C26‐Induced Cancer Cachexia Impairs Skeletal Muscle Mitochondrial Function

Abstract

Cancer cachexia is characterized by a rapid ‘loss of muscle with or without loss of fat mass'1 that can impede cancer treatments resulting in significantly increased mortality rate in afflicted individuals. Whereas impaired skeletal muscle respiratory capacity likely plays a role in cancer‐induced fatigue, few studies have evaluated mitochondrial function in models of cancer cachexia2, and none in the well‐characterized colon 26 carcinoma (C26)‐induced cancer cachexia model. The present study thus aimed to evaluate the impact of C26‐induced cancer cachexia on skeletal muscle mitochondrial respiration and content.Twelve six‐week old male CD2F1 mice were injected subcutaneously with 5 × 105 C26‐cells diluted in 100 μl of PBS per flank (C26 group), whereas 12 age‐matched mice received an equivalent PBS vehicle injection (Control group). Mice were sacrificed ~ 26 days after tumor or vehicle injection. At sacrifice, C26 mice showed a reduced body weight (~ 20%) compared to control mice (p<0.05). Muscle atrophy was observed in C26 soleus, gastrocnemii‐plantaris complex (GasPL) and tibialis anterior (−21%, −10% and −11% respectively, vs. Control; p<0.05). Soleus permeabilized muscle fiber bundles from C26 mice showed a 20% reduction in maximal mitochondrial respiration compared to Controls in the presence of 10 mM of glutamate, 5 mM of malate and 5 mM of adenosine diphosphate (p<0.05). Furthermore, a 15% lower acceptor control ratio (State 3/State 2, an index of mitochondrial coupling) was observed in the C26 vs. Controls (p<0.05). Evaluation of mitochondrial content and relative expression of the different mitochondrial components involved in the oxidative phosphorylation process is currently ongoing. Preliminary results suggest that GasPL VDAC (as an index of mitochondrial content) relative protein expression is reduced in the C26 vs. Controls (~ −20%). Similarly, reductions in representative subunits of complex I, II, III and IV (CI‐IV) expressions were observed in C26‐GasPL compared to Controls (~ −19–24%), but there was no differences in complex V (CV) relative expression (~ −8%).In conclusion, C26‐induced cancer cachexia appears to lead to a reduced mitochondrial content associated with a reduced maximal respiration capacity. Moreover, in addition to the reduced mitochondrial content, an alteration of the remaining mitochondria could be observed as mitochondrial coupling was impeded. The reduced maximal respiratory capacity appears largely to be due to reduced mitochondrial content. The temporal relationships between these changes and the progression of muscle atrophy, and whether these changes are reversible if the cancer is survived remain important areas for future investigation.Support or Funding InformationDaria Neyroud salary is supported by an Early Post‐doc fellowship obtained from the Swiss National Science Foundation. In addition, this work was supported by NIH grants obtained by Prof. Judge (R01AR060209 and 1R21CA194118‐01) and internal funding obtained by Prof. Hepple through the University of Florida Cancer Center.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.