Exercise-linked skeletal irisin ameliorates diabetes-associated osteoporosis by inhibiting the oxidative damage-dependent miR-150-FNDC5/pyroptosis axis

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.