Upregulation of MuRF1 and MAFbx participates to muscle wasting upon gentamicin-induced acute kidney injury.
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 development 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.
Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche (UMR) 1019, Unité de Nutrition Humaine (UNH), Centre de Recherche en Nutrition Humaine (CNRH) Auvergne, Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, UNH, BP 10448, Clermont-Ferrand, France; Service de Néphrologie Réanimation Médicale, Pôle Respiratoire, Endocrinologie-Diabétologie, Urologie, Néphrologie-Dialyse, Nutrition Clinique, Infectiologie, Réanimation Médicale, Hygiène Hospitalière (REUNNIRH), Clermont-Ferrand, France.
Julien
J
Aniort
Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche (UMR) 1019, Unité de Nutrition Humaine (UNH), Centre de Recherche en Nutrition Humaine (CNRH) Auvergne, Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, UNH, BP 10448, Clermont-Ferrand, France.
Cécile
C
Polge
Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche (UMR) 1019, Unité de Nutrition Humaine (UNH), Centre de Recherche en Nutrition Humaine (CNRH) Auvergne, Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, UNH, BP 10448, Clermont-Ferrand, France.
Agnès
A
Claustre
Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche (UMR) 1019, Unité de Nutrition Humaine (UNH), Centre de Recherche en Nutrition Humaine (CNRH) Auvergne, Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, UNH, BP 10448, Clermont-Ferrand, France.
Lydie
L
Combaret
Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche (UMR) 1019, Unité de Nutrition Humaine (UNH), Centre de Recherche en Nutrition Humaine (CNRH) Auvergne, Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, UNH, BP 10448, Clermont-Ferrand, France.
Daniel
D
Béchet
Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche (UMR) 1019, Unité de Nutrition Humaine (UNH), Centre de Recherche en Nutrition Humaine (CNRH) Auvergne, Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, UNH, BP 10448, Clermont-Ferrand, France.
Didier
D
Attaix
Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche (UMR) 1019, Unité de Nutrition Humaine (UNH), Centre de Recherche en Nutrition Humaine (CNRH) Auvergne, Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, UNH, BP 10448, Clermont-Ferrand, France; Service de Néphrologie Réanimation Médicale, Pôle Respiratoire, Endocrinologie-Diabétologie, Urologie, Néphrologie-Dialyse, Nutrition Clinique, Infectiologie, Réanimation Médicale, Hygiène Hospitalière (REUNNIRH), Clermont-Ferrand, France.
Anne-Elisabeth
AE
Heng
Institut National de la Recherche Agronomique (INRA), Unité Mixte de Recherche (UMR) 1019, Unité de Nutrition Humaine (UNH), Centre de Recherche en Nutrition Humaine (CNRH) Auvergne, Clermont-Ferrand, France; Clermont Université, Université d'Auvergne, UNH, BP 10448, Clermont-Ferrand, France. Electronic address: daniel.taillandier@clermont.inra.fr.
Daniel
D
Taillandier
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000150:complications; D000818:Animals; D005839:Gentamicins / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009133:Muscular Atrophy / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000070584:Tripartite Motif Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
D005839:Gentamicins; D007328:Insulin; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C499086:Trim63 protein, rat; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
Acute kidney injury; MAFbx; MuRF1; Muscle wasting; Ubiquitin-proteasome system