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

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.

Keywords: amino acids; autophagy; chronic diseases; heart failure; malnutrition.

Figure 1

Failing heart. (A) Typical anti-LC3 immunofluorescence (green) of cardiomyocytes in an advanced stage of autophagic damage. Green bodies (arrows) are present around and much more at the pole of nuclei. Cardiomyocytes with massive green staining, in combination with the red staining of the nucleus, assume a “strawberry-like” appearance. N = nucleus in red; (B) Damaged cardiomyocytes show nuclei (N) very irregular in shape as if he had been bitten. Around these nuclei, the cytoplasm is devoid of organelles, and there are always clumps of brown debris bodies (arrow) (eosin and hematoxylin staining); (C) Representative transmission electron microscopy pictures show a damaged cardiomyocyte, with chromatin condensation in the nucleus (N) and deep invaginations of the nuclear envelope. Cytoplasmic granular material without organelles is present around the nucleus and near the nuclear pole (arrows).

Figure 2

Schematic representation of the link between chronic diseases, malnutrition, hypercatabolic syndrome, and autophagy. The increase in catabolism induced by chronic diseases and malnutrition favors the activation of autophagy to guarantee the cells sufficient energy and materials to cope with accelerated metabolism. This results in a cascade of events, leading to protein disarrangements (the severe alteration of the protein components of the body), and then to metabolic impairment. This creates a vicious circle which, in the absence of adequate nutritional interventions, maintains and favors the hypercatabolic syndrome. Furthermore, in patients with advanced chronic diseases, like the end stage of CHF, autophagy is severely triggered, and the autophagic machinery may also drive the cells to self-destruction.

Figure 3

Schematic representation of the influence of amino acids, nutrients, starvation, low ATP/AMP ratio, and caloric restriction on mTORC1 and autophagy. Amino acid availability inhibits autophagy by inhibiting TSC2/1 and activating Rehb that could facilitate the transport of amino acids into the cell and which, in turn, could activate TORC1 that inhibits ULK-complex (black line). In case of low availability of amino acids, autophagy is activated through the TORC2 complex (black dotted line). Up thick arrow = increase. Akt = protein kinase B; ATP = adenosine triphosphate; 4EBP1 = eIF4E-binding protein-1; PI3K = phosphoinositide 3-kinase; Rheb = Ras homolog enriched in brain; S6 = S6-kinase; TSC1/2 = tuberous sclerosis complex 1/2; ULK (Unc-51 like autophagy activating kinase).