Division of Nephrology, Department of Medicine, Tufts Medical Center.
Division of Nephrology, Department of Medicine, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts, USA.
Curr Opin Nephrol Hypertens. 2018 Mar;27(2):113-120. doi: 10.1097/MNH.0000000000000393.
Sarcopenia and muscle weakness contribute to fragility and limit exercise tolerance among patients with CKD. This review focuses on the role of reduction in mitochondrial mass and function in the myopathy associated with CKD, causes for these muscle mitochondrial abnormalities, and potential therapeutic interventions that may improve mitochondrial biogenesis and function as well as skeletal muscle function and performance in patients with CKD.
Multiple abnormalities of mitochondrial structure, function, and composition have been shown in both experimental models and patients with CKD. A significant reduction in mitochondrial respiratory function and an increase in mitochondrial complex 1 enzyme activity has been demonstrated in the muscle tissue of male Sprague-Dawley rats following 5/6 nephrectomy. These changes were associated with a substantial reduction in skeletal muscle mitochondrial mass. In patients with CKD, in-vivo magnetic resonance and optical spectroscopy show significantly elevated resting skeletal muscle oxygen consumption and lower mean mitochondrial coupling ratio indicating disrupted muscle mitochondrial metabolism and uncoupling of oxidative phosphorylation. Skeletal muscle biopsies from patients with advanced CKD show lower mitochondrial volume density and mitochondrial DNA (mtDNA) copy number than controls.
Advanced CKD is associated with decreased exercise capacity, skeletal muscle weakness, and muscle atrophy. Impaired mitochondrial respiratory function, reduced muscle mitochondrial mass, and decreased energy production in skeletal muscle play a critical role in this 'acquired mitochondrial myopathy' of CKD. It is reasonable, therefore, to develop therapeutic interventions that enhance mitochondrial biogenesis and function as well as skeletal muscle function and performance in patients with CKD.
肌肉减少症和肌肉无力导致 CKD 患者易脆和运动耐量受限。本文重点介绍了 CKD 相关肌肉病中线粒体质量和功能减少的作用、引起这些肌肉线粒体异常的原因，以及可能改善 CKD 患者线粒体生物发生和功能以及骨骼肌功能和表现的潜在治疗干预措施。
在 CKD 的实验模型和患者中已经显示出多种线粒体结构、功能和组成异常。在雄性 Sprague-Dawley 大鼠 5/6 肾切除术后，肌肉组织中线粒体呼吸功能显著降低，线粒体复合物 1 酶活性增加。这些变化与骨骼肌线粒体质量的大量减少有关。在 CKD 患者中，体内磁共振和光光谱显示静息骨骼肌耗氧量显著升高，平均线粒体偶联比降低，表明肌肉线粒体代谢受损和氧化磷酸化解偶联。与对照组相比，晚期 CKD 患者的骨骼肌活检显示线粒体体积密度和线粒体 DNA（mtDNA）拷贝数降低。
总之，晚期 CKD 与运动能力下降、骨骼肌无力和肌肉萎缩有关。呼吸功能受损、肌肉线粒体质量减少和骨骼肌能量产生减少在 CKD 的这种“获得性线粒体肌病”中起着关键作用。因此，有理由开发能够增强 CKD 患者线粒体生物发生和功能以及骨骼肌功能和表现的治疗干预措施。
