Skeletal Muscle Regeneration and Oxidative Stress Are Altered in Chronic Kidney Disease.
Skeletal Muscle Regeneration and Oxidative Stress Are Altered in Chronic Kidney Disease.
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在慢性肾脏疾病中，骨骼肌再生和氧化应激发生了改变。
DOI：
10.1371/journal.pone.0159411
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Moe SM
中科院分区：
文献类型：
--
作者：
Avin KG;Chen NX;Organ JM;Zarse C;O'Neill K;Conway RG;Konrad RJ;Bacallao RL;Allen MR;Moe SM
骨骼肌萎缩和肌肉功能受损与慢性肾脏疾病（CKD）患者较低的健康相关生活质量、更大的残疾和死亡风险相关。然而，CKD中骨骼功能障碍的发病机制尚不清楚。我们使用进展缓慢、自然发生的CKD大鼠模型（Cy/+大鼠），其激素异常与CKD的临床表现一致，以研究骨骼肌信号。CKD大鼠骨骼肌再生增强，肌肉细胞激活和分化信号升高（即Pax-7降低，MyoD和肌原素RNA表达升高）。然而，CKD肌肉中蛋白水解标志物（Atrogin-1和MuRF-1）的表达也高于正常水平。与正常动物相比，CKD动物的氧化应激指标更高，血浆中氧化应激标志物8-羟基-2' -脱氧鸟苷（8-OHdG）水平升高，肌肉中琥珀酸脱氢酶（SDH）和Nox4表达增加，线粒体形态改变。此外，我们发现与正常动物相比，CKD动物骨骼肌中肌生长抑制素的血清水平和表达明显更高。综上所述，这些数据表明，在CKD的情况下，异常的再生和蛋白水解信号与氧化应激和高水平的肌生长抑制素有关。这些变化可能在CKD中存在的骨骼肌功能受损中发挥作用。
Skeletal muscle atrophy and impaired muscle function are associated with lower health-related quality of life, and greater disability and mortality risk in those with chronic kidney disease (CKD). However, the pathogenesis of skeletal dysfunction in CKD is unknown. We used a slow progressing, naturally occurring, CKD rat model (Cy/+ rat) with hormonal abnormalities consistent with clinical presentations of CKD to study skeletal muscle signaling. The CKD rats demonstrated augmented skeletal muscle regeneration with higher activation and differentiation signals in muscle cells (i.e. lower Pax-7; higher MyoD and myogenin RNA expression). However, there was also higher expression of proteolytic markers (Atrogin-1 and MuRF-1) in CKD muscle relative to normal. CKD animals had higher indices of oxidative stress compared to normal, evident by elevated plasma levels of an oxidative stress marker, 8-hydroxy-2' -deoxyguanosine (8-OHdG), increased muscle expression of succinate dehydrogenase (SDH) and Nox4 and altered mitochondria morphology. Furthermore, we show significantly higher serum levels of myostatin and expression of myostatin in skeletal muscle of CKD animals compared to normal. Taken together, these data show aberrant regeneration and proteolytic signaling that is associated with oxidative stress and high levels of myostatin in the setting of CKD. These changes likely play a role in the compromised skeletal muscle function that exists in CKD.