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
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
复制标题
DOI：
10.1017/s0007114513004091
复制
发表时间：
2014-02
影响因子：
3.6
通讯作者：
Dong-tao Wang;Lu Lu-Lu;Ying Shi;Zhenbo Geng;Yi-jian Yin;Ming Wang;Lianbo Wei
中科院分区：
文献类型：
--
作者：
Dong-tao Wang;Lu Lu-Lu;Ying Shi;Zhenbo Geng;Yi-jian Yin;Ming Wang;Lianbo Wei
已知酮酸(KA)可改善低蛋白饮食(CKD-LPD)慢性肾脏病(CKD)患者的肌肉质量，但其预防肌肉萎缩的机制仍不清楚。由于CKD大鼠肌肉萎缩可能与Wnt7a/Akt/p70S6K通路下调、泛素-蛋白酶体系统(UPS)激活和细胞凋亡信号通路激活有关，因此可以很容易地得出这样的假设，即补充KA通过上调Wnt7a/Akt/p70S6K通路，抵消依赖UPS和caspase-3的细胞凋亡，从而改善CKD-LPD大鼠的肌肉质量。将5/6肾切除大鼠随机分为3组，分别给予22%蛋白质饲料(NPD)、6%蛋白质饲料(LPD)和5%蛋白质+1%KA饲料喂养24周。以NPD灌胃的假手术大鼠为对照。结果表明，补充KA可促进CKD-LPD大鼠肌肉蛋白质合成，增加Wnt7a、磷酸化Akt和p70S6K等相关介质的表达。它还能抑制蛋白质降解，抑制CKD-LPD大鼠肌肉中泛素及其连接酶MAFbx(肌肉萎缩F-box)和MuRF1(肌肉环指-1)的增加，并减弱蛋白酶体活性。补充KA后，CKD-LPD大鼠骨骼肌DNA片段减少，caspase-3和14 kDa肌动蛋白片段断裂，Bax/BCL-2比值下调。本文揭示的有益效果进一步证实，KA可能是治疗CKD-LPD肌肉萎缩的更好的治疗策略。
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.