InACTIVatINg cancer cachexia

a debilitating muscle-and fat-wasting condition that is associated with multiple diseases, including cancer, diabetes, AIDS and tuberculosis, as well as injuries. Estimates reveal that up to 80% of all cancer patients suffer from cachexia, which not only leads to a decrease in the quality of life due to impaired mobility but also accounts directly for ~20% of cancer-related deaths (Fearon, 2008; Tisdale, 2009). Death from muscle wasting occurs mostly as a consequence of impaired respiratory and heart muscle function. The highest incidence of cachexia and associated weight loss is seen in patients with solid tumors, such as those with pancreatic, gastric or lung cancers: for instance, 85% of pancreatic cancer patients exhibit such a high degree of cachexia that it is one of the diagnostic features of the disease (Fearon, 2008; Tisdale, 2009). In a study of lung cancer patients who lost 30% of their pre-illness body weight, it was found that their body composition changed dramatically with respect to body fat mass (which decreased by 85%) and skeletal muscle protein mass (which decreased by 75%) (Preston et al., 1987). Such drastic losses in the amount of skeletal muscle and body fat have potentially large implications on whole body metabolism. Under normal conditions, adult skeletal muscle retains its mass owing to a balance between the signals that regulate muscle hypertrophy (increased muscle protein synthesis) and atrophy (increased muscle protein degradation). Stimuli such as exercise or steroids can shift this balance towards muscle hypertrophy, whereas muscle disuse or disease states such as cachexia can cause muscle atrophy. Studying how this balance is maintained normally and how it is disrupted in disease conditions will be crucial for understanding and developing treatment regimes for skeletal muscle cachexia. Some of the signaling molecules that are important in regulating this balance have been identified and are discussed below. Currently, there are no efficient treatments that specifically target skeletal muscle cachexia, although drugs such as steroids that increase appetite can be administered, but with limited success on reducing muscle wasting. Mice are an excellent model for the study of cancer cachexia, as several mouse models of cancer exhibit this muscle wasting condition (Matzuk et al., 1994; Lazarus et al., 1999). Furthermore, human cancer cells can be transplanted onto immunocompromised nude mice, and such heterologous models are helpful for studying how human cancer cells might cause muscle wasting in vivo (Cannon et al., 2007). Moreover, several pathways …