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Upregulation of MuRF1 and MAFbx participates to muscle wasting upon gentamicin-induced acute kidney injury
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The authors thank C. Deval for helpful technical assistance during the review process. This work was supported by grants to D. T., C. P. and D. A. from the Institut National de la Recherche Agronomique. Acute Kidney Injury (AKI) is frequently encountered in hospitalized patients where it is associated with increased mortality and morbidity notably affecting muscle wasting. Increased protein degradation has been shown to be the main actor of AKI-induced muscle atrophy, but the proteolytic pathways involved are poorly known. The Ubiquitin Proteasome System (UPS) is almost systematically activated in various catabolic situations, and the E3 ligases MuRF1 and MAFbx are generally up regulated in atrophying muscles. We hypothesized that the UPS may be one of the main actors in catabolic skeletal muscles from AKI animals. We used gentamicin-induced acute kidney disease (G-AKI) in rats fed a high protein diet to promote acidosis. We first addressed the impact of G-AKI in the development of mild catabolic conditions. We found that both muscle atrophy and UPS activation were induced with the développement of G-AKI. In addition, the phasic muscles were more sensitive to 7-days G-AKI (−11 to −17%, P < 0.05) than the antigravity soleus muscle (−11%, NS), indicating a differential impact of AKI in the musculature. We observed an increased expression of the muscle-specific E3 ligases MuRF1 and MAFbx in phasic muscles that was highly correlated to the G-AKI severity (R2 = 0.64, P < 0.01 and R2 = 0.71, P < 0.005 respectively). Conversely, we observed no variation in the expression of three other E3 ligases (Nedd4, Trim32 and Fbxo30/MUSA1). Altogether, our data indicate that MuRF1 and MAFbx are sensitive markers and potential targets to prevent muscle atrophy during G-AKI.Abbreviations : UPS, ubiquitin proteasome system; AKI, acute kidney injury; ATN, acute tubular necrosis; CKD, chronic kidney disease; MuRF1, muscle ring finger protein-1; MAFbx, muscle atrophy F-box protein; MUSA1, muscle ubiquitin ligase of the SCF complex in atrophy-1; Nedd4, neuronally expressed developmentally downregulated 4 protein; Trim32, tripartite motif-containing protein 32; Ub, ubiquitin; EDL, extensor digitorum longus; TGF, transforming growth factor
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