Dissecting the possible role of p97 in muscle wasting during cancer cachexia

Background. Half of patients with malignancies develops muscle wasting (i.e. cachexia) and aerobic exercise ameliorates their prognosis. The p97/VCP ATPase complex facilitates the rapid degradation of myofibrillar proteins during muscle atrophy caused by denervation or fasting. The aim of this study was to investigate if p97 plays a role also during cancer cachexia and if it is modulated by physical exercise. Methods. To induce cachexia in mice, we injected subcutaneously colon adenocarcinoma (C26) or Lewis Lung Carcinoma (LLC) cells. To understand if aerobic exercise improves cancer cachexia through p97 modulation in muscle, C26-bearing mice were run on treadmill for 5 days at 12 m/min and 15° inclination for 45 min/day. By Q-PCR or Western Blotting we measured the expression of p97 and its main adaptor proteins (Ufd1, Ufd2, p47) in cachectic Tibialis Anterior (TA) muscle. In vitro we performed luciferase assay to test the possible effect of p97 or its dominant negative mutant (DNp97) on dexamethasone-induced MuRF1 signalling. Results. In vivo, we found that the mRNA levels of p97 and its interactors Ufd1, Ufd2 and p47 were induced in cachectic TA muscle from C26-carrying mice, undergoing body weight loss (i.e. cachexia). The protein levels of p97 and Ufd1 were also enhanced. Interestingly, treadmill exercise protected C26-bearing mice from muscle loss, with no effect on tumor growth, and rescued the C26-induced upregulation of p97 and its adaptors in muscles. As expected, MuRF1 was induced in dexamethasone-stimulated myoblasts. Surprisingly, we found that, unlike WTp97, exogenous DNp97 further upregulated dexamethasone-induced MuRF1 signalling. Conclusions. Our preliminary data suggest that p97/VCP ATPase may play a role in muscle wasting also during cancer in mice but it remains to be established whether -and how- DNp97 is able to recapitulate the beneficial effects of aerobic exercise in vivo.