有氧運動訓練調控能量代謝路徑對糖尿病db/db小鼠腎功能之影響

Abstract

Sirtuin 1（SIRT1）、AMP-activated protein kinase （AMPK）及peroxisome proliferator-activated receptor gamma coactivator 1-α （PGC1-α）為細胞內調節能量代謝的關鍵樞紐，AMPKα/SIRT1/PGC1α路經的受損伴隨粒線體失能是導致糖尿病腎臟病的機轉之一。長期規律有氧運動可以改善早期糖尿病腎臟病變，避免病症繼續惡化。然而，運動訓練經由AMPKα/SIRT1/PGC1α路徑改善糖尿病腎病變的機制，目前仍尚未釐清。本研究假設為有氧運動訓練能上調腎臟中代謝路徑以及同時抑制發炎路徑的活化，達到改善早期糖尿病腎病變的效果。方法：本研究使用糖尿病動物模式，5週齡 BKS.CgDock7m +/+ Leprdb/J（db/db）小鼠購至國家實驗動物中心，實驗動物在適應一周後，隨機分配控制組（n=8）及運動組（n=8）。運動處方：跑步速度為5.2m/min，每天運動1小時，每週訓練 5 天，共進行 8 週。運動訓練結束後將小鼠犧牲，以PAS染色法觀察腎臟組織型態，西方墨點法（Western blot analyses）分析能量代謝（AMPKα/SIRT1/PGC1-α）及發炎路徑（IκB-α/NF-κB）。結果：八週有氧運動訓練後可以改善db/db小鼠腎絲球基質膜擴張，並增加 SIRT1蛋白表現及AMPKα活性，同時抑制NF-κB磷酸化。IκB-α、PGC1-α在運動組及控制組間無顯差異。結論：本研究證實有氧運動訓練是透過活化能量代謝路徑和抑制發炎路徑來延緩糖尿病腎病變惡化。The AMPK-SIRT1-PGC-1α axis has a crucial role in regulating the energy metabolism and mitochondrial function. Downregulation of AMPK/SIRT1/PGC1α pathway is the mechanism leading to diabetic nephropathy. The purpose of this study was to determine whether exercise training upregulates the energy metabolism pathway and inhibits inflammatory pathway, thereby preventing the early stages of diabetic nephropathy. Male diabetic（db/db）mice were used in the present study. At the age of 5 weeks, db/db mice were divided into two groups: db/db mice (n =8) with exercise training for 8 weeks (db/db + Ex) and db/db (n = 8) remained sedentary throughout the study. Aerobic exercise training (5.2 m/min, 1 h/day, and 5 days/week for a total of 8 weeks) was started from 5-week-old. The results showed that decreased the glomerular matrix expansion score, increased SIRT1 protein expression and AMPKα activity, and decreased NF-κB phosphorylation were observed in db/db + Ex compared with db/db mice. There were no significant changes in IκB-α and PGC1-α. Therefore, the present study confirms that aerobic exercise training alleviates the progression of diabetic nephropathy by activating AMPK-SIRT1 pathway and inhibiting NF-κB activity.