Abstract
BackgroundA low-protein diet supplemented with ketoacids (LPD + KA) maintains the nutritional status of patients with chronic kidney disease (CKD). Oxidative damage and mitochondrial dysfunction associated with the upregulation of p66SHC and FoxO3a have been shown to contribute to muscle atrophy. This study aimed to determine whether LPD + KA improves muscle atrophy and attenuates the oxidative stress and mitochondrial damage observed in CKD rats.Methods5/6 nephrectomy rats were randomly divided into three groups and fed with either 22% protein (normal-protein diet; NPD), 6% protein (low-protein diets; LPD) or 5% protein plus 1% ketoacids (LPD + KA) for 24 weeks. Sham-operated rats with NPD intake were used as the control.ResultsKA supplementation improved muscle atrophy and function in CKD + LPD rats. It also reduced the upregulation of genes related to the ubiquitin-proteasome system and 26S proteasome activity, as well as protein and mitochondrial oxidative damage in the muscles of CKD + LPD rats. Moreover, KA supplementation prevented the drastic decrease in activities of mitochondrial electron transport chain complexes, mitochondrial respiration, and content in the muscles of CKD + LPD rats. Furthermore, KA supplementation reversed the elevation in p66Shc and FoxO3a expression in the muscles of CKD + LPD rats.ConclusionsOur results showed that KA supplementation to be beneficial to muscle atrophy in CKD + LPD, which might be associated with improvement of oxidative damage and mitochondrial dysfunction through suppression of p66Shc and FoxO3a.
Highlights
A low-protein diet supplemented with ketoacids (LPD + KA) maintains the nutritional status of patients with chronic kidney disease (CKD)
Ketoacid supplementation improves mitochondrial oxidative capacity in the muscles of CKD + low-protein diets (LPD) rats To analyse the consequences of KA supplementation on mitochondrial oxidative capacity, we evaluated the levels of mitochondrial H2O2, catalase and superoxide dismutase (SOD) in the skeletal muscle of the experimental rats
We have shown that isolated skeletal muscle mitochondria from CKD + LPD rats exhibit an increase in H2O2 generation, which was consistent with the role of mitochondria as a contributor to CKD-related muscle oxidative damage [41]
Summary
A low-protein diet supplemented with ketoacids (LPD + KA) maintains the nutritional status of patients with chronic kidney disease (CKD). Oxidative damage and mitochondrial dysfunction associated with the upregulation of p66SHC and FoxO3a have been shown to contribute to muscle atrophy. Dietary protein restriction is one of the major components of therapy for patients with chronic kidney disease (CKD). It can minimise uremic symptoms and slow the progression of renal failure [1]. Hydrogen peroxide (H2O2) is a major component of ROS, generated during mitochondrial respiration, which induced mitochondrial dysfunction in skeletal muscle [9]. This antioxidant defence system is composed of antioxidant enzymes such as superoxide dismutase (SOD) and catalase [11]. The role of p66Shc and FoxO3a in mediating oxidative stress in the skeletal muscle of CKD has not been reported
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