Muscle wasting in diabetic and in tumor-bearing rats: role of oxidative stress.
Cachexia is a debilitating syndrome characterized by body weight loss, muscle wasting, and anemia. Muscle wasting results from an altered balance between protein synthesis and degradation rates. Reactive oxygen species are indicated as crucial players in the onset of muscle protein hypercatabolism by upregulating elements of the ubiquitin-proteasome pathway. The present study has been aimed at evaluating comparatively the involvement of oxidative stress in the pathogenesis of skeletal muscle wasting in two different experimental models: rats rendered hyperglycemic by treatment with streptozotocin and rats bearing the Yoshida AH-130 ascites hepatoma. For this purpose, both tumor bearers and diabetic animals have been treated with dehydroepiandrosterone (DHEA), a multifunctional steroid endowed with multitargeted antioxidant properties. We show that diabetic rats and AH-130 rats share several features, hypoinsulinemia, occurrence of oxidative stress, and positive response to DHEA administration, although the extent of the effects of DHEA largely differs between diabetic animals and tumor-bearing rats. The hypercatabolism, evaluated in terms of proteasome activity and expression of atrogin-1 and MuRF1, is activated in AH-130 rats, whereas it is lacking in streptozotocin-treated rats. Moreover, we demonstrate that the role of oxidative stress can interfere with muscle wasting through different mechanisms, not necessarily involving NF-kappaB activation. In conclusion, the present results show that, although skeletal muscle wasting occurs in both diabetic rats and tumor-host rats, the underlying mechanisms are different. Moreover, despite oxidative stress being detectable in both experimental models, its contribution to muscle wasting is not comparable.
Mastrocola
Raffaella
R
Department of Experimental Medicine and Oncology, University of Turin, Corso Raffaello 30, 10125 Turin, Italy. rafaella.mastrocola@unito.it
Reffo
Patrizia
P
Penna
Fabio
F
Tomasinelli
Chiara Elena
CE
Boccuzzi
Giuseppe
G
Baccino
Francesco Maria
FM
Aragno
Manuela
M
Costelli
Paola
P
D000818:Animals; D004247:DNA / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism; D008297:Male; D009133:Muscular Atrophy / Q000209:etiology*; D017570:MyoD Protein / Q000032:analysis; D055435:Myostatin; D016328:NF-kappa B / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000150:complications* / Q000378:metabolism; D018384:Oxidative Stress; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D016212:Transforming Growth Factor beta / Q000032:analysis
C525913:Mstn protein, rat; D017570:MyoD Protein; D055435:Myostatin; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D016212:Transforming Growth Factor beta; D003687:Dehydroepiandrosterone; D013311:Streptozocin; D004247:DNA