Regulation of Cardiac Metabolism by Autophagy

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Publication Type dissertation
School or College School of Medicine
Department Human Genetics
Author Li, Zhonggang
Title Regulation of Cardiac Metabolism by Autophagy
Date 2016-12
Description Autophagy is a catabolic pathway thatdegradesdamaged proteins and organelles in lysosome; however, the exact role ofautophagy in cardiac function in physiological and pathological statesis incompletely understood. To investigate the role of autophagy in the heart, we generated a cardiac-specific autophagy-deficient mousemodel with deletion of ATG3 gene (cATG3 KO)incardiomyocytes. ATG3-deficient heartsexhibited reduced ATG3 proteinand decreased autophagic flux. cATG3 KOmice developed cardiac contractile dysfunction at 4 weeks old in the absence of fibrosis. Mitochondrial function was impairedin cATG3 KO mouseheartsat 1 week old, which precedes cardiac contractile dysfunction. Interestingly, we found thatNAD+metabolic fluxwas alteredin cATG3 KO mousehearts, characterized by increased nicotinamide N-Methyltransferase(NNMT) expression and accelerated NAD+degradation.NNMT overexpression was sufficient to cause mitochondrial dysfunction and NNMT inhibition prevented mitochondrial dysfunctionin CQ-treated H9C2 cells. Moreover, nicotinamide mononucleotide(NMN), the precursor of NAD+, raised cardiac NAD+content and rescuedcardiac contractile dysfunction in cATG3 KO mice. Thesedatasuggest that autophagy playsan essential role in maintaining cardiac functionby regulating NNMT expression and NAD+homeostasis in the heart.Exercise training has been shownto be beneficial for cardiac function, although the exact molecularmechanism isunclear. To investigate the role of autophagy in maintaining cardiac homeostasisunder exercise conditions, mice with germline haplo-insufficiency of the autophagy regulator beclin 1(Atg6)weresubject to6 weeks treadmill ivtraining, and wild-type (WT) mice were used as control. Compared to WT mice,beclin 1 heterozygous mice exhibitedimpaired autophagyin response to exercise training.Interestingly, we found mitochondrial biogenesis andcardiac contractilefunction improvement wasattenuated after exercise trainingin beclin 1 heterozygous mouse heart. These results indicate autophagyalso plays anessentialrolefor mediating the increase in cardiac functionin response to exerciseby promoting mitochondrial biogenesis.
Type Text
Publisher University of Utah
Subject MESH Autophagy; Apoptosis; Beclin-1; Mitochondria; Nicotinamide Mononucleotide; Organelle Biogenesis; NAD; Metabolism; Sirtuins; Lysosomes; NAD+ Nucleosidase; Homeostasis; Heart; Myocytes, Cardiac; Myocardial Contraction; Cardiac Output; Heart Failure; Metabolic Diseases; Exercise; Models, Animal; Mice; Mice, Transgenic; Physical Conditioning, Animal; Physical Endurance
Dissertation Institution University of Utah
Dissertation Name Doctor of Philosophy
Language eng
Relation is Version of Digital version of Regulation of Cardiac Metabolism by Autophagy
Rights Management Copyright © ZhonggangLi 2016
Format Medium application/pdf
Source Original in Marriott Library Special Collections
ARK ark:/87278/s6jm6jjr
Setname ir_etd
Date Created 2018-10-01
Date Modified 2021-05-06
ID 1371511
Reference URL https://collections.lib.utah.edu/ark:/87278/s6jm6jjr
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