Unacylated ghrelin normalizes skeletal muscle oxidative stress and prevents muscle catabolism by enhancing tissue mitophagy in experimental chronic kidney disease

Abstract

Unacylated ghrelin (UnAG) may lower skeletal muscle oxidative stress, inflammation, and insulin resistance in lean and obese rodents. UnAG-induced autophagy activation may contribute to these effects, likely involving removal of dysfunctional mitochondria (mitophagy) and redox state maintenance. In chronic kidney disease (CKD) oxidative stress, inflammation and insulin resistance may negatively influence patient outcome by worsening nutritional state through muscle mass loss. Here we show in a 5/6 nephrectomy (Nx) CKD rat model that 4 d s.c. UnAG administration (200 µg twice a day) normalizes CKD-induced loss of gastrocnemius muscle mass and a cluster of high tissue mitochondrial reactive oxygen species generation, high proinflammatory cytokines, and low insulin signaling activation. Consistent with these results, human uremic serum enhanced mitochondrial reactive oxygen species generation and lowered insulin signaling activation in C2C12 myotubes while concomitant UnAG incubation completely prevented these effects. Importantly, UnAG enhanced muscle mitophagy and silencing RNA-mediated autophagy protein 5 silencing blocked UnAG activities in myotubes. UnAG therefore normalizes CKD-induced skeletal muscle oxidative stress, inflammation, and low insulin signaling as well as muscle loss. UnAG effects are mediated by autophagy activation at the mitochondrial level. UnAG administration and mitophagy activation are novel potential therapeutic strategies for skeletal muscle metabolic abnormalities and their negative clinical impact in CKD.-Gortan Cappellari, G., Semolic, A., Ruozi, G., Vinci, P., Guarnieri, G., Bortolotti, F., Barbetta, D., Zanetti, M., Giacca, M., Barazzoni, R. Unacylated ghrelin normalizes skeletal muscle oxidative stress and prevents muscle catabolism by enhancing tissue mitophagy in experimental chronic kidney disease.

Acylated ghrelin treatment normalizes skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rat chronic heart failure

“…C2C12 myoblasts were differentiated in myotubes as previously reported . After 4 day incubation periods with differentiation medium and 18 h starvation, they were treated with AG (0.1 or 1 μmol/L) for 48 h, followed by collection and processing.…”

Omega 3 Polyunsaturated Fatty Acids Improve Endothelial Dysfunction in Chronic Renal Failure: Role of eNOS Activation and of Oxidative Stress

“…A 5/6 nephrectomy was chosen as the model of renal disease [ 14 ]. Animals were randomly assigned to receive single-step laparotomic 5/6 nephrectomy or sham operation as recently described by the authors of [ 15 ]. After anaesthesia (premedication: Dexmedetomidine 0.05 mg/kg IP, anaesthesia: Zoletil 25 mg/kg IP, lidocaine 4 mg/kg local infiltration), median laparotomy, opening of the retro-peritoneum and left kidney isolation, the renal artery was clamped and the inferior and superior poles were resected.…”

Role of Oxidative Stress as Key Regulator of Muscle Wasting during Cachexia

“…Recently, a study employing a murine model of sepsis induced by cecal ligation and perforation showed that limb muscles exhibit higher autophagy than do respiratory muscles [ 188 ]. Another recent study using an experimental model of CKD revealed a correlation between skeletal muscle oxidative stress, muscle catabolism, and autophagy, finding that inhibition of oxidative stress could improve muscle atrophy by enhancing mitophagy [ 189 ]. Moreover, a C26 cell-induced cancer model demonstrated that exercise increased autophagy flux, improving muscle homeostasis, probably due to the removal of damaged proteins and mitochondria [ 190 ].…”