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 throu gh erosion of the respiratory muscles. Nutritional supplementation or appet ite stimulants are unable to restore the loss of lean body mass, since prot ein catabolism is increased mainly as a result of the activation of the ATP -ubiquitin-dependent proteolytic pathway. Several mediators have been propo sed. An enhanced protein degradation is seen in skeletal muscle of mice adm inistered tumour necrosis factor (TNF), which appears to be mediated by oxi dative stress. There is some evidence that this may be a direct effect and is associated with an increase in total cellular-ubiquitin-conjugated muscl e proteins. Another cytokine, interleukin-6 (IL-6), may play a role in musc le wasting in certain animal tumours, possibly through both lysosomal (cath epsin) and nonlysosomal (proteasome) pathways. A tumour product, proteolysi s-inducing factor (PIF) is produced by cachexia-inducing murine and human t umours and initiates muscle protein degradation directly through activation of the proteasome pathway. The action of PIF is blocked by eicosapentaenoi c acid (EPA), which has been shown to attenuate the development of cachexia in pancreatic cancer patients. When combined with nutritional supplementat ion EPA leads to accumulation of lean body mass and prolongs survival. Furt her knowledge on the biochemical mechanisms of muscle protein catabolism wi ll aid the development of effective therapy for cachexia.