Cytokines and oxidative signalling in skeletal muscle

Abstract

A growing body of literature indicates that cytokines regulate skeletal muscle function, including gene expression and adaptive responses. Tumour necrosis factor-α (TNF-α) is the cytokine most prominently linked to muscle pathophysiology and, therefore, has been studied most extensively in muscle-based systems. TNF-α is associated with muscle catabolism and loss of muscle function in human diseases that range from cancer to heart failure, from arthritis to AIDS. Recent advances have established that TNF-α causes muscle weakness via at least two mechanisms, accelerated protein loss and contractile dysfunction. Protein loss is a chronic response that occurs over days to weeks. Changes in gene expression required for TNF-α induced catabolism are regulated by the transcription factor nuclear factor-κB which is essential for the net loss of muscle protein caused by chronic TNF-α exposure. Contractile dysfunction is an acute response to TNF-α stimulation, developing over hours and resulting in decreased force production. Both actions of TNF-α involve a rapid rise in endogenous oxidants as an essential step in post-receptor signal transduction. These oxidants appear to include reactive oxygen species derived from mitochondrial electron transport. Such information provides insight into the cellular and molecular mechanisms of TNF-α action in skeletal muscle and establishes a scientific basis for continued research into cytokine signalling.