Muscle RING-Finger Protein-1 (MuRF1) as a Connector of Muscle Energy Metabolism and Protein Synthesis

Department of Enzymatic Regulation for Cell Functions (Calpain Project), Tokyo Metropolitan Institute of Medical Science (Rinshoken), Tokyo 113-8613, Japan.
Journal of Molecular Biology (Impact Factor: 4.33). 04/2008; 376(5):1224-36. DOI: 10.1016/j.jmb.2007.11.049
Source: PubMed


During pathophysiological muscle wasting, a family of ubiquitin ligases, including muscle RING-finger protein-1 (MuRF1), has been proposed to trigger muscle protein degradation via ubiquitination. Here, we characterized skeletal muscles from wild-type (WT) and MuRF1 knockout (KO) mice under amino acid (AA) deprivation as a model for physiological protein degradation, where skeletal muscles altruistically waste themselves to provide AAs to other organs. When WT and MuRF1 KO mice were fed a diet lacking AA, MuRF1 KO mice were less susceptible to muscle wasting, for both myocardium and skeletal muscles. Under AA depletion, WT mice had reduced muscle protein synthesis, while MuRF1 KO mice maintained nonphysiologically elevated levels of skeletal muscle protein de novo synthesis. Consistent with a role of MuRF1 for muscle protein turnover during starvation, the concentrations of essential AAs, especially branched-chain AAs, in the blood plasma significantly decreased in MuRF1 KO mice under AA deprivation. To clarify the molecular roles of MuRF1 for muscle metabolism during wasting, we searched for MuRF1-associated proteins using pull-down assays and mass spectrometry. Muscle-type creatine kinase (M-CK), an essential enzyme for energy metabolism, was identified among the interacting proteins. Coexpression studies revealed that M-CK interacts with the central regions of MuRF1 including its B-box domain and that MuRF1 ubiquitinates M-CK, which triggers the degradation of M-CK via proteasomes. Consistent with MuRF1's role of adjusting CK activities in skeletal muscles by regulating its turnover in vivo, we found that CK levels were significantly higher in the MuRF1 KO mice than in WT mice. Glucocorticoid modulatory element binding protein-1 and 3-hydroxyisobutyrate dehydrogenase, previously identified as potential MuRF1-interacting proteins, were also ubiquitinated MuRF1-dependently. Taken together, these data suggest that, in a multifaceted manner, MuRF1 participates in the regulation of AA metabolism, including the control of free AAs and their supply to other organs under catabolic conditions, and in the regulation of ATP synthesis under metabolic-stress conditions where MuRF1 expression is induced.

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    • "We have shown that using static markers to infer changes in the dynamic processes of MPS and MPB is inherently flawed (Rennie et al. 2008) so any data using such markers should be interpreted with caution. Moreover, as the 'atrogenes', MAFBx and MuRF-1 act to limit MPS by 'tagging' key initiation factors regulating the capacity for MPS, extra care should be taken in assigning their role exclusively to MPB (Koyama et al. 2008, Lagirand-Cantaloube et al. 2008). Crucially, loss of muscle mass during disuse is a feature of both dysregulated post-absorptive and postprandial MPS. "
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    • "The levels of mRNA expression were normalized by those of housekeeping Hprt because its expression was stable during fasting in all tested tissues. As the ubiquitin–proteasome system marker, we examined the expression of Atrogin-1 (also known as MAFbx [Muscle Atrophy F-box]) and MuRF1 (Muscle RING Finger 1; also known as Trim63 [Muscle Atrophy F-box]), the two E3 ubiquitin ligases involved in skeletal muscle atrophy [9] [10]. The expression of Atrogin-1 was significantly upregulated upon fasting in skeletal muscle >> small intestine, thymus > heart, colon, lung > spleen, kidney > stomach (Fig. 2A). "
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    • "However, given the normal hypertrophic response to FO in the MuRF1 KO mice, it seems that MuRF1 is not essential for muscle growth. Considering that protein synthesis is higher in MuRF1 KO mice under atrophy conditions (Koyama et al., 2008; Baehr et al., 2011), it may be that the major role of MuRF1 in skeletal muscle is to suppress protein synthesis. Thus, deletion of MuRF1 is advantageous to muscle growth and consequently, the MuRF1 KO mice maintain an ability to hypertrophy throughout their lifetime. "
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