Skeletal muscle wasting in tumor-bearing rats is associated with MyoD down-regulation.
ABSTRACT Cachexia is a syndrome characterized by profound skeletal muscle wasting that frequently complicates malignancies. A number of studies indicate that protein hypercatabolism, largely mediated by classical hormones and cytokines, is the major component of muscle depletion. Impaired regeneration has been suggested to contribute to the reduction of muscle size. In particular, it has been shown that the expression of MyoD, a muscle-specific transcription factor, is down-regulated by cytokines such as TNFalpha and IFNgamma in a NF-kappaB-dependent posttranscriptional manner. The present study investigated whether modulations of the transcription factor MyoD are associated with the onset of muscle wasting in a well established model of cancer cachexia. Rats bearing the Yoshida AH-130 hepatoma develop a condition of muscle protein hypercatabolism, largely dependent on TNFalpha bioactivity. In the gastrocnemius of these animals the expression of MyoD was markedly reduced, paralleling the decrease of muscle weight. This pattern is associated with increased nuclear translocation of AP-1, while DNA-binding assays did not detect any change in NF-kappaB activity. This is the first observation demonstrating that muscle depletion in tumor-bearing rats is associated with a down-regulation of MyoD levels. Although the underlying mechanisms remain to be clarified, this change is compatible with the hypothesis that a reduced expression of molecules involved in the regulation of the regenerative response may concur to muscle wasting in cancer cachexia.
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- "Even the expression of components of the ATP–ubiquitin-dependent proteolytic system, MuRF1 in particular , seems to be regulated by NF-κB . Previous data showed that the DNA-binding activity of NF-κB does not change in the skeletal muscle of rats bearing the AH-130 tumor . By contrast, we show here that the amount of NF-κB p65 in the nuclear extract from the gastrocnemius of STZ-treated rats is significantly higher than in controls and that this pattern is effectively prevented by DHEA administration (Fig. 4A), whereas in the gastrocnemius of AH-130 hosts, treated or not with DHEA, the nuclear level of NF-κB p65 did not change with respect to controls. "
ABSTRACT: 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.Free Radical Biology and Medicine 03/2008; 44(4):584-93. DOI:10.1016/j.freeradbiomed.2007.10.047 · 5.71 Impact Factor
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ABSTRACT: The cachectic syndrome, characterized by a marked weight loss, anorexia, asthenia, and anemia is invariably associated with the presence and growth of the tumor and leads to a malnutrition status due to the induction of anorexia or decreased food intake. In addition, the competition for nutrients between the tumor and the host leads to an accelerated starvation state, which promotes severe metabolic disturbances in the host, including hypermetabolism, which leads to an increased energetic inefficiency. Although the search for the cachectic factor(s) started a long time ago, and although many scientific and economic efforts have been devoted to its discovery, we are still a long way from knowing the whole truth. Present investigation is devoted to revealing the different signaling pathways, in particular transcriptional factors involved in muscle wasting. The main aim of the present review is to summarize and evaluate the different molecular mechanisms and catabolic mediators (both humoral and tumoral) involved in cancer cachexia since they may represent targets for future promising clinical investigations.Nutrition 10/2005; 21(9):977-85. DOI:10.1016/j.nut.2005.02.003 · 3.05 Impact Factor
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ABSTRACT: The cachectic syndrome, characterized by a marked weight loss, anorexia, asthenia and anemia, is invariably associated with the presence and growth of the tumour and leads to a malnutrition status due to the induction of anorexia or decreased food intake. In addition, the competition for nutrients between the tumour and the host leads to an accelerated catabolic state, which promotes severe metabolic disturbances in the host, including hypermetabolism, which leads to an increased energetic inefficiency. Although the search for the cachectic factor(s) started a long time ago, and although many scientific and economic efforts have been devoted to its discovery, we are still a long way from knowing the whole truth. Present investigation is devoted to unrevealing the different signaling pathways (particulary transcriptional factors) involved in muscle wasting. The main aim of the present review is to summarize and evaluate the different molecular mechanisms and catabolic mediators involved in cancer cachexia since they may represent targets for future promising clinical investigations.The International Journal of Biochemistry & Cell Biology 11/2005; 37(10):2036-46. DOI:10.1016/j.biocel.2005.03.014 · 4.24 Impact Factor