Colon 26 adenocarcinoma (C26)-induced cancer cachexia impairs skeletal muscle mitochondrial function and content

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 Information Daria 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 Flor...

Distinct cachexia profiles in response to human pancreatic tumours in mouse limb and respiratory muscle

“…Additional genes annotating to this category are involved in apoptosis, including Alkbh7 and Mtfp1 , and two genes encoding mitochondrial ribosomal proteins, Mrpl34 and Mrpl45 . This reduced expression of mitochondria‐related genes in the DIA of PDAC‐PDX mice aligns with published studies, which show mitochondrial deficits in cachectic tumour‐bearing hosts including altered mitochondrial biogenesis, fission/fusion, mitophagy, and mitochondrial function . Importantly, our findings are also consistent with repression of mitochondrial‐related genes in the skeletal muscle of cachectic PDAC patients …”

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

“…Recently published work from Neyroud et al demonstrated increased mitochondrial uncoupling and a reduction in mitochondrial respiratory capacity in the soleus muscle of cachectic C26 tumor-bearing mice [6]. In an extension of those findings, we show here compromised mitochondrial function in the heart and diaphragm of cachectic C26 tumor-bearing mice.…”

“…Although the underlying mechanisms driving cancer-induced cardiorespiratory muscle weakness remain unknown, emerging evidence reveals that cancer promotes mitochondrial damage, resulting in alterations to electron transport chain complex activity, impaired ATP synthesis and the production of reactive oxygen species (ROS) [6]. Additionally, mitochondrial impairment in muscle tissue has been shown to cause profound functional and structural disorganization [7][8][9].…”

Phenotypic features of cancer cachexia‐related loss of skeletal muscle mass and function: lessons from human and animal studies

“…Accordingly, mitochondrial respiration rate is also reduced in isolated mitochondria from skeletal muscle of cachectic cancer mice compared with control mice. 192,195,196 Therefore, animal studies clearly indicate that the entire mitochondrial oxidative pathway is profoundly impaired by cancer cachexia.…”