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Anti-TNF treatment reduces rat skeletal muscle wasting in monocrotaline-induced cardiac cachexia
Brian T Steffen1, Simon J Lees, Frank W Booth
1Department of Medical Pharmacology, Dalton Cardiovascular Institute, University of Missouri, Columbia, Missouri 65211, USA.
Abstract:
The aim was to explore efficacy of tumor necrosis factor (TNF) inhibitors in attenuating increases in anorexia and ubiquitin proteasome pathway transcripts in cardiac cachexia, a potentially lethal condition that responds poorly to current treatments. Cardiac cachexia was rapidly induced with monocrotaline in Sprague-Dawley rats. Either soluble TNF receptor-1 or the general inhibitor of TNF production, pentoxifylline, was given to diminish TNF action on the first indication of cachexia. Animals were anesthetized with a ketamine-xylazine-acepromazine cocktail, and then skeletal muscles were removed for subsequent measurements including ubiquitin proteasome pathway transcripts and Western blots. Both soluble TNF receptor-1 and pentoxifylline attenuated losses in both body and skeletal muscle masses and also reduced increases in selected ubiquitin proteasome pathway transcripts. The action of soluble TNF receptor-1 was partly through reversal of reduced food consumption, while the effects of pentoxifylline were independent of food intake. Here we demonstrate, for the first time, that attenuation of anorexia by soluble TNF receptor-1 treatment in monocrotaline-induced cardiac cachexia is responsible for attenuating increases in some ubiquitin proteasome pathway transcripts as well as preserving body mass and attenuating loss of skeletal muscle mass.
Insights
Tumor necrosis factor (TNF) inhibitors, including soluble TNF receptor-1 and pentoxifylline, effectively treat cardiac cachexia by preserving body and muscle mass. Soluble TNF receptor-1 works by reducing anorexia, while pentoxifylline
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Pharmacology
Background:
- Cardiac cachexia is a severe condition characterized by progressive weight loss and muscle wasting, often associated with poor treatment outcomes.
- Tumor necrosis factor (TNF) plays a significant role in the pathogenesis of cardiac cachexia, contributing to anorexia and muscle protein degradation.
- The ubiquitin proteasome pathway (UPP) is implicated in muscle atrophy during cachexia, but its modulation by TNF inhibitors is not fully understood.
Purpose of the Study:
- To investigate the efficacy of TNF inhibitors in attenuating anorexia and UPP activation in a rat model of cardiac cachexia.
- To determine whether soluble TNF receptor-1 or pentoxifylline can prevent body and skeletal muscle mass loss in cardiac cachexia.
- To elucidate the mechanisms by which TNF inhibition impacts food intake and UPP activity in this condition.
Main Methods:
- Cardiac cachexia was induced in Sprague-Dawley rats using monocrotaline.
- Animals received either soluble TNF receptor-1 or pentoxifylline upon the first signs of cachexia.
- Skeletal muscle tissues were analyzed for UPP transcripts and protein levels using Western blotting.
Main Results:
- Both soluble TNF receptor-1 and pentoxifylline significantly attenuated losses in body and skeletal muscle mass.
- Treatment with these TNF inhibitors reduced the upregulation of selected UPP transcripts.
- Soluble TNF receptor-1's beneficial effects were partly mediated by reversing anorexia, whereas pentoxifylline's effects were independent of food intake.
Conclusions:
- TNF inhibition is a promising therapeutic strategy for managing cardiac cachexia.
- Soluble TNF receptor-1 effectively preserves body and muscle mass, partly by improving appetite.
- Pentoxifylline also mitigates cardiac cachexia independently of food intake, suggesting distinct therapeutic pathways.
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