Abstract 18792: Beclin-1 Haploinsufficiency Protects Against Obesity-induced Cardiac Dysfunction Through Compensatory Mitophagy and Alternative Autophagy

Abstract

Background: Though autophagy including the selective mitophagy is essential for cellular homeostasis, its role in obese heart function remains controversial. Beclin-1 plays a cardinal role in conventional autophagy and has recently been implicated in alternative autophagy and mitophagy. This study was designed to examine the impact of Beclin-1 haploinsufficiency using heterozygous deletion of Beclin-1 (BCN-KO) on high fat diet (HFD)-induced cardiac anomalies. Methods and Results: Adult wild type (WT) and BCN-KO mice were fed low fat diet (LFD) or HFD for 12 weeks. HFD triggered comparable body weight gain in WT and BCN-KO mice. However, BCN-KO improved HFD-induced glucose intolerance and countered against HFD-induced cardiomyocyte contractile dysfunction manifested as decreased peak shortening, +dL/dt, -dL/dt and prolonged TR 90 . Levels of Beclin-1 were downregulated following HFD feeding although such effect was masked by BCN haploinsufficiency. Levels of autophagy markers LC3B-II/I and Atg5 were downregulated in a comparable manner in both HFD groups. Interestingly, Rab9, an essential regulator for alternative autophagy, was upregulated in HFD groups with a more pronounced effect in BCN-KO mice. Level of p62 was increased by HFD in WT but not BCN-KO group. Furthermore, the mitochondrial coupling protein for LC3B Bnip3 (also a key molecule for alternative autophagy-induced mitophagy) was upregulated in HFD groups with a more pronounced effect in BCN-KO mice. Moreover, Pink1 and AMPK phosphorylation, two key regulators in mitophagy were decreased by HFD in WT but not BCN-KO group. In line with these results, PGC-1 a (a marker of mitochondrial biogenesis) was downregulated by HFD, the effect of which was rescued by BCN-KO. Conclusion: Taken together, our data revealed that HFD led to cardiac contractile defect accompanied with dampened conventional autophagy and facilitated alternative autophagy. Our data suggested that adaptive mitophagy may play a pivotal role in BCN haploinsufficiency-induced beneficial effect. Such as beneficial effect was achieved through promoting HFD-induced alternative autophagy, which may contribute to increased mitophagy under HFD intake possibly via AMPK, Rab9 and Bnip3-mediated signaling pathways.