Albadawi Hassan, Oklu Rahmi, Milner John D, Uong Thuy P, Yoo Hyung-Jin, Austen William G, Watkins Michael T
Division of Vascular and Endovascular Surgery, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Division of Vascular and Interventional Radiology, Department of Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
J Surg Res. 2015 Oct;198(2):515-24. doi: 10.1016/j.jss.2015.04.008. Epub 2015 Apr 9.
Obesity is a major risk factor for diabetes and peripheral arterial disease, which frequently leads to lower limb demand ischemia. Skeletal muscle autophagy and mitochondrial biogenesis are important processes for proper oxidative capacity and energy metabolism, which are compromised in diabetes. This study compares autophagy, mitochondrial biogenesis, energy metabolism, and morphology in the hind limbs of obese diabetic mice subjected to demand or sedentary ischemia.
Unilateral hind limb demand ischemia was created in a group of diet-induced obese mice after femoral artery ligation and 4 wk of daily exercise. A parallel group of mice underwent femoral artery ligation but remained sedentary for 4 wk. Hind limb muscles were analyzed for markers of autophagy, mitochondrial biogenesis, adenosine triphosphate, and muscle tissue morphology.
At the end of the 4-wk exercise period, demand ischemia increased the autophagy mediator Beclin-1, but it did not alter the autophagy indicator, LC3B-II/I ratio, or markers of mitochondrial biogenesis, optic atrophy/dynamin-related protein. In contrast, exercise significantly increased the level of mitochondrial protein-succinate dehydrogenase subunit-A and reduced adipocyte accumulation and the percentage of centrally nucleated myofibers in the demand ischemia limb. In addition, demand ischemia resulted in decreased uncoupling protein-3 levels without altering muscle adenosine triphosphate or pS473-Akt levels.
Limb demand ischemia markedly decreased adipocyte accumulation and enhanced muscle regeneration in obese mice, but it did not appear to enhance autophagy, mitochondrial biogenesis, energy metabolism, or insulin sensitivity. Future studies aimed at evaluating novel therapies that enhance autophagy and mitochondrial biogenesis in diabetes with peripheral arterial disease are warranted.
肥胖是糖尿病和外周动脉疾病的主要危险因素，常导致下肢需求性缺血。骨骼肌自噬和线粒体生物合成是维持适当氧化能力和能量代谢的重要过程，而糖尿病会损害这些过程。本研究比较了肥胖糖尿病小鼠后肢在需求性或久坐性缺血情况下的自噬、线粒体生物合成、能量代谢及形态。
对一组饮食诱导肥胖小鼠进行股动脉结扎，并在术后4周每天进行运动，造成单侧后肢需求性缺血。另一组平行小鼠进行股动脉结扎，但保持久坐4周。分析后肢肌肉的自噬标志物、线粒体生物合成标志物、三磷酸腺苷及肌肉组织形态。
在4周运动期结束时，需求性缺血增加了自噬调节因子Beclin-1，但未改变自噬指标LC3B-II/I比值或线粒体生物合成标志物视神经萎缩蛋白/动力相关蛋白。相比之下，运动显著增加了线粒体蛋白琥珀酸脱氢酶亚基A的水平，并减少了需求性缺血肢体中的脂肪细胞积聚及中央核肌纤维百分比。此外，需求性缺血导致解偶联蛋白-3水平降低，但未改变肌肉三磷酸腺苷或pS473-Akt水平。
肢体需求性缺血显著减少了肥胖小鼠的脂肪细胞积聚并增强了肌肉再生，但似乎并未增强自噬、线粒体生物合成、能量代谢或胰岛素敏感性。有必要开展进一步研究，以评估可增强外周动脉疾病糖尿病患者自噬和线粒体生物合成的新型疗法。
