the disease. Secondly, our data show that a fat-restricted diet was able not only to prevent HF but also extends the lifespan of cYKO mice. We studied the molecular mechanisms underlying this cardioprotective effect. The mitochondrial ultrastructure indicates a restored mitochondrial number and enlarged size, which is not accompanied by enhanced mitochondrial respiration. Moreover, autophagy defects were still present. However, we speculate that better modulation of ER Ca2+ handling under this diet could be involved in enhanced cardiac performance. These intriguing data call for a comprehensive evaluation of the mechanisms leading to HF prevention and to identifying a diet that could then be translated into clinics

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 26-01-2023

Esta tesis tiene embargado el acceso al texto completo hasta el 26-07-2024