Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo, Japan.
Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
J Appl Physiol (1985). 2023 Oct 1;135(4):731-746. doi: 10.1152/japplphysiol.00226.2023. Epub 2023 Aug 10.
Chronic kidney disease (CKD)-related cachexia increases the risks of reduced physical activity and mortality. However, the physiological phenotype of skeletal muscle fatigue and changes in intramuscular metabolites during muscle fatigue in CKD-related cachexia remain unclear. In the present study, we performed detailed muscle physiological evaluation, analysis of mitochondrial function, and comprehensive analysis of metabolic changes before and after muscle fatigue in a 5/6 nephrectomized rat model of CKD. Wistar rats were randomized to a sham-operation (Sham) group that served as a control group or a 5/6 nephrectomy (Nx) group. Eight weeks after the operation, in situ torque and force measurements in plantar flexor muscles in Nx rats using electrical stimulation revealed a significant decrease in muscle endurance during subacute phase related to mitochondrial function. Muscle mass was reduced without changes in the proportions of fiber type-specific myosin heavy chain isoforms in Nx rats. Pyruvate-malate-driven state 3 respiration in isolated mitochondria was impaired in Nx rats. Protein expression levels of mitochondrial respiratory chain complexes III and V were decreased in Nx rats. Metabolome analysis revealed that the increased supply of acetyl CoA in response to fatigue was blunted in Nx rats. These findings suggest that CKD deteriorates skeletal muscle endurance in association with mitochondrial dysfunction and inadequate supply of acetyl-CoA during muscle fatigue. Mitochondrial dysfunction is associated with decreased skeletal muscle endurance in chronic kidney disease (CKD), but the muscle physiological phenotype and major changes in intramuscular metabolites during muscle fatigue in CKD-related cachexia remain unclear. By using a 5/6 nephrectomized CKD rat model, the present study revealed that CKD is associated with reduced tetanic force in response to repetitive stimuli in a subacute phase, impaired mitochondrial respiration, and inadequate supply of acetyl-CoA during muscle fatigue.
慢性肾脏病（CKD）相关恶病质增加了体力活动减少和死亡率增加的风险。然而，CKD 相关恶病质中骨骼肌疲劳的生理表型以及肌肉疲劳过程中肌内代谢物的变化尚不清楚。在本研究中，我们对 5/6 肾切除的 CKD 大鼠模型进行了详细的肌肉生理学评估、线粒体功能分析以及肌肉疲劳前后代谢变化的综合分析。Wistar 大鼠被随机分为假手术（Sham）组作为对照组或 5/6 肾切除（Nx）组。手术后 8 周，用电刺激对 Nx 大鼠进行足底屈肌的原位扭矩和力测量，结果显示与线粒体功能相关的亚急性期肌肉耐力显著下降。Nx 大鼠的肌肉质量减少，而纤维型肌球蛋白重链同工型的比例没有变化。Nx 大鼠分离的线粒体中丙酮酸-苹果酸驱动的状态 3 呼吸受损。Nx 大鼠的线粒体呼吸链复合物 III 和 V 的蛋白表达水平降低。代谢组学分析显示，Nx 大鼠疲劳时乙酰 CoA 的供应增加受到抑制。这些发现表明 CKD 与肌肉疲劳时的线粒体功能障碍和乙酰 CoA 供应不足有关，从而导致骨骼肌耐力下降。线粒体功能障碍与 CKD 相关的骨骼肌耐力下降有关，但 CKD 相关恶病质中肌肉疲劳时的肌肉生理表型和肌内主要代谢物变化仍不清楚。通过使用 5/6 肾切除的 CKD 大鼠模型，本研究表明 CKD 与亚急性期对重复刺激的强直力下降、线粒体呼吸受损以及肌肉疲劳时乙酰 CoA 供应不足有关。
