Journal article
Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function
Autophagy, Vol.18(9), pp.2161-2177
02/02/2022
DOI: 10.1080/15548627.2021.2022289
PMCID: PMC9466614
PMID: 35104184
Abstract
Impairments in macroautophagy/autophagy, which degrades dysfunctional organelles as well as long-lived and aggregate proteins, are associated with several cardiomyopathies; however, the regulation of cardiac autophagy remains insufficiently understood. In this regard, ULK1 and ULK2 are thought to play primarily redundant roles in autophagy initiation, but whether their function is developmentally determined, potentially having an impact on cardiac integrity and function remains unknown. Here, we demonstrate that perinatal loss of ULK1 or ULK2 in cardiomyocytes (cU1-KO and cU2-KO mice, respectively) enhances basal autophagy without altering autophagy machinery content while preserving cardiac function. This increased basal autophagy is dependent on the remaining ULK protein given that perinatal loss of both ULK1 and ULK2 in cU1/2-DKO mice impaired autophagy causing age-related cardiomyopathy and reduced survival. Conversely, adult loss of cardiac ULK1, but not of ULK2 (i.e., icU1-KO and icU2-KO mice, respectively), led to a rapidly developing cardiomyopathy, heart failure and early death. icU1-KO mice had impaired autophagy with robust deficits in mitochondrial respiration and ATP synthesis. Trehalose ameliorated autophagy impairments in icU1-KO hearts but did not delay cardiac dysfunction suggesting that ULK1 plays other critical, autophagy-independent, functions in the adult heart. Collectively, these results indicate that cardiac ULK1 and ULK2 are functionally redundant in the developing heart, while ULK1 assumes a more unique, prominent role in the adult heart.
Details
- Title: Subtitle
- Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function
- Creators
- Matthew P. Harris - University of IowaQuan J. Zhang - Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USACole T. Cochran - University of IowaJessica Ponce - University of IowaSean Alexander - University of IowaAna Kronemberger - University of IowaJordan D. Fuqua - University of IowaYuan Zhang - Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USARanan Fattal - University of IowaTyler Harper - University of IowaMatthew L. Murry - University of IowaChad E. Grueter - University of IowaE. Dale Abel - University of IowaVitor A. Lira - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Autophagy, Vol.18(9), pp.2161-2177
- DOI
- 10.1080/15548627.2021.2022289
- PMID
- 35104184
- PMCID
- PMC9466614
- NLM abbreviation
- Autophagy
- ISSN
- 1554-8627
- eISSN
- 1554-8635
- Publisher
- Taylor & Francis
- Number of pages
- 17
- Grant note
- 16SDG30360001 / American Heart Association R56AG063820; R01HL108379; U01 HL087947 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Fraternal Order of Eagles Diabetes Research Center
- Language
- English
- Electronic publication date
- 02/02/2022
- Academic Unit
- Cardiovascular Medicine; Craniofacial Anomalies Research Center; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Health, Sport, and Human Physiology ; Internal Medicine
- Record Identifier
- 9984259398502771
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