Skeletal Muscle Force and Fatigability in Cancer Cachexia
Authors: Greenman Angela Claire , Rosemarie Quincy , Albrecht Dawn , Halberg Richard , Diffee Gary 
Published: November 2023

Cancer Cachexia is a disease characterized by severe loss of muscle mass, even with controlled nutritional intake. This muscle wasting disease leads to increased risk of morbidity and mortality in cancer patients. Although loss of muscle mass is a hallmark of cachexia, little is known regarding how cancer cachexia affects contractile function of skeletal muscle. Changes in muscle contractile function, similar to other muscle atrophy conditions, may provide some clues to the underlying processes of muscle atrophy in cancer cachexia. The purpose of this study was to measure contractile function of cachectic skeletal muscle in ApcMin/+ PIK3ca* mice, a recently developed model of colon cancer. ApcMin/+ PIK3ca* mice spontaneously develop colon tumors starting at birth. We hypothesized that, in tumor‐bearing mice, there would be a decline in maximal tetanic force, as well as an increase in muscle fatigability. Male and female tumor‐bearing ApcMin/+ PIK3ca* mice and control mice (wt C57BI6) were sacrificed between 2–3 months of age and the extensor digitorum longus (EDL) and gastrocnemius (GAS) were removed, weighed and either frozen for later analysis (GAS and EDL) or immediately prepared for contractile measurements (EDL). The EDL was attached to a force transducer and a motor positioner (Aurora Scientific) via hooks tied to the proximal and distal tendons. The EDL was then stimulated via platinum electrodes while being perfused with oxygenated Tyrodes solution. Muscles were stretched to their optimal length, and stimulated at a voltage and frequency capable of eliciting maximal force. After determining maximal tetanic force, muscles were continuously stimulated for 10 minutes, and the force at this time point was determined to be the fatigue force. The recovery force was measured after 20 minutes without stimulation. Total protein in the GAS was measured using the Bradford assay. There were no significant differences in GAS or EDL muscle weights when normalized to body size. However, in ApcMin/+ PIK3ca* mice, the GAS had lower total protein content compared to controls (6.87 mg vs. 9.75 mg, respectively, p=0.033) and a lower protein content normalized to muscle mass (0.071 mg/mg of muscle mass vs. 0.082 mg/mg of muscle mass, respectively). There was no difference in EDL tetanic force between the two groups when force was normalized to muscle mass. However, the muscles from tumor‐bearing mice showed increased fatigability as, in ApcMin/+ PIK3ca* mice, force declined to 25% of initial force, whereas in controls, force declined to 41%. Recovery of force was similar between tumor‐bearing mice and controls. These results indicate that declines in muscle mass during cancer cachexia are accompanied by declines in muscle function, represented by the increased fatigability in tumor‐bearing ApcMin/+ PIK3ca* mice. This suggests additional alterations in the metabolic pathways or contractile apparatus during cachexia, in addition to the decline in mass.

Support or Funding Information

Marsh Center for Research in Exercise and Movement, University of Wisconsin‐Madison