DRC members Vitor Lira and Dale Abel collaborate on the identification of new regulators mediating diabetic heart disease

Diabetes Mellitus is associated with cardiomyopathy. As a result, diabetic men and women are at high risk to develop heart failure. A major challenge in developing therapies for preventing diabetes-related heart failure relates to the several cellular processes that become altered in heart cells of people with diabetes. One of these key processes called autophagy. Autophagy is required for proper function of the heart. When autophagy is deficient in the heart, dysfunctional mitochondria accumulate. This is problematic because mitochondria are the powerhouse of the cell (i.e., are responsible for energy production). Dysfunctional mitochondria cause heart cells to lose their ability to function properly. Therefore, a better understanding on how autophagy is regulated in cardiac cells may help identify proteins that could be targeted for therapy to keep diabetic cardiomyopathy at bay.

In this context, the labs of Vitor Lira and Dale Abel at the FOEDRC recently published a collaborative and comprehensive study in mice investigating the role of two heart proteins named ULK1 and ULK2  (Harris et al., Autophagy, 2022). These two proteins regulate cardiac autophagy and function during development and adulthood. They demonstrated that cardiac loss of ULK1 or ULK2 early during development enhances cardiac autophagy, preserving cardiac function in adulthood. On the other hand, adult loss of cardiac ULK1, but not of ULK2, led to a rapid development of cardiomyopathy followed by heart failure and early death. Further investigation into the potential mechanisms involved revealed that adult loss of cardiac ULK1 impaired autophagy and compromised mitochondrial respiration and energy availability in cardiac cells (i.e., energy production). They then tested if rescuing autophagy in mice with adult loss of ULK1 could alleviate cardiac dysfunction. To do so, they administered a compound (trehalose) that is known to stimulate autophagy to these cardiac ULK1 deficient mice. They found that even though administration of trehalose lessened some of the autophagy impairments, it did not delay or prevent the development of cardiac dysfunction. Collectively, these results demonstrate for the first time that cardiac ULK1 and ULK2 are functionally redundant regulating autophagy in the developing heart, while ULK1 plays additional autophagy-independent functions in the adult heart. Future studies will focus on deciphering these additional ULK1 roles and testing if stimulation of ULK1 is protective against diabetic cardiomyopathy.

This work was funded by grants from the American Heart Association and the National Institutes of Health to both Vitor Lira and Dale Abel.

Reference:

Harris MP, Zhang QJ, Cochran CT, Ponce J, Alexander S, Kronemberger A, Fuqua JD, Zhang Y, Fattal R, Harper T, Murry ML, Grueter CE, Abel ED, Lira VA. Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function. Autophagy. 2022 Feb 1;:1-17. doi: 10.1080/15548627.2021.2022289. [Epub ahead of print] PubMed PMID: 35104184.

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