Control of ubiquitination in skeletal muscle wasting

Abstract: The ubiquitin proteasome system is now well recognized to play a role in mediating skeletal muscle protein wasting. Ubiquitin exerts its effects by covalent attachment to other proteins. Increased ubiquitination of muscle proteins has been observed in a number of conditions of atrophy suggesting that flux through the pathway may be regulated by controlling availability of ubiquitinated substrates for the proteasome. Therefore the enzymes that control ubiquitination of proteins likely play critical roles in regulating flux through the pathway, are sites of activation by catabolic stimuli and potentially good drug targets in the search for therapies for wasting disorders. In this article, the enzymes that can modulate ubiquitination are briefly reviewed and the current data regarding regulation of these enzymes in skeletal muscle are described. Physiological regulators of muscle size appear to modulate many of these enzymes and several of these regulators appear to do so via signaling pathways that involve Akt or NFκB. Further work needs to be done to identify all the enzymes that are involved in controlling ubiquitination in muscle, to characterize their regulation by non-transcriptional mechanisms also, and most importantly to identify their target substrates and to determine how these various pathways of ubiquitination work together to mediate the catabolic stimulus. [Copyright &y& Elsevier]