title: Inhibition of AMPK accentuates prolonged caloric restriction-induced change in cardiac contractile function through disruption of compensatory autophagy.
abstract: Prolonged caloric restriction often results in alteration in heart geometry and function although the underlying mechanism remains poorly defined. Autophagy, a conserved pathway for bulk degradation of intracellular proteins and organelles, preserves energy and nutrient in the face of caloric insufficiency. This study was designed to examine the role of AMPK in prolonged caloric restriction-induced change in cardiac homeostasis and the underlying mechanism(s) involved with a focus on autophagy. Wild-type (WT) and AMPK kinase dead (KD) mice were caloric restricted (by 40%) for 30 weeks. Echocardiographic, cardiomyocyte contractile and intracellular Ca²⁺ properties, autophagy and autophagy regulatory proteins were evaluated. Caloric restriction compromised echocardiographic indices (decreased ventricular mass, left ventricular diameters, and cardiac output), cardiomyocyte contractile and intracellular Ca²⁺ properties associated with upregulated autophagy (Beclin-1, Atg5 and LC3BII-to-LC3BI ratio), increased autophagy adaptor protein p62, elevated phosphorylation of AMPK and TSC1/2, depressed phosphorylation of mTOR and ULK1. Although AMPK inhibition did not affect cardiac mechanical function, autophagy and autophagy signaling proteins, it significantly accentuated caloric restriction-induced changes in myocardial contractile function and intracellular Ca²⁺ handling. Interestingly, AMPK inhibition reversed caloric restriction-induced changes in autophagy and autophagy signaling. AMPK inhibition led to dampened levels of Beclin-1, Atg 5 and LC3B ratio along with suppressed phosphorylation of AMPK and TSC1/2 as well as elevated phosphorylation of mTOR and ULK1. Taken together, these data suggest an indispensible role for AMPK in the maintenance of cardiac homeostasis under prolonged caloric restriction-induced pathological changes possibly through autophagy regulation. This article is part of a Special Issue entitled: Autophagy and protein quality control in cardiometabolic diseases.
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Qijun
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Department of Physiology, Fourth Military Medical University, Xi'an, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Han
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Anna F
authors.initials: AF
authors.lastname: Huff
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Cui
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Babcock
authors.affiliation: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Yu
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: yingmeimeganzhang@gmail.com.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D031204:Caloric Restriction; D004452:Echocardiography; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D002118:Calcium
keywords: AMPK; Autophagy; Caloric restriction; Myocardial; mTOR