Cancer-Related Cachexia: The Vicious Circle between Inflammatory Cytokines, Skeletal Muscle, Lipid Metabolism and the Possible Role of Physical Training

Abstract

Cachexia is a multifactorial and multi-organ syndrome that is a major cause of morbidity and mortality in late-stage chronic diseases. The main clinical features of cancer-related cachexia are chronic inflammation, wasting of skeletal muscle and adipose tissue, insulin resistance, anorexia, and impaired myogenesis. A multimodal treatment has been suggested to approach the multifactorial genesis of cachexia. In this context, physical exercise has been found to have a general effect on maintaining homeostasis in a healthy life, involving multiple organs and their metabolism. The purpose of this review is to present the evidence for the relationship between inflammatory cytokines, skeletal muscle, and fat metabolism and the potential role of exercise training in breaking the vicious circle of this impaired tissue cross-talk. Due to the wide-ranging effects of exercise training, from the body to the behavior and cognition of the individual, it seems to be able to improve the quality of life in this syndrome. Therefore, studying the molecular effects of physical exercise could provide important information about the interactions between organs and the systemic mediators involved in the overall homeostasis of the body.

Keywords: cancer-related cachexia; inflammatory cytokines; physical training; skeletal muscle.

Figure 1

Maintenance and modulation of skeletal muscle mass are attributed to protein turnover. In blue, the insulin growth factor-1(IGF-1)–phosphoinositide−3−kinase (PI3K)–Akt/protein kinase B (PKB)–mammalian target of rapamycin (mTOR) pathway leading to protein synthesis. In red, the signaling pathway activated by myostatin that inhibits protein synthesis and reduces myotube size, leading to muscle wasting. In green, the role of inflammatory cytokines in protein degradation.

Figure 2

Exercise training regulates the balance between muscle growth and muscle wasting by modulating key protein synthesis and degradation processes. In blue, the direct effect of exercise training onto the IGF1 pathway and the central role of PGC1α in modulating both IGF1 and inflammatory pathways. In red and green, the negative modulation of exercise training on the inflammatory and myostatin/activin A pathways leading to muscle wasting. Positive modulation = ; Negative modulation = .