Myocardial glycophagy flux dysregulation and glycogen accumulation characterize diabetic cardiomyopathy

Kimberley M Mellor; Upasna Varma; Parisa Koutsifeli; Lorna J Daniels; Victoria L Benson; Marco Annandale; Xun Li; Yohanes Nursalim; Johannes V Janssens; Kate L Weeks; Kim L Powell; Terence J O'Brien; Rajesh Katare; Rebecca H Ritchie; James R Bell; Roberta A Gottlieb; Lea M D Delbridge

doi:10.1016/j.yjmcc.2024.02.009

Myocardial glycophagy flux dysregulation and glycogen accumulation characterize diabetic cardiomyopathy

J Mol Cell Cardiol. 2024 Apr:189:83-89. doi: 10.1016/j.yjmcc.2024.02.009. Epub 2024 Mar 13.

Authors

Kimberley M Mellor¹, Upasna Varma², Parisa Koutsifeli³, Lorna J Daniels⁴, Victoria L Benson³, Marco Annandale³, Xun Li³, Yohanes Nursalim³, Johannes V Janssens⁵, Kate L Weeks⁶, Kim L Powell⁷, Terence J O'Brien⁷, Rajesh Katare⁸, Rebecca H Ritchie⁹, James R Bell¹⁰, Roberta A Gottlieb¹¹, Lea M D Delbridge¹²

Affiliations

¹ Department of Physiology, University of Auckland, Auckland, New Zealand; Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand; Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia.
² Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia.
³ Department of Physiology, University of Auckland, Auckland, New Zealand.
⁴ Department of Physiology, University of Auckland, Auckland, New Zealand; Radcliffe Department of Medicine, OCDEM, University of Oxford, United Kingdom.
⁵ Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia; Department of Biomedical Sciences, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, USA.
⁶ Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Victoria, Australia.
⁷ Department of Medicine, University of Melbourne & Department of Neuroscience, Central Clinical School Monash University, Melbourne, Victoria, Australia.
⁸ Department of Physiology, Heart Otago, University of Otago, Dunedin, New Zealand.
⁹ Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Victoria, Australia; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia.
¹⁰ Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia; Department of Microbiology, Anatomy, Physiology & Pharmacology, La Trobe University, Australia.
¹¹ Department of Biomedical Sciences, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, USA.
¹² Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia. Electronic address: lmd@unimelb.edu.au.

PMID: 38484473
DOI: 10.1016/j.yjmcc.2024.02.009

Abstract

Diabetic heart disease morbidity and mortality is escalating. No specific therapeutics exist and mechanistic understanding of diabetic cardiomyopathy etiology is lacking. While lipid accumulation is a recognized cardiomyocyte phenotype of diabetes, less is known about glycolytic fuel handling and storage. Based on in vitro studies, we postulated the operation of an autophagy pathway in the myocardium specific for glycogen homeostasis - glycophagy. Here we visualize occurrence of cardiac glycophagy and show that the diabetic myocardium is characterized by marked glycogen elevation and altered cardiomyocyte glycogen localization. We establish that cardiac glycophagy flux is disturbed in diabetes. Glycophagy may represent a potential therapeutic target for alleviating the myocardial impacts of metabolic disruption in diabetic heart disease.

Keywords: Autophagy; Cardiac glycogen; Cardiac metabolism; Diabetic heart disease; Glycophagy.

MeSH terms

Autophagy
Diabetes Mellitus* / metabolism
Diabetic Cardiomyopathies* / drug therapy
Glycogen / metabolism
Humans
Myocardium / metabolism
Myocytes, Cardiac / metabolism

Substances

Glycogen