Paeoniflorin Ameliorates Skeletal Muscle Atrophy in Chronic Kidney Disease via AMPK/SIRT1/PGC-1α-Mediated Oxidative Stress and Mitochondrial Dysfunction

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.

Muscle‐specific overexpression of Atg2 gene and endurance exercise delay age‐related deteriorations of skeletal muscle and heart function via activating the AMPK/Sirt1/PGC‐1α pathway in male Drosophila

“…In addition, AMPK activation triggers a PGC‐1α‐dependent antioxidant response, thereby limiting ROS production 25 . Cells lacking AMPK activity exhibit elevated mitochondrial ROS levels, increased oxidative damage, and premature senescence 42,43 . This evidence suggests an important role for the AMPK/Sirt1/PGC‐1α signaling pathway in regulating mitochondrial biogenesis during exercise and that activation of this pathway reduces the negative effects of oxidative stress on skeletal muscle 32 …”

“…25 Cells lacking AMPK activity exhibit elevated mitochondrial ROS levels, increased oxidative damage, and premature senescence. 42,43 This evidence suggests an important role for the AMPK/Sirt1/PGC-1α signaling pathway in regulating mitochondrial biogenesis during exercise and that activation of this pathway reduces the negative effects of oxidative stress on skeletal muscle. 32 In the present study, we found that endurance exercise significantly delayed the age-related accelerated decline in climbing ability in Atg2 knockdown Drosophila.…”

Thioredoxin-1 Promotes Mitochondrial Biogenesis Through Regulating AMPK/Sirt1/PGC1α Pathway in Alzheimer's Disease

“…Trx-1 Reversed AMPK/Sirt1/PGC1α Pathway in PC12 Cells and the Hippocampus AMPK/Sirt1/PGC1α pathway has been demonstrated to promote mitochondrial biogenesis in various diseases, such as ischemia/reperfusion, chronic kidney disease, and colitis ( El-Ghannam et al, 2022;Li et al, 2022a;Wang, 2022). However, it is still largely unclear whether AMPK/Sirt1/ PGC1α pathway plays a role in the neuroprotection of Trx-1 in AD.…”