Exercise-Linked Skeletal Irisin Ameliorates Diabetes-Associated Osteoporosis by Inhibiting the Oxidative Damage-Dependent miR-150-FNDC5/Pyroptosis Axis.
Animals
Female
Mice
Diabetes Mellitus, Experimental
/ genetics
Diabetes Mellitus, Type 2
/ complications
Fibronectins
/ metabolism
Glucose Intolerance
/ metabolism
Mice, Inbred C57BL
Muscle, Skeletal
/ metabolism
NLR Family, Pyrin Domain-Containing 3 Protein
/ genetics
Osteoporosis
/ genetics
Oxidative Stress
Pyroptosis
X-Ray Microtomography
MicroRNAs
/ genetics
Journal
Diabetes
ISSN: 1939-327X
Titre abrégé: Diabetes
Pays: United States
ID NLM: 0372763
Informations de publication
Date de publication:
01 12 2022
01 12 2022
Historique:
received:
30
06
2021
accepted:
22
06
2022
pubmed:
9
7
2022
medline:
24
11
2022
entrez:
8
7
2022
Statut:
ppublish
Résumé
Recent evidence suggests that physical exercise (EX) promotes skeletal development. However, the impact of EX on the progression of bone loss and deterioration of mechanical strength in mice with type 2 diabetic mellitus (T2DM) remains unexplored. In the current study, we investigated the effect of EX on bone mass and mechanical quality using a diabetic mouse model. The T2DM mouse model was established with a high-fat diet with two streptozotocin injections (50 mg/kg/body wt) in C57BL/6 female mice. The diabetic mice underwent treadmill exercises (5 days/week at 7-11 m/min for 60 min/day) for 8 weeks. The data showed that diabetes upregulated miR-150 expression through oxidative stress and suppressed FNDC5/Irisin by binding to its 3'-untranslated region. The decreased level of irisin further triggers the pyroptosis response in diabetic bone tissue. EX or N-acetyl cysteine or anti-miRNA-150 transfection in T2DM mice restored FNDC5/Irisin expression and bone formation. Furthermore, EX or recombinant irisin administration prevented T2DM-Induced hyperglycemia and improved glucose intolerance in diabetic mice. Furthermore, osteoblastic knockdown of Nlrp3 silencing (si-Nlrp3) or pyroptosis inhibitor (Ac-YVADCMK [AYC]) treatment restores bone mineralization in diabetic mice. Micro-computed tomography scans and mechanical testing revealed that trabecular bone microarchitecture and bone mechanical properties were improved after EX in diabetic mice. Irisin, either induced by skeleton or daily EX or directly administered, prevents bone loss by mitigating inflammasome-associated pyroptosis signaling in diabetic mice. This study demonstrates that EX-induced skeletal irisin ameliorates diabetes-associated glucose intolerance and bone loss and possibly provides a mechanism of its effects on metabolic osteoporosis.
Identifiants
pubmed: 35802043
pii: 147211
doi: 10.2337/db21-0573
pmc: PMC9750954
doi:
Substances chimiques
Fibronectins
0
FNDC5 protein, mouse
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
Mirn150 microRNA, mouse
0
MicroRNAs
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2777-2792Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 by the American Diabetes Association.
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