Abstract
Skeletal muscle atrophy is a common and serious complication of chronic kidney disease (CKD). Oxidative stress and mitochondrial dysfunction are involved in the pathogenesis of muscle atrophy. The aim of this study was to explore the effects and mechanisms of paeoniflorin on CKD skeletal muscle atrophy. We demonstrated that paeoniflorin significantly improved renal function, calcium/phosphorus disorders, nutrition index and skeletal muscle atrophy in the 5/6 nephrectomized model rats. Paeoniflorin ameliorated the expression of proteins associated with muscle atrophy and muscle differentiation, including muscle atrophy F-box (MAFbx/atrogin-1), muscle RING finger 1 (MuRF1), MyoD and myogenin (MyoG). In addition, paeoniflorin modulated redox homeostasis by increasing antioxidant activity and suppressing excessive accumulation of reactive oxygen species (ROS). Paeoniflorin alleviated mitochondrial dysfunction by increasing the activities of electron transport chain complexes and mitochondrial membrane potential. Furthermore, paeoniflorin also regulates mitochondrial dynamics. Importantly, paeoniflorin upregulated the expression of silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and phosphorylation of AMP-activated protein kinase (AMPK). Similar results were observed in C2C12 myoblasts treated with TNF-α and paeoniflorin. Notably, these beneficial effects of paeoniflorin on muscle atrophy were abolished by inhibiting AMPK and SIRT1 and knocking down PGC-1α. Taken together, this study showed for the first time that paeoniflorin has great therapeutic potential for CKD skeletal muscle atrophy through AMPK/SIRT1/PGC-1α-mediated oxidative stress and mitochondrial dysfunction.
Highlights
chronic kidney disease (CKD) has increasingly become a medical problem globally (Kalantar-Zadeh et al, 2021)
PF treatment reduced the occurrence of renal lesions and inhibited renal fibrosis caused by 5/6 nephrectomy surgery (Figure 1E)
Based on IHC staining and immunoblotting analysis in the CKD model, we further explored whether the effects of PF were related to the activation of the AMPK/silent information regulator 1 (SIRT1)/proliferator-activated receptor gamma coactivator-1α (PGC-1α) signaling pathway in C2C12 myoblasts
Summary
CKD has increasingly become a medical problem globally (Kalantar-Zadeh et al, 2021). The number of CKD patients accounted for 9.1% of the world’s total population in 2017, which resulted in 1.2 million deaths each year (GBD Chronic Kidney Disease Collaboration, 2020) and greatly increased the economic burden. In CKD patients, persistent imbalances between protein degradation and synthesis result in skeletal muscle atrophy, which is closely related to the rate of morbidity and mortality in CKD patients (Zhang et al, 2018; Teixeira et al, 2019; Watanabe et al, 2019). Numerous researchers have reported that inflammation, oxidative stress and subsequent mitochondrial dysfunction are important processes in the maintenance of skeletal muscle function in CKD (Watanabe et al, 2019; Chalupsky et al, 2021). The excessive accumulation of ROS has been proven to be an important link that leads to oxidative stress and mitochondrial dysfunction in CKD skeletal muscle atrophy (Abrigo et al, 2018). Oxidative stress is involved in the pathogenesis of cancer, CKD, chronic heart failure and diabetes mellitus (Uddin et al, 2021), which contribute to the degradation of myofibrillar proteins. Studies have shown that mitochondrial dynamics play an important role in modulating mitochondrial morphology and maintaining mitochondrial homeostasis (Srinivasan et al, 2017)
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