Embryonic versus adult cardiomyocyte loss of ULK1 and ULK2 uncover temporally distinct effects on autophagy and cardiac function

Abstract

Autophagy is a conserved cellular process that degrades dysfunctional organelles and long‐lived proteins. Insufficient autophagy contributes to several cardiomyopathies; however, the regulation of cardiac autophagy is still evolving. To this matter, Unc‐51 like autophagy activating kinases 1 and 2 (ULK1 and ULK2) are thought to play a primarily redundant role in autophagy initiation but their function in the heart remains insufficiently understood. Here, we first studied mice with embryonic cardiac‐specific deletion of Ulk1 or Ulk2 (cU1‐KO and cU2‐KO). Unexpectedly, adult cU1‐KO and cU2‐KO mice presented enhanced basal cardiac autophagy despite unchanged expression of essential autophagy machinery proteins. Cardiac function was unaltered in these mice. We then tested if this autophagy overcompensation relied on the remaining ULK protein by studying mice with embryonic cardiac‐specific deletion of both Ulk1 and Ulk2 (cU1/2‐DKO). Indeed, autophagy was impaired in cU1/2‐DKO leading to an aging‐associated cardiomyopathy and reduced survival. Next, we tested if the overall autophagy overcompensation resulting from the loss of a single cardiac Ulk was only feasible at early stages of development by studying mice with adult deletion of either Ulk1 or Ulk2 (i.e., icU1‐KO and icU2‐KO). Interestingly, while adult loss of ULK2 had no discernable effect on cardiac autophagy or function, loss of ULK1 caused a rapidly developing cardiomyopathy, heart failure and early death. Mechanistically, adult loss of cardiac ULK1 impaired autophagy and led to an overall fissed mitochondrial reticulum with deficiencies in respiration and ATP re‐synthesis. Altogether our results demonstrate that the impact of ULK1 and ULK2 loss on cardiac autophagy and function is developmentally determined. Further, although ULK1 and ULK2 appear to have redundant roles in modulating cardiac autophagy during development, only ULK1 is essential for maintenance of basal cardiac homeostasis in adulthood.