维生素D对衰老相关骨骼肌NF-κB活化的调控作用

Sarcopenia is a newly recognized geriatric syndrome characterized by age-related decline of skeletal muscle plus low muscle strength. Our preliminary studies found NF-κB pathway activation in aging mice, suggesting that sarcopenia is related to chronic low-grade inflammation in muscle tissue. Replacement of vitamin D in persons with low levels increases strength and function and decreases falls. However, the mechanism between vitamin D supplementation and prevention of skeletal muscle loss has not been clearly elucidated. We hypothesized that vitamin D and its receptor may interfere with NF-κB, which regulate the expression of inflammatory markers at several levels. Senescence-accelerated mouse prone 8 (SAMP8）mice were divided into 4 groups: (1) untreated young, (2) untreated old, (3) vitamin D supplementation, and (4) vitamin D supplementation and voluntary wheel running. Change of muscle mass, structure and functions were examined after treatment. Activation of the NF-κB pathway were measured in the skeletal muscle by western blotting and EMSA. Mouse differentiated skeletal muscle C2C12 cells were treated with 1,25(OH) 2D3. NF-κB activation were induced by cytokines or over-expression of inhibitory kappa B kinase beta. Vitamin D receptor gene was evaluated by small interfering (si)RNA knockdown. The purpose of the study is to investigate whether vitamin D play a pivotal role in sarcopenia through the modulation of NF-κB involved with vitamin D receptor.

骨骼肌减少症是一种与衰老相关，以骨骼肌质量、力量和（或）功能下降为表现的老年综合征，目前缺乏有效的治疗药物。临床上发现补充维生素D有助于改善肌肉功能、减少跌倒，但具体机制尚不清楚。本课题组前期研究发现，随着年龄的增加，NF-κB炎症通路呈活化状态，提示慢性炎症是肌少症的病因之一。我们提出1,25(OH) 2D3可能通过维生素D受体(VDR)调节骨骼肌NF-κB通路的活化，从而减轻骨骼肌慢性炎症。本课题拟采用SAMP8快速衰老小鼠模型，给予维生素D3干预，观察动物骨骼肌质量、肌纤维转换、握力、离体肌肉收缩力等指标的变化。在体外以C2C12肌细胞为模型，利用炎症因子及高表达IKKβ激活NF-κB，小分子干扰RNA沉默VDR基因的表达，深入研究1,25(OH) 2D3是否通过VDR调节NF-κB的活化。本课题研究维生素D对骨骼肌NF-κB通路的调节作用，有望为临床骨骼肌减少症的治疗提供新的思路。

骨骼肌减少症是一种与衰老相关，以骨骼肌质量、力量和（或）功能下降为表现的老年综.合征，目前缺乏有效的治疗药物。我们使用高脂诱导的肥胖小鼠，以及体外细胞模型，研究了药物对维生素D受体的影响。结果发现：棕榈酸可以降低C2C12肌管细胞维生素D受体的基因表达水平，而静脉胰岛素则不影响。使用钠/葡萄糖共转运蛋白2（SGLT2i，canagliflozin）治疗肥胖/肌肉胰岛素抵抗的小鼠，对于肌肉质量没有影响，但可以降低肥胖，改善葡萄糖耐量，增加血酮和改善血脂分布，减少血浆胰岛素水平，增加脂肪酸氧化，减少肝脂肪变性和二酰基甘油含量，并增加肝和血浆FGF21的水平。同时对于子代的肌肉质量也没有影响。课题发表SCI论文2篇。有望为临床骨骼肌减少症的治疗提供新的思路。