3070Caloric Restriction Increases Lifespan in Dilated Cardiomyopathy Mice by Enhancing Mitochondrial Quality Control

Abstract Background/Introduction Dilated cardiomyopathy (DCM) is a leading cause of heart failure (HF) in young and middle aged individuals worldwide. Alterations in mitochondrial dynamics (fusion/fission) and quality control (mitophagy) are critical for normal cardiac function. Imbalanced mitochondrial dynamics towards fission has been shown to contribute to DCM development in mice with ablation of the mitochondrial protease YME1L, which results in altered OPA1 processing precluding mitochondrial fusion. In these mice, the DCM phenotype includes a metabolic reprogramming of cardiomyocytes, shifting from fatty acid (FA) oxidation towards glucose. High fat diet (HFD) in these mice results in reversal of this metabolic reprogramming and rescue from DCM despite the genetic defect (lack of YME1) still present. These results opened a new venue for dietary approaches as a therapeutic strategy in HF. To understand whether the fat itself contained in the HFD was responsible of HF rescue, we studied the trajectories of cardiac function in mice with altered mitochondrial dynamics under HFD, caloric restriction and control chow. Methods Cardiomyocyte-specific Yme1l knock-out (cYKO) male mice (N=10–15) known to develop DCM phenotype at 20–25 weeks of age were randomized to 3 different diets (1: HFD containing >30% crude fat; 2: non-fat diet containing <0.5% crude fat, and 3: control diet containing 10% crude fat) at 10 weeks of age. Every 10 weeks, cardiac function was tested by echocardiography. At 30 weeks, animals underwent a multitracer microPET/CT (glucose and FA uptake) to evaluate myocardial substrate utilization. At the end of the study, animals were sacrificed and hearts were harvested for histological and further tissue analyses. Results As expected, HFD was associated with a better left ventricular ejection fraction (LVEF; %) at 30 weeks: 37.97±8.59 vs. 29.16±8.9 in control diet, p=0.04. This functional improvement was associated with an increase in FA uptake on microPET/CT. Non-fat diet was associated with even higher LVEF at 30 weeks: 44.94±11 vs. 29.16±8.9 in control diet, p=0.0001, as well as smaller LV diameter (mm): 3.58±0.29 vs. 4.3±0.39 in control diet, p<0.0001 (A). Lifespan of mice on non-fat diet was significantly prolonged (70% extension compared to control) (B). Enhanced mitochondrial clearance (mitophagy) mediated by Parkin, together with an increase in autophagy related protein as LC3B was identified in the non-fat diet group (C). Conclusion Different dietary approaches have been shown to be beneficial in the prevention of DCM in mice with altered mitochondrial dynamics. Caloric restriction (non-fat diet) is able to prevent DCM, reverse metabolic reprogramming, increase mitochondrial quality control and ultimately prolong lifespan in mice with genetic defect associated with altered mitochondrial dynamics. Interventions aiming at enhancing cardiac mitophagy might represent a new therapeutic option in DCM.