title: 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.
authors: Nephropathy Center of Integrated Traditional Chinese Medicine and Western Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People's Republic of China.
authors: Dong-Tao
authors: DT
authors: Wang
authors: Nephropathy Center of Integrated Traditional Chinese Medicine and Western Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People's Republic of China.
authors: Lu
authors: L
authors: Lu
authors: Nephropathy Center of Integrated Traditional Chinese Medicine and Western Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People's Republic of China.
authors: Ying
authors: Y
authors: Shi
authors: Nephropathy Center of Integrated Traditional Chinese Medicine and Western Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People's Republic of China.
authors: Zhen-Bo
authors: ZB
authors: Geng
authors: Nephropathy Center of Integrated Traditional Chinese Medicine and Western Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People's Republic of China.
authors: Yi
authors: Y
authors: Yin
authors: Nephropathy Center of Integrated Traditional Chinese Medicine and Western Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People's Republic of China.
authors: Ming
authors: M
authors: Wang
authors: Nephropathy Center of Integrated Traditional Chinese Medicine and Western Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People's Republic of China.
authors: Lian-Bo
authors: LB
authors: Wei
mesh_terms: D000818:Animals; D017209:Apoptosis; D018753:Diet, Protein-Restricted / Q000009:adverse effects; D019587:Dietary Supplements; D004195:Disease Models, Animal; D015536:Down-Regulation; D007651:Keto Acids / Q000627:therapeutic use*; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology / Q000517:prevention & control*; D009392:Nephrectomy / Q000009:adverse effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000819:agonists* / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000178:diet therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D054875:Ubiquitination; D015854:Up-Regulation; D051153:Wnt Proteins / Q000819:agonists* / Q000378:metabolism
chemical_list: D007651:Keto Acids; D009124:Muscle Proteins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; C490507:Wnt7a protein, rat; D046988:Proteasome Endopeptidase Complex