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      How Can Malnutrition Affect Autophagy in Chronic Heart Failure? Focus and Perspectives

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          Abstract

          Chronic heart failure (CHF) is a disease with important clinical and socio-economic ramifications. Malnutrition and severe alteration of the protein components of the body (protein disarrangements), common conditions in CHF patients, are independent correlates of heart dysfunction, disease progression, and mortality. Autophagy, a prominent occurrence in the heart of patients with advanced CHF, is a self-digestive process that prolongs myocardial cell lifespan by the removal of cytosolic components, such as aging organelles and proteins, and recycles the constituent elements for new protein synthesis. However, in specific conditions, excessive activation of autophagy can lead to the destruction of molecules and organelles essential to cell survival, ultimately leading to organ failure and patient death. In this review, we aim to describe the experimental and clinical evidence supporting a pathophysiological role of nutrition and autophagy in the progression of CHF. The understanding of the mechanisms underlying the interplay between nutrition and autophagy may have important clinical implications by providing molecular targets for innovative therapeutic strategies in CHF patients.

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          Most cited references89

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          AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.

          Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.
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            The AMPK signalling pathway coordinates cell growth, autophagy and metabolism.

            One of the central regulators of cellular and organismal metabolism in eukaryotes is AMP-activated protein kinase (AMPK), which is activated when intracellular ATP production decreases. AMPK has critical roles in regulating growth and reprogramming metabolism, and has recently been connected to cellular processes such as autophagy and cell polarity. Here we review a number of recent breakthroughs in the mechanistic understanding of AMPK function, focusing on a number of newly identified downstream effectors of AMPK.
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              Self-eating and self-killing: crosstalk between autophagy and apoptosis.

              The functional relationship between apoptosis ('self-killing') and autophagy ('self-eating') is complex in the sense that, under certain circumstances, autophagy constitutes a stress adaptation that avoids cell death (and suppresses apoptosis), whereas in other cellular settings, it constitutes an alternative cell-death pathway. Autophagy and apoptosis may be triggered by common upstream signals, and sometimes this results in combined autophagy and apoptosis; in other instances, the cell switches between the two responses in a mutually exclusive manner. On a molecular level, this means that the apoptotic and autophagic response machineries share common pathways that either link or polarize the cellular responses.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                24 March 2021
                April 2021
                : 22
                : 7
                : 3332
                Affiliations
                [1 ]Department of Clinical and Experimental Sciences, Division of Human Anatomy and Physiopathology, University of Brescia, 25123 Brescia, Italy; cla300482@ 123456gmail.com
                [2 ]Cardiac Rehabilitation Division, Scientific Clinical Institutes Maugeri (IRCCS), Lumezzane, 25065 Brescia, Italy; evpasini@ 123456gmail.com
                [3 ]Hunter Holmes McGuire Veterans Affairs Medical Centre (VAMC), Division of Cardiology, Richmond, VA 23249, USA; chenscarabelli@ 123456hotmail.com
                [4 ]Centre for Heart and Vessel Preclinical Studies at St. John Hospital and Medical Centre, Wayne State University, Detroit, MI 48202, USA; tscarabelli@ 123456hotmail.com
                [5 ]Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, 67100 L’Aquila, Italy; vincenzo.flati@ 123456univaq.it
                [6 ]Department of Medicine at St. John Hospital, Wayne State University, Detroit, MI 48202, USA; louis.saravolatz@ 123456ascension.org
                [7 ]Department of Internal Medicine, University of Cagliari, 09124 Cagliari, Italy; fsdioguardi@ 123456gmail.com
                Author notes
                [* ]Correspondence: giovanni.corsetti@ 123456unibs.it ; Fax: +39-030-3717486
                Author information
                https://orcid.org/0000-0003-0326-0644
                https://orcid.org/0000-0003-1014-297X
                https://orcid.org/0000-0003-0445-3106
                Article
                ijms-22-03332
                10.3390/ijms22073332
                8036550
                33805128
                5cbe48ac-08be-46ad-b0ac-f51dfa795f2e
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 01 March 2021
                : 21 March 2021
                Categories
                Review

                Molecular biology
                malnutrition,autophagy,heart failure,chronic diseases,amino acids
                Molecular biology
                malnutrition, autophagy, heart failure, chronic diseases, amino acids

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