Understanding the common mechanisms of heart and skeletal muscle wasting in cancer cachexia

Abstract

Cachexia is a severe complication of cancer that adversely affects the course of the disease, with currently no effective treatments. It is characterized by a progressive atrophy of skeletal muscle and adipose tissue, resulting in weight loss, a reduced quality of life, and a shortened life expectancy. Although the cachectic condition primarily affects the skeletal muscle, a tissue that accounts for ~40% of total body weight, cachexia is considered a multi-organ disease that involves different tissues and organs, among which the cardiac muscle stands out for its relevance. Patients with cancer often experience severe cardiac abnormalities and manifest symptoms that are indicative of chronic heart failure, including fatigue, shortness of breath, and impaired exercise tolerance. Furthermore, cardiovascular complications are among the major causes of death in cancer patients who experienced cachexia. The lack of effective treatments for cancer cachexia underscores the need to improve our understanding of the underlying mechanisms. Increasing evidence links the wasting of the cardiac and skeletal muscles to metabolic alterations, primarily increased energy expenditure, and to increased proteolysis, ensuing from activation of the major proteolytic machineries of the cell, including ubiquitin-dependent proteolysis and autophagy. This review aims at providing an overview of the key mechanisms of cancer cachexia, with a major focus on those that are shared by the skeletal and cardiac muscles.

Fig. 1. Multi-organ alterations in cancer-induced cachexia.

Cancer cells, together with the activation of the inflammatory response and the toxic effects of chemotherapy, contribute to concomitant and interconnected alterations in multiple distant organs, including the cardiac and skeletal muscles and the gut, in the course of cancer-induced cachexia. ILs interleukins, TNF tumor necrosis factor, TGF transforming growth factor, TLRs toll-like receptors, DAMPs damage-associated molecular patterns, FAO fatty acid oxidation, PAMPs pathogen-associated molecular patterns.

Fig. 2. Pathological alterations underlying muscle wasting in cancer cachexia.

The mechanisms underlying cancer cachexia are multiple and intertwined. Either factors released by skeletal and cardiac muscles (myokines and cardiokines respectively; pink boxes) or factors secreted by cancer and cancer-associated immune cells (violet boxes) trigger a cascade of processes which ultimately result in cachexia. The circulating factors (pink), intracellular signaling pathways (orange), and final effectors of wasting (yellow) that lead to skeletal (left side of the figure) and cardiac (right side of the figure) muscle wasting are reported. Albeit the biological processes underlying skeletal and cardiac muscle wasting are similar, their relative contribution and the specific molecular players involved differ slightly. Red arrows indicate those factors that are increased as a consequence of chemotherapy. DAMPs damage-associated molecular patterns, GDF15 growth differentiation factor 15, ILs interleukins, LIF leukemia inhibitory Factor, TNF-α tumor necrosis factor alpha, TGF-β transforming growth factor beta.