Mitochondrial dysfunction and therapeutic approaches in respiratory and limb muscles of cancer cachectic mice

    loading  Checking for direct PDF access through Ovid


New Findings

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.

Related Topics

    loading  Loading Related Articles