Benfotiamine improves dystrophic pathology and exercise capacity in mdx mice by reducing inflammation and fibrosis.

Autor:	Coles CA; Murdoch Childrens Research Institute, The Royal Children's Hospital, 50 Flemington Road, Parkville, Victoria 3052, Australia.; Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Flemington Road, Parkville, Victoria 3052, Australia., Woodman KG; Murdoch Childrens Research Institute, The Royal Children's Hospital, 50 Flemington Road, Parkville, Victoria 3052, Australia.; Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Flemington Road, Parkville, Victoria 3052, Australia.; Department of Genetics, Yale Medical School, Yale University, 333 Cedar Street, New Haven, Connecticut 06520, USA., Gibbs EM; Department of Integrative Biology and Physiology, University of California, 612 Charles E Young Dr S, Los Angeles 90095, California, USA.; Center for Duchenne Muscular Dystrophy, University of California, 615 Charles E Young Dr S, Los Angeles 90095, California, USA., Crosbie RH; Department of Integrative Biology and Physiology, University of California, 612 Charles E Young Dr S, Los Angeles 90095, California, USA.; Center for Duchenne Muscular Dystrophy, University of California, 615 Charles E Young Dr S, Los Angeles 90095, California, USA.; Department of Neurology, David Geffen School of Medicine, University of California, 610 Charles E Young Dr S, Los Angeles, California 90095, USA., White JD; Murdoch Childrens Research Institute, The Royal Children's Hospital, 50 Flemington Road, Parkville, Victoria 3052, Australia.; Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Flemington Road, Parkville, Victoria 3052, Australia.; Charles Sturt University, Office of the Deputy Vice Chancellor Research, Boorooma Street, Wagga Wagga, NSW 2678, Australia., Lamandé SR; Murdoch Childrens Research Institute, The Royal Children's Hospital, 50 Flemington Road, Parkville, Victoria 3052, Australia.; Department of Paediatrics, University of Melbourne, 50 Flemington Road, Parkville, Victoria 3052, Australia.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2024 Jul 22; Vol. 33 (15), pp. 1339-1355.
DOI:	10.1093/hmg/ddae066
Abstrakt:	Duchenne Muscular Dystrophy (DMD) is a progressive and fatal neuromuscular disease. Cycles of myofibre degeneration and regeneration are hallmarks of the disease where immune cells infiltrate to repair damaged skeletal muscle. Benfotiamine is a lipid soluble precursor to thiamine, shown clinically to reduce inflammation in diabetic related complications. We assessed whether benfotiamine administration could reduce inflammation related dystrophic pathology. Benfotiamine (10 mg/kg/day) was fed to male mdx mice (n = 7) for 15 weeks from 4 weeks of age. Treated mice had an increased growth weight (5-7 weeks) and myofibre size at treatment completion. Markers of dystrophic pathology (area of damaged necrotic tissue, central nuclei) were reduced in benfotiamine mdx quadriceps. Grip strength was increased and improved exercise capacity was found in mdx treated with benfotiamine for 12 weeks, before being placed into individual cages and allowed access to an exercise wheel for 3 weeks. Global gene expression profiling (RNAseq) in the gastrocnemius revealed benfotiamine regulated signalling pathways relevant to dystrophic pathology (Inflammatory Response, Myogenesis) and fibrotic gene markers (Col1a1, Col1a2, Col4a5, Col5a2, Col6a2, Col6a2, Col6a3, Lum) towards wildtype levels. In addition, we observed a reduction in gene expression of inflammatory gene markers in the quadriceps (Emr1, Cd163, Cd4, Cd8, Ifng). Overall, these data suggest that benfotiamine reduces dystrophic pathology by acting on inflammatory and fibrotic gene markers and signalling pathways. Given benfotiamine's excellent safety profile and current clinical use, it could be used in combination with glucocorticoids to treat DMD patients. (© The Author(s) 2024. Published by Oxford University Press.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu