Supplementation of ketoacids contributes to the up-regulation of the Wnt7a/Akt/p70S6K pathway and the down-regulation of apoptotic and ubiquitin–proteasome systems in the muscle of 5/6 nephrectomised rats

Abstract

Ketoacids (KA) are known to improve muscle mass among patients with chronic kidney disease (CKD) on a low-protein diet (CKD-LPD), but the mechanism of its preventive effects on muscle atrophy still remains unclear. Since muscle atrophy in CKD may be attributable to the down-regulation of the Wnt7a/Akt/p70S6K pathway and the activation of the ubiquitin -proteasome system (UPS) and the apoptotic signalling pathway, a hypothesis can readily be drawn that KA supplementation improves muscle mass by up-regulating the Wnt7a/Akt/p70S6K pathway and counteracting the activation of the UPS and caspase-3-dependent apoptosis in the muscle of CKD-LPD rats. Rats with 5/6 nephrectomy were randomly divided into three groups, and fed with either 22 % protein (normal-protein diet; NPD), 6 % protein (LPD) or 5 % protein plus 1 % KA for 24 weeks. Sham-operated rats with NPD intake were used as the control. The results demonstrated that KA supplementation improved protein synthesis and increased related mediators such as Wnt7a, phosphorylated Akt and p70S6K in the muscle of CKD-LPD rats. It also inhibited protein degradation, withheld the increase in ubiquitin and its ligases MAFbx (muscle atrophy F-box) and MuRF1 (muscle ring finger-1) as well as attenuated proteasome activity in the muscle of CKD-LPD rats. Moreover, KA supplementation gave rise to a reduction in DNA fragment, cleaved caspase-3 and 14 kDa actin fragment via the down-regulation of the Bax:Bcl-2 ratio in the muscle of CKD-LPD rats. The beneficial effects unveiled herein further consolidate that KA may be a better therapeutic strategy for muscle atrophy in CKD-LPD.

Resveratrol Improves Muscle Atrophy by Modulating Mitochondrial Quality Control in STZ‐Induced Diabetic Mice

“…Snap‐frozen Quad muscle tissues were homogenized in lysis buffer, as we previously reported . Cytosolic and mitochondrial proteins were separated on a 10% SDS‐PAGE gel and then transferred to a PVDF membrane (Bio‐Rad Laboratories, Hercules, CA, USA).…”

Astragalus polysaccharides decrease muscle wasting through Akt/mTOR, ubiquitin proteasome and autophagy signalling in 5/6 nephrectomised rats

“…Each animal in the nephrectomised group underwent a 5/6 nephrectomy, consisting of ablation of two thirds of the mass of the left kidneys, followed by right unilateral nephrectomy after 1 week. In the sham-operated rats, a sham operation was performed according to previous methods (Wang et al, 2014c).…”

“…Myofibre cross-sectional area and C2C12 fibre size measurements were performed according previous experiments (Lu et al, 2013c;Wang et al, 2014a). Tibias anterior (TA) muscle samples were fixed in paraformaldehyde and embedded in paraffin.…”

“…Then, the weight of every sample was measured. Protein synthesis/degradation rates were measured using our previous protocol (Wang et al, 2014c). Protein synthesis was measured in vitro in the soleus muscle using the incorporation of [ 14 C] phenylalanine as described previously.…”

Is There a Role for Ketoacid Supplements in the Management of CKD?

“…29,[33][34][35][36] The mechanisms for these possible anabolic effects are not clear, but in a rat model of CKD, when animals are fed KA/ EAA-supplemented VLPDs, they show evidence of suppression of apoptotic and ubiquitin pathways in muscle, with increased protein synthesis and inhibited protein degradation. 37 …”