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Vitamin D receptor/sirtuin 3 pathway mediates the cardioprotective effects of aerobic exercise in diabetic mice.

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Τίτλος: Vitamin D receptor/sirtuin 3 pathway mediates the cardioprotective effects of aerobic exercise in diabetic mice.
Συγγραφείς: Cui XN; School of Exercise and Health, Shanghai University of Sport, Shanghai, China., Li C; School of Exercise and Health, Shanghai University of Sport, Shanghai, China., Qin YH; School of Exercise and Health, Shanghai University of Sport, Shanghai, China., Liu JJ; School of Exercise and Health, Shanghai University of Sport, Shanghai, China., Jia CK; School of Exercise and Health, Shanghai University of Sport, Shanghai, China., Sun XY; School of Exercise and Health, Shanghai University of Sport, Shanghai, China., Lu SQ; School of Exercise and Health, Shanghai University of Sport, Shanghai, China., Zhu Z; School of Exercise and Health, Shanghai University of Sport, Shanghai, China., Cao ZB; School of Exercise and Health, Shanghai University of Sport, Shanghai, China; Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China. Electronic address: caozb_edu@yahoo.co.jp.
Πηγή: Free radical biology & medicine [Free Radic Biol Med] 2026 Aug 16; Vol. 252, pp. 664-676. Date of Electronic Publication: 2026 Apr 28.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier Science Country of Publication: United States NLM ID: 8709159 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-4596 (Electronic) Linking ISSN: 08915849 NLM ISO Abbreviation: Free Radic Biol Med Subsets: MEDLINE
Imprint Name(s): Publication: Tarrytown, NY : Elsevier Science
Original Publication: New York : Pergamon, c1987-
Ιατρικοί όροι (MeSH): Receptors, Calcitriol*/metabolism , Receptors, Calcitriol*/genetics , Diabetic Cardiomyopathies*/metabolism , Diabetic Cardiomyopathies*/pathology , Diabetic Cardiomyopathies*/etiology , Diabetic Cardiomyopathies*/prevention & control , Diabetic Cardiomyopathies*/therapy , Diabetic Cardiomyopathies*/genetics , Sirtuin 3*/metabolism , Sirtuin 3*/genetics , Diabetes Mellitus, Experimental*/metabolism , Diabetes Mellitus, Experimental*/pathology , Diabetes Mellitus, Experimental*/therapy , Physical Conditioning, Animal*, Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Cholecalciferol/pharmacology ; Animals ; Mice ; Male ; Mice, Inbred C57BL ; Signal Transduction ; Cell Line
Περίληψη: Aerobic exercise ameliorates diabetic cardiomyopathy (DCM) by improving myocardial mitochondrial function; however, the underlying mechanisms remain unclear. Vitamin D alleviates DCM by upregulating vitamin D receptor (VDR) expression, and aerobic exercise also increases VDR expression. Whether VDR mediates the cardioprotective effects of aerobic exercise against DCM remains unknown. This study aims to probe whether aerobic exercise alleviates DCM by upregulating VDR. A DCM mouse model was established using male C57BL/6J mice via high-fat diet feeding and streptozotocin injection, while mice fed a standard diet served as controls. Cardiac-specific VDR knockdown and overexpression were achieved via recombinant adeno-associated virus-mediated delivery in diabetic mice. Diabetic mice were further subjected to vitamin D3 supplementation and exercise intervention. Additionally, H9C2 cardiomyocytes were exposed to high glucose and palmitate to mimic diabetic conditions in vitro. Notably, diabetic mice exhibited significant cardiac mitochondrial dysfunction, along with inflammation, fibrosis, and impaired cardiac function. However, vitamin D3 supplementation and aerobic exercise upregulated VDR expression and enhanced mitochondrial function, thereby alleviating the pathological manifestations of DCM in diabetic mice. VDR activation also mitigated high glucose and palmitate-induced mitochondrial dysfunction in H9C2 cardiomyocytes, but this effect was abrogated by sirtuin (SIRT)-3 inhibition. These results suggest that VDR promotes SIRT3-dependent enhancement of mitochondrial function, thereby alleviating DCM. Moreover, exercise-induced cardioprotective effects on mitochondrial function were impaired by cardiac-specific VDR knockdown but mimicked by cardiac-specific VDR overexpression. Overall, this study suggests that the VDR/SIRT3 axis is an essential mechanism mediating the cardioprotective effects of aerobic exercise against DCM.
(Copyright © 2026 Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of competing interest The authors have no relevant interests to declare.
Contributed Indexing: Keywords: Aerobic exercise; Diabetic cardiomyopathy; Mitochondrial function; Sirtuin 3; Vitamin D receptor
Substance Nomenclature: 0 (Receptors, Calcitriol)
EC 3.5.1.- (Sirtuin 3)
0 (Sirt3 protein, mouse)
1C6V77QF41 (Cholecalciferol)
0 (Vdr protein, mouse)
Entry Date(s): Date Created: 20260430 Date Completed: 20260612 Latest Revision: 20260612
Update Code: 20260613
DOI: 10.1016/j.freeradbiomed.2026.04.153
PMID: 42061479
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1873-4596
DOI:10.1016/j.freeradbiomed.2026.04.153