ADAR2 deficiency ameliorates non-alcoholic fatty liver disease and muscle atrophy through modulating serum amyloid A1.

Autor: Kung ML; Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan., Yang TH; Department of Biomedical Engineering, College of Engineering, National Cheng Kung University, Tainan, Taiwan.; Department of Orthopedic Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Lin CC; Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Ho JY; Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Hung TC; Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Chang CH; Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Huang KW; Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Chen CC; Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan.; Department of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.; Ph.D. Program in Translational Medicine, Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.; Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan., Chen YW; Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Jazyk: angličtina
Zdroj: Journal of cachexia, sarcopenia and muscle [J Cachexia Sarcopenia Muscle] 2024 Jun; Vol. 15 (3), pp. 949-962. Date of Electronic Publication: 2024 Mar 27.
DOI: 10.1002/jcsm.13460
Abstrakt: Background: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength, which is commonly associated with NAFLD. Adenosine-to-inosine editing, catalysed by adenosine deaminase acting on RNA (ADAR), is an important post-transcriptional modification of genome-encoded RNA transcripts. Three ADAR gene family members, including ADAR1, ADAR2 and ADAR3, have been identified. However, the functional role of ADAR2 in obesity-associated NAFLD and sarcopenia remains unclear.
Methods: ADAR2 +/+ /GluR-B R/R mice (wild type [WT]) and ADAR2 -/- /GluR-B R/R mice (ADAR2 knockout [KO]) were subjected to feeding with standard chow or high-fat diet (HFD) for 20 weeks at the age of 5 weeks. The metabolic parameters, hepatic lipid droplet, grip strength test, rotarod test, muscle weight, fibre cross-sectional area (CSA), fibre types and protein associated with protein degradation were examined. Systemic and local tissues serum amyloid A1 (SAA1) were measured. The effects of SAA1 on C2C12 myotube atrophy were investigated.
Results: ADAR2 KO mice fed with HFD exhibited lower body weight (-7.7%, P < 0.05), lower liver tissue weight (-20%, P < 0.05), reduced liver lipid droplets in concert with a decrease in hepatic triglyceride content (-24%, P < 0.001) and liver injury (P < 0.01). ADAR2 KO mice displayed protection against HFD-induced glucose intolerance, insulin resistance and dyslipidaemia. Skeletal muscle mass (P < 0.01), muscle strength (P < 0.05), muscle endurance (P < 0.001) and fibre size (CSA; P < 0.0001) were improved in ADAR2 KO mice fed with HFD compared with WT mice fed with HFD. Muscle atrophy-associated transcripts, such as forkhead box protein O1, muscle atrophy F-box/atrogin-1 and muscle RING finger 1/tripartite motif-containing 63, were decreased in ADAR2 KO mice fed with HFD compared with WT mice fed with HFD. ADAR2 deficiency attenuates HFD-induced local liver and skeletal muscle tissue inflammation. ADAR2 deficiency abolished HFD-induced systemic (P < 0.01), hepatic (P < 0.0001) and muscular (P < 0.001) SAA1 levels. C2C12 myotubes treated with recombinant SAA1 displayed a decrease in myotube length (-37%, P < 0.001), diameter (-20%, P < 0.01), number (-39%, P < 0.001) and fusion index (-46%, P < 0.01). Myogenic markers (myosin heavy chain and myogenin) were decreased in SAA1-treated myoblast C2C12 cells.
Conclusions: These results provide novel evidence that ADAR2 deficiency may be important in obesity-associated sarcopenia and NAFLD. Increased SAA1 might be involved as a regulatory factor in developing sarcopenia in NAFLD.
(© 2024 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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