Cancer cachexia and skeletal muscle atrophy in clinical studies: what do we really know?

Abstract

Research investigators have shown a growing interest in investigating alterations underlying skeletal muscle wasting in patients with cancer. However, skeletal muscle dysfunctions associated with cancer cachexia have mainly been studied in preclinical models. In the present review, we summarize the results of clinical studies in which skeletal muscle biopsies were collected from cachectic vs. non-cachectic cancer patients. Most of these studies suggest the presence of significant physiological alterations in skeletal muscle from cachectic cancer patients. We suggest a hypothesis, which connects structural and metabolic parameters that may, at least in part, be responsible for the skeletal muscle atrophy characteristic of cancer cachexia. Finally, we discuss the importance of a better standardization of the diagnostic criteria for cancer cachexia, as well as the requirement for additional clinical studies to improve the robustness of these conclusions.

Keywords: Cancer cachexia; Clinical studies; Mitochondria; Myosteatosis; Skeletal muscle alterations.

Figure 1

Summary of the hypothetical associations between metabolic and structural dysfunctions that may, at least in part, be responsible for skeletal muscle atrophy in cachectic cancer patients and for the aggravating role of obesity. In red are represented our hypotheses on the effects of cancer cachexia and in green, our hypotheses on the effects of obesity. An accumulation of lipid droplets, mitochondrial dysfunctions, and endoplasmic reticulum (ER) stress could lead to increased proteolysis, via the ubiquitin–proteasome system (UPS) and autophagy, and decreased protein synthesis, both of which induce atrophy of skeletal muscle fibres and loss of muscle mass. The production of reactive oxygen species (ROS) following mitochondrial alterations may also participate in muscle wasting, by activating apoptotic pathways. In the adipose compartment, lipolysis, which is increased in obese patients, could lead to a greater accumulation of lipid droplets in muscle fibres, mitochondrial dysfunctions, and disturbances in the integrity of mitochondria‐associated ER membranes (MAMs), which may worsen skeletal muscle atrophy.