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Anti-TNF treatment reduces rat skeletal muscle wasting in monocrotaline-induced cardiac cachexia

Departments of Medical Pharmacology and Physiology and of Biomedical Sciences, Dalton Cardiovascular Institute, University of Missouri, Columbia, Missouri

Submitted 8 July 2008 ; accepted in final form 16 September 2008

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.

atrophy; nutrition; proinflammatory cytokine