Mechanism of attenuation of skeletal muscle protein catabolism in cancer cachexia by eicosapentaenoic acid

Cancer cachexia is characterized by selective depletion of skeletal muscle protein reserves. Soleus muscles from mice bearing a cachexia-inducing tumo r (MAC16) showed an increased protein degradation in vitro, as measured by tyrosine release, when compared with muscles from nontumor-bearing animals. After incubation under conditions that modify different proteolytic system s, lysosomal, calcium-dependent, and ATP-dependent proteolysis were found t o contribute to the elevated protein catabolism. Treatment of mice bearing the MAC16 tumor with the polyunsaturated fatty acid, eicosapentaenoic acid (EPA), attenuated loss of body weight and significantly suppressed protein catabolism in soleus muscles through an inhibition of an ATP-dependent prot eolytic pathway. The ATP-ubiquitin-dependent proteolytic pathway is conside red to play a major role in muscle catabolism in cachexia, and functional p roteasome activity, as determined by "chymotrypsin-like'' enzyme activity, was significantly elevated in gastrocnemius muscle of mice bearing the MAC1 6 tumor as a eight loss progressed. When animals bearing the MAC16 tumor we re treated with EPA, functional proteasome activity was completely suppress ed, together with attenuation of the expression of 20S proteasome alpha -su bunits and the p42 regulator, whereas there was no effect on the expression of the ubiquitin-conjugating enzyme (E2(14k)). These results suggest that EPA induces an attenuation of the up-regulation of proteasome expression in cachectic mice, and this was correlated with an increase in myosin express ion, confirming retention of contractile proteins. EPA also inhibited growt h of the MAC16 tumor in a dose-dependent manner, and this correlated with s uppression of the expression of the 20S proteasome alpha -subunits in tumor cells, suggesting that this may be the mechanism of tumor growth inhibitio n, Thus EPA antagonizes loss of skeletal muscle proteins in cancer cachexia by down-regulation of proteasome expression, and this may also be the mech anism for inhibition of tumor growth.