The Skeletal Muscle as an Active Player Against Cancer Cachexia

Abstract

The management of cancer patients is frequently complicated by the occurrence of cachexia. This is a complex syndrome that markedly impacts on quality of life as well as on tolerance and response to anticancer treatments. Loss of body weight, wasting of both adipose tissue and skeletal muscle and reduced survival rates are among the main features of cachexia. Skeletal muscle wasting has been shown to depend, mainly at least, on the induction of protein degradation rates above physiological levels. Such hypercatabolic pattern is driven by overactivation of different intracellular proteolytic systems, among which those dependent on ubiquitin-proteasome and autophagy. Selective rather than bulk degradation of altered proteins and organelles was also proposed to occur. Within the picture described above, the muscle is frequently considered a sort of by-stander tissue where external stimuli, directly or indirectly, can poise protein metabolism toward a catabolic setting. By contrast, several observations suggest that the muscle reacts to the wasting drive imposed by cancer growth by activating different compensatory strategies that include anabolic capacity, the activation of autophagy and myogenesis. Even if muscle response is eventually ill-fated, its occurrence supports the idea that in the presence of appropriate treatments the development of cancer-induced wasting might not be an ineluctable event in tumor hosts.

Keywords: adaptive response; energy metabolism; muscle wasting; myogenesis; oxidative stress; protein turnover.

Figure 1

Relevance of muscle wasting to cancer patient management. The occurrence of metabolic changes that result in muscle protein hypercatabolism and impaired regeneration capacity negatively impinges on both patient quality of life and survival. k_s = fractional rate of protein synthesis; k_d = fractional rate of protein degradation.

Figure 2

Humoral mediators of cancer cachexia. Humoral mediators differentially involved in the inflammatory response play a crucial, but probably not exclusive, role in the pathogenesis of cancer cachexia.

Figure 3

Muscle compensatory mechanisms activated in response to tumor growth. The skeletal muscle is a plastic tissue able to autonomously respond to the wasting stimuli in order to maintain the homeostasis. Muscle loss occurs as a consequence of the failure to adapt to the alterations induced by the tumor. Anti-cachexia drugs targeting specific cellular and molecular processes will boost the muscle adaptation potential, counteracting the wasting process.