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.

中文翻译：

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运动相关的骨骼鸢尾素通过抑制氧化损伤依赖性 miR-150-FNDC5/Pyroptosis 轴来改善糖尿病相关的骨质疏松症

最近的证据表明，体育锻炼 (EX) 可以促进骨骼发育。然而，EX 对 2 型糖尿病 (T2DM) 小鼠骨质流失进展和机械强度恶化的影响仍未得到探索。在本研究中，我们使用糖尿病小鼠模型研究了 EX 对骨量和机械质量的影响。通过在 C57BL/6 雌性小鼠中注射两次链脲佐菌素 (STZ) (50 mg/kg/体重) 的高脂肪饮食 (HFD) 建立 T2DM 小鼠模型。糖尿病小鼠接受跑步机锻炼（5 天/周，7-11 m/min，每天 60 分钟），持续 8 周。数据显示，糖尿病通过氧化应激上调 miR-150 表达，并通过与其 3'-UTR 结合抑制 FNDC5/鸢尾素。鸢尾素水平的降低进一步触发了糖尿病骨组织中的细胞焦亡反应。T2DM 小鼠中的 EX 或 N-乙酰半胱氨酸 (NAC) 或抗 miRNA-150 转染恢复了 FNDC5/鸢尾素的表达和骨形成。此外，EX 或 r-irisin 给药可预防 T2DM 诱导的高血糖症并改善糖尿病小鼠的葡萄糖耐受不良。此外，成骨细胞敲除 Nlrp3 沉默 (siNlrp3) 或焦亡抑制剂 (AYC) 治疗可恢复糖尿病小鼠的骨矿化。Micro-CT 扫描和力学测试显示，糖尿病小鼠 EX 后骨小梁微结构和骨力学性能得到改善。鸢尾素（由骨骼或每日 EX 诱导或直接给药）通过减轻糖尿病小鼠炎症小体相关的细胞焦亡信号传导来防止骨质流失。