Skeletal muscle wasting in tumor-bearing rats is associated with MyoD down-regulation

Dipartimento di Medicina ed Oncologia Sperimentale, Universitá di Torino, I-10125 Torino, Italy.
International Journal of Oncology (Impact Factor: 3.03). 07/2005; 26(6):1663-8. DOI: 10.3892/ijo.26.6.1663
Source: PubMed


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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    • "Liu et al. used a myostatin anti-sense RNA and found that the oligonucleotides could suppress myostatin expression in vivo resulting in an increase in muscle growth both in healthy and cachectic mice [17]. Interestingly, the effect of the RNA oligonucleotides was a significant upregulation of MyoD expression, therefore reinforcing the role of this transcription factor in muscle wasting [18, 19]. Although the use of the deacetylase inhibitors to increase the levels of follistatin (an antagonist of myostatin) has not lead to any positive results in the treatment of cachexia in experimental animals [20, 21], the use of the activin receptor extracellular domain/Fc fusion protein (ACVR2B-Fc) has been shown to be effective in the treatment of muscle wasting in tumor-bearing animals [21]. "
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    ABSTRACT: Cachexia is a multiorganic syndrome associated with cancer, characterized by body weight loss, muscle and adipose tissue wasting and inflammation. The aim of this investigation was to examine the effect of the soluble receptor antagonist of myostatin (sActRIIB) in cachectic tumor-bearing animals analyzing changes in muscle proteolysis and in quality of life. Administration of sActRIIB resulted in an improvement in body and muscle weights. Administration of the soluble receptor antagonist of myostatin also resulted in an improvement in the muscle force. These results suggest that blocking myostatin pathway could be a promising therapeutic strategy for the treatment of cancer cachexia.
    Full-text · Article · Mar 2012
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    • "MyoD levels, previously reported to be reduced in the muscle of AH-130 bearers [20], are unaffected in the gastrocnemius of the C26 hosts (Fig. 5B), while the marked decrease of myogenin is rescued by PD treatment (Fig. 5B). Of interest, two myogenin isoforms can be observed in the TB muscles (Fig. 5B). "
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    ABSTRACT: The onset of cachexia is a frequent feature in cancer patients. Prominent characteristic of this syndrome is the loss of body and muscle weight, this latter being mainly supported by increased protein breakdown rates. While the signaling pathways dependent on IGF-1 or myostatin were causally involved in muscle atrophy, the role of the Mitogen-Activated-Protein-Kinases is still largely debated. The present study investigated this point on mice bearing the C26 colon adenocarcinoma. C26-bearing mice display a marked loss of body weight and muscle mass, this latter associated with increased phosphorylated (p)-ERK. Administration of the ERK inhibitor PD98059 to tumor bearers attenuates muscle depletion and weakness, while restoring normal atrogin-1 expression. In C26 hosts, muscle wasting is also associated with increased Pax7 expression and reduced myogenin levels. Such pattern, suggestive of impaired myogenesis, is reversed by PD98059. Increased p-ERK and reduced myosin heavy chain content can be observed in TNFα-treated C2C12 myotubes, while decreased myogenin and MyoD levels occur in differentiating myoblasts exposed to the cytokine. All these changes are prevented by PD98059. These results demonstrate that ERK is involved in the pathogenesis of muscle wasting in cancer cachexia and could thus be proposed as a therapeutic target.
    Full-text · Article · Oct 2010 · PLoS ONE
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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 [38]. 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 [36]. 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. "
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    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.
    Full-text · Article · Mar 2008 · Free Radical Biology and Medicine
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