Loss of skeletal muscle in cancer: biochemical mechanisms.
Patients with cancer often undergo a specific loss of skeletal muscle mass, while the visceral protein reserves are preserved. This condition known as cachexia reduces the quality of life and eventually results in death through erosion of the respiratory muscles. Nutritional supplementation or appetite stimulants are unable to restore the loss of lean body mass, since protein catabolism is increased mainly as a result of the activation of the ATP-ubiquitin-dependent proteolytic pathway. Several mediators have been proposed. An enhanced protein degradation is seen in skeletal muscle of mice administered tumour necrosis factor (TNF), which appears to be mediated by oxidative stress. There is some evidence that this may be a direct effect and is associated with an increase in total cellular-ubiquitin-conjugated muscle proteins. Another cytokine, interleukin-6 (IL-6), may play a role in muscle wasting in certain animal tumours, possibly through both lysosomal (cathepsin) and non-lysosomal (proteasome) pathways. A tumour product, proteolysis-inducing factor (PIF) is produced by cachexia-inducing murine and human tumours and initiates muscle protein degradation directly through activation of the proteasome pathway. The action of PIF is blocked by eicosapentaenoic acid (EPA), which has been shown to attenuate the development of cachexia in pancreatic cancer patients. When combined with nutritional supplementation EPA leads to accumulation of lean body mass and prolongs survival. Further knowledge on the biochemical mechanisms of muscle protein catabolism will aid the development of effective therapy for cachexia.
Tisdale
M J
MJ
Pharmaceutical Sciences Research Institute, Aston University, Birmingham B4 7ET, UK. M.J.Tisdale@aston.ac.uk
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002100:Cachexia / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009369:Neoplasms / Q000150:complications / Q000378:metabolism*; D011509:Proteoglycans; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015431:Weight Loss
D001798:Blood Proteins; D007375:Interleukin-1; D015850:Interleukin-6; D009124:Muscle Proteins; D011509:Proteoglycans; D014409:Tumor Necrosis Factor-alpha; C042057:proteolysis-inducing peptide; D007371:Interferon-gamma