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Updated: May 11, 2026
Measurement of Mitochondrial Respiration in Human and Mouse Skeletal Muscle Fibers by High-Resolution Respirometry
Published on: October 4, 2024
Mitochondrial dysfunction and therapeutic approaches in respiratory and limb muscles of cancer cachectic mice
Clara Fermoselle1, Elena García-Arumí, Ester Puig-Vilanova
1Pulmonology Department, Lung Cancer Group, IMIM-Hospital del Mar, Universitat Pompeu Fabra, Barcelona Biomedical Resarch Park, Barcelona, Spain.
New Findings:
What is the central question of this study? We explored whether experimental cancer-induced cachexia may alter mitochondrial respiratory chain (MRC) complexes and oxygen uptake in respiratory and peripheral muscles,and whether signalling pathways, proteasome and oxidative stress influence that process. What is the main finding and what is its importance? In cancer cachectic mice, MRC complexes and oxygen consumption were decreased in the diaphragm and gastrocnemius. Blockade of nuclear factor-κB and mitogen-activated protein kinase actions partly restored the muscle mass and force and corrected the MRC dysfunction,while concomitantly reducing tumour burden. Antioxidants improved mitochondrial oxygen consumption without eliciting effects on the loss of muscle mass and force or the tumour size,whereas bortezomib reduced tumour burden without influencing muscle mass and strength or MRC function. Abnormalities in mitochondrial content, morphology and function have been reported in several muscle-wasting conditions. We specifically explored whether experimental cancer-induced cachexia may alter mitochondrial respiratory chain (MRC) complexes and oxygen uptake in respiratory and peripheral muscles, and whether signalling pathways, proteasomes and oxidative stress may influence that process. We evaluated complex I, II and IV enzyme activities (specific activity assays) and MRC oxygen consumption (polarographic measurements) in diaphragm and gastrocnemius of cachectic mice bearing the LP07 lung tumour, with and without treatment with N-acetylcysteine, bortezomib and nuclear factor-κB (sulfasalazine) and mitogen-activated protein kinases (MAPK, U0126) inhibitors (n = 10 per group for all groups). Whole-body and muscle weights and limb muscle force were also assessed in all rodents at baseline and after 1 month. Compared with control animals, cancer cachectic mice showed a significant reduction in body weight gain, smaller sizes of the diaphragm and gastrocnemius, lower muscle strength, decreased activity of complexes I, II and IV and decreased oxygen consumption in both muscles. Blockade of nuclear factor-κB and MAPK actions restored muscle mass and force and corrected the MRC dysfunction in both muscles, while partly reducing tumour burden. Antioxidants improved mitochondrial oxygen uptake without eliciting significant effects on the loss of muscle mass and force or tumour size, whereas the proteasome inhibitor reduced tumour burden without significantly influencing muscle mass and strength or mitochondrial function. In conclusion, nuclear factor-κB and MAPK signalling pathways modulate muscle mass and performance and MRC function of respiratory and limb muscles in this model of experimental cancer cachexia, thus offering targets for therapeutic intervention.
Insights
Cancer cachexia in mice reduces muscle mitochondrial function. Targeting nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways restored muscle mass, strength, and mitochondrial respiration, offering therapeutic potential.
Area of Science:
- Biochemistry
- Cellular Biology
- Physiology
Background:
- Mitochondrial dysfunction is implicated in various muscle-wasting conditions.
- Cancer cachexia involves significant muscle mass loss and functional decline.
- The specific impact of cancer cachexia on mitochondrial respiratory chain (MRC) complexes and oxygen consumption in different muscle types requires further elucidation.
Purpose of the Study:
- To investigate the effects of experimental cancer-induced cachexia on MRC complexes and oxygen uptake in respiratory and peripheral muscles.
- To determine the influence of signaling pathways, proteasomes, and oxidative stress on these mitochondrial alterations in cachexia.
- To evaluate the therapeutic potential of targeting specific pathways for mitigating cachexia-associated muscle dysfunction.
Main Methods:
- Mice bearing LP07 lung tumors were used to model cancer cachexia.
- Measurements included MRC complex I, II, and IV enzyme activities and oxygen consumption in diaphragm and gastrocnemius muscles.
- Treatments involved N-acetylcysteine (antioxidant), bortezomib (proteasome inhibitor), and inhibitors of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK).
- Muscle mass, body weight, and limb muscle force were assessed.
Main Results:
- Cancer cachectic mice exhibited reduced body weight gain, smaller diaphragm and gastrocnemius muscles, decreased muscle strength, and impaired MRC complex activities and oxygen consumption.
- Inhibition of NF-κB and MAPK signaling pathways partially restored muscle mass, strength, and MRC function, while also reducing tumor burden.
- Antioxidant treatment improved mitochondrial oxygen consumption but did not affect muscle mass, strength, or tumor size.
- The proteasome inhibitor reduced tumor burden but had no significant impact on muscle function or mitochondrial parameters.
Conclusions:
- NF-κB and MAPK signaling pathways play a crucial role in modulating muscle mass, performance, and MRC function in experimental cancer cachexia.
- Targeting these specific signaling pathways presents a promising therapeutic strategy for combating muscle dysfunction in cancer cachexia.
- Mitochondrial oxygen consumption is affected by cachexia, but interventions targeting oxidative stress or proteasomes alone may not fully restore muscle function.
