TNF-α is involved in activating DNA fragmentation in skeletal muscle

Cancer Research Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Diagonal 645, 08028-Barcelona, Spain.
British Journal of Cancer (Impact Factor: 4.84). 04/2002; 86(6):1012-6. DOI: 10.1038/sj.bjc.6600167
Source: PubMed


Intraperitoneal administration of 100 μg kg−1 (body weight) of tumour necrosis factor-α to rats for 8 consecutive days resulted in a significant decrease in protein content, which was concomitant with a reduction in DNA content. Interestingly, the protein/DNA ratio was unchanged in the skeletal muscle of the tumour necrosis factor-α-treated animals as compared with the non-treated controls. Analysis of muscle DNA fragmentation clearly showed enhanced laddering in the skeletal muscle of tumour necrosis factor-α-treated animals, suggesting an apoptotic phenomenon. In a different set of experiments, mice bearing a cachexia-inducing tumour (the Lewis lung carcinoma) showed an increase in muscle DNA fragmentation (9.8-fold) as compared with their non-tumour-bearing control counterparts as previously described. When gene-deficient mice for tumour necrosis factor-α receptor protein I were inoculated with Lewis lung carcinoma, they were also affected by DNA fragmentation; however the increase was only 2.1-fold. These results suggest that tumour necrosis factor-α partly mediates DNA fragmentation during experimental cancer-associated cachexia.
British Journal of Cancer (2002) 86, 1012–1016. DOI: 10.1038/sj/bjc/6600167
© 2002 Cancer Research UK

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    • "This is particularly true with TNFα, which promotes muscle wasting by enhancing the activity of the ubiquitin proteasome pathway (Langen et al 2006). TNFα also promotes muscle wasting by inducing apoptosis (Carbo et al 2002). Loss of nuclei, a result of increased apoptosis in skeletal muscle fibers, alters myonuclear domain size (the amount of cytoplasm per myonucleus), eventually resulting in muscle atrophy. "
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a debilitating disease characterized by inflammation-induced airflow limitation and parenchymal destruction. In addition to pulmonary manifestations, patients with COPD develop systemic problems, including skeletal muscle and other organ-specific dysfunctions, nutritional abnormalities, weight loss, and adverse psychological responses. Patients with COPD often complain of dyspnea on exertion, reduced exercise capacity, and develop a progressive decline in lung function with increasing age. These symptoms have been attributed to increases in the work of breathing and in impairments in gas exchange that result from airflow limitation and dynamic hyperinflation. However, there is mounting evidence to suggest that skeletal muscle dysfunction, independent of lung function, contributes significantly to reduced exercise capacity and poor quality of life in these patients. Limb and ventilatory skeletal muscle dysfunction in COPD patients has been attributed to a myriad of factors, including the presence of low grade systemic inflammatory processes, nutritional depletion, corticosteroid medications, chronic inactivity, age, hypoxemia, smoking, oxidative and nitrosative stresses, protein degradation and changes in vascular density. This review briefly summarizes the contribution of these factors to overall skeletal muscle dysfunction in patients with COPD, with particular attention paid to the latest advances in the field.
    International Journal of COPD 02/2008; 3(4):637-58. · 3.14 Impact Factor
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    • "In addition to the massive muscle protein loss, during cancer cachexia muscle DNA is also decreased, similarly to what is observed in skeletal muscle of chronic heart failure patients suffering from cardiac cachexia [22], this leading to apoptosis measured as DNA fragmentation [23]. Interestingly, TNF-a can mimic the apoptotic response in muscle of healthy animals [24]. "
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    ABSTRACT: The aim of the present study was to investigate a possible role of the AP-1 signaling cascade in the process of wasting associated with cancer cachexia at the level of skeletal muscle. The injection of virus containing the TAM67 protein (a blocker of the AP-1 protein) to the gastrocnemius muscle of tumour-bearing rats resulted in a significant recovery of the muscle mass (which is dramatically reduced as a result of tumour burden), therefore suggesting that AP-1 is certainly involved in the signaling associated with muscle protein accretion. In conclusion, the gene therapy approach presented here clearly suggests an important role for AP-1 in muscle signaling during catabolic states.
    FEBS Letters 02/2006; 580(2):691-6. DOI:10.1016/j.febslet.2005.12.084 · 3.17 Impact Factor
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    • "High plasma levels of tumour necrosis factor-a (TNF) [13] and perturbations in the hormonal homeostasis [14] may play an important role in forcing the metabolic balance towards the catabolic side. In addition to increased muscle protein degradation during cancer growth, the presence of the tumour also induces an increased rate of apoptosis in skeletal muscle in rats [15], which also seems to be activated by cytokines, TNF in particular [16]. Oxidative stress due to greater levels of reactive oxygen species (ROS) production than those normally neutralized by intracellular antioxidant defenses has recently gained much attention for its possible involvement in cancer cachexia . "
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