Calycosin inhibited autophagy and oxidative stress in chronic kidney disease skeletal muscle atrophy by regulating AMPK/SKP2/CARM1 signalling pathway

• Published in: Journal of cellular and molecular medicine Vol. 24; no. 19; pp. 11084 - 11099
• Main Authors: Hu, Rong, Wang, Ming‐qing, Liu, Ling‐yu, You, Hai‐yan, Wu, Xiao‐hui, Liu, Yang‐yang, Wang, Yan‐jing, Lu, Lu, Xiao, Wei, Wei, Lian‐bo
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2020; John Wiley and Sons Inc
• Subjects: AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Apoptosis; Apoptosis - drug effects; Arginine - metabolism; Atrophy; Autophagy; Autophagy - drug effects; Biosynthesis; Body Weight - drug effects; Calycosin; CARM1; Catalase; Cell Line; Creatinine; Cytotoxicity; Down-Regulation - drug effects; Experiments; Fibrosis; FOXO3 protein; Glutathione peroxidase; Histones - metabolism; Inflammation; Isoflavones - pharmacology; Kidney - drug effects; Kidney - pathology; Kidney - physiopathology; Kidney diseases; Kinases; Male; Malondialdehyde; Methylation; Mice; Molecular modelling; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; Muscle Fibers, Skeletal - pathology; Muscle, Skeletal - pathology; Muscular Atrophy - pathology; Musculoskeletal system; Myotubes; Nephrectomy; Original; Oxidative stress; Oxidative Stress - drug effects; Phagocytosis; Phosphorylation; Protein-Arginine N-Methyltransferases - metabolism; Proteins; Rats, Sprague-Dawley; Renal function; Renal Insufficiency, Chronic - pathology; Renal Insufficiency, Chronic - physiopathology; S-Phase Kinase-Associated Proteins - metabolism; Signal Transduction; Skeletal muscle; skeletal muscle atrophy; SKP2; Superoxide dismutase; Tumor necrosis factor; Tumor Necrosis Factor-alpha; Urea; United States > US; China; autophagy; skeletal muscle atrophy; CARM1; AMPK; Calycosin; SKP2; oxidative stress
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.15514

Skeletal muscle atrophy is a common and serious complication of chronic kidney disease (CKD). Oxidative stress and autophagy are the primary molecular mechanisms involved in muscle atrophy. Calycosin, a major component of Radix astragali, exerts anti‐inflammatory, anti‐oxidative stress and anti‐autophagy effects. We investigated the effects and mechanisms of calycosin on skeletal muscle atrophy in vivo and in vitro. 5/6 nephrectomy (5/6 Nx) rats were used as a model of CKD. We evaluated bodyweight and levels of serum creatinine (SCr), blood urea nitrogen (BUN) and serum albumin (Alb). H&E staining, cell apoptosis, oxidative stress biomarkers, autophagosome and LC3A/B levels were performed and evaluated in skeletal muscle of CKD rat. Calycosin treatment improved bodyweight and renal function, alleviated muscle atrophy (decreased the levels of MuRF1 and MAFbx), increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH‐Px) activity and reduced malondialdehyde (MDA) levels in skeletal muscle of CKD rats. Importantly, calycosin reduced autophagosome formation, down‐regulated the expression of LC3A/B and ATG7 through inhibition of AMPK and FOXO3a, and increased SKP2, which resulted in decreased expression of CARM1, H3R17me2a. Similar results were observed in C2C12 cells treated with TNF‐α and calycosin. Our findings showed that calycosin inhibited oxidative stress and autophagy in CKD induced skeletal muscle atrophy and in TNF‐α‐induced C2C12 myotube atrophy, partially by regulating the AMPK/SKP2/CARM1 signalling pathway.