Cancer cachexia is a syndrome characterized by loss of skeletal muscle protein, which is mainly accounted for by enhanced protein breakdown. Previous studies have shown that TNFa is critically involved in the pathogenesis of this hypercatabolic state, likely by inducing perturbations of the balance between anabolic and catabolic mediators. Among these, myostatin (MST) has been proposed as a negative modulator of muscle mass, while IGF-1 is a positive regulator of muscle growth and differentiation. The present work has been aimed at investigating whether muscle depletion in rats bearing the Yoshida AH-130 hepatoma is associated with changes of MST and IGF-1 mRNA levels.
Methods: Male Wistar rats have been implanted with the AH-130 hepatoma and sacrificed 2, 4, and 7 days after transplantation. MST, IGF-1, and IGF- 1R expression in the gastrocnemius have been analyzed by RT-PCR.
Results: Rats bearing the AH-130 hepatoma show a progressive loss of gastrocnemius mass. MST mRNA levels are comparable between controls and tumor hosts both at days 2 and 4, while decrease at day 7 (59% of controls, p=0.019). A marked reduction of IGF-1 mRNA (50% of controls) is detectable in AH-130 hosts at day 4 and day 7 (p=0.0024 and p<0.0001, respectively). The IGF-1R expression in the gastrocnemius increases at day 7 (three times control values, p=0.007).
Conclusions: These results show that muscle protein hypercatabolism in cancer cachexia involves modulations in the expression of two key regulators of skeletal muscle mass. The reduction of IGF-1 as well as the increase of IGF-IR mRNA levels are suggestive of perturbations on the anabolic side of muscle metabolism. By contrast, MST down-regulation may be viewed as an attempt to counteract the loss of muscle mass. The data shown in the present work suggest that interventions aimed at modulating both these pathways may be of interest to design therapeutic strategies to improve the management of cachectic cancer patients.