Background
The enzymes of the ubiquitylation pathway play a pivotal role in a number of cellular processes including the regulated and targeted proteasome-dependent degradation of substrate proteins. Three classes of enzymes are involved in the process of ubiquitylation; activating enzymes (E1s), conjugating enzymes (E2s) and protein ligases (E3s). Muscle Ring Finger protein 1 (MuRF1) is a member of the E3 protein ligase family and cloning of the human gene was first described by Dai and Liew et al. (2001). Muscle atrophy is a pathological condition associated with a number of diseases including cancer, metabolic disorders and AIDS. The associated up-regulation of MuRF1 and increased muscle protein turnover observed in disease models highlights the potential value of targeting this E3 ligase in order to address muscle wasting conditions. Atrophy of skeletal muscle can occur through lack of use and denervation associated with disease states such as cancer cachexia, cardiac failure and other muscle wasting conditions in humans (Cohen et al., 2009; Rottbauer et al., 2006; Seidman et al., 2001; Poetter et al., 1996). Myosin Light Chain 1 (MyLC1) and MyLC2 are required for thick-filament stabilization and normal contractility in the myofibrils of skeletal muscle. Loss of function mutations in these proteins results in a perturbation of contractility and a striking disorganization of the thick filaments which leads to muscle wasting conditions (Cohen et al., 2009; Seidman et al., 2001). Rapid loss in muscle mass due to protein degradation of the myofibrilar components is mediated by the ubiquitin proteasome pathway. During this process there is a marked increase in MuRF1 concentration which is thought to act directly on specific components of the myofibril to promote its disassembly and degradation during atrophy (Cohen et al., 2009). Mice lacking the RING domain of MuRF1 show significantly reduced loss of muscle mass following denervation highlighting the therapeutic importance of this target in muscle wasting disease (Cohen et al., 2009).
References
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