Exercise-Linked Skeletal Irisin Ameliorates Diabetes-Associated Osteoporosis by Inhibiting the Oxidative Damage–Dependent miR-150-FNDC5/Pyroptosis Axis

Abstract

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 type 2 diabetic (T2DM) mice remains unexplored. In the present study, we investigated the effect of EX on bone mass and mechanical quality using a diabetic mouse model. The T2DM mouse model was established by a high-fat diet (HFD) with two streptozotocin (STZ) injections (50 mg/kg/body weight) in C57BL/6 female mice. The diabetic mice underwent treadmill exercises (5 days/week at 7-11 m/min for 60 minutes per day) for 8 weeks. The data showed that diabetes upregulated miR-150 expression through an oxidative stress and suppressed FNDC5/irisin by binding to its 3’-UTR. The decreased level of irisin further triggers the pyroptosis response in diabetic bone tissue. EX or N-acetyl cysteine (NAC) or anti-miRNA-150 transfection in T2DM mice restored FNDC5/irisin expression and bone formation. Furthermore, EX or r-irisin administration prevented T2DM-induced hyperglycemia and improved glucose intolerance in diabetic mice. Furthermore, osteoblastic knockdown of Nlrp3 silencing (siNlrp3) or pyroptosis inhibitor (AYC) treatment restores bone mineralization in diabetic mice. Micro-CT 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.

The effects on type 2 diabetes mellitus mouse femoral bone achieved by anti-osteoporosis exercise interventions

“…Previous studies have shown that moderate-/low-intensity treadmill exercise could increase femoral BMD in T2DM mice (63)(64)(65). In addition, previous mCT scans and mechanical tests revealed that the trabecular bone microarchitecture and bone mechanical properties of T2DM mice were improved after 8 weeks of treadmill exercises (66). Our mCT data also suggested that the AE group had better performance in terms of bone microstructure and bone biomechanics.…”

Tetrahedral Framework Nucleic Acids Based Small Interfering RNA Targeting Receptor for Advanced Glycation End Products for Diabetic Complications Treatment

“…Tsi Protects against Hyperglycemia and AGEs-Induced Inflammatory Lesions in Multiple Organs. To create a hyperglycemic environment that accelerated the accumulation of AGEs in vivo , we established a diabetes model (TD) by combining a high-fat high-sugar diet (HFD) with streptozotocin (STZ). ,, As outlined in Figure A, mice were subjected to long-term HFD feeding and received low-dose STZ injections for 7 consecutive days. The mice were then randomly divided into cages (n = 6) and administered with equimolar amounts of siRNA, sTDN, Tsi, or saline via intravenous injection twice a week.…”

Epigenetic regulation in metabolic diseases: mechanisms and advances in clinical study

“…Irisin, induced by physical exercise or administered directly, can help to reverse FNDC5 and irisin downregulation to facilitate osteoblast function and bone formation. 257 Exosomal miR-21-5p from BMSCs could promote osteoblastic differentiation and ameliorate osteoporosis by interacting with KLF3. 258 In osteoclasts, activating transcription factor 1 (ATF1) can activate miR-214-5p transcriptionally and reduce the expression of ITGA7, thus contributing to osteoclastogenesis and altering OVXinduced bone absorption.…”