Exercise Physiology Laboratory, Department of Human Movement Science, Seoul Women's University , Seoul , Korea.
Division of Endocrinology and Metabolism, Asan Medical Center , Seoul , Korea.
J Appl Physiol (1985). 2018 Sep 1;125(3):715-722. doi: 10.1152/japplphysiol.00984.2016. Epub 2018 Jun 28.
Angiopoietin-like protein 4 (Angptl4)/fasting-induced adipose factor (Fiaf) expression levels are increased by exercise in skeletal muscle. We have previously shown that Angptl4 regulates food intake and energy expenditure via modulation of hypothalamic AMP-activated protein kinase (AMPK) activity. AMPK is an important signaling molecule that integrates skeletal muscle metabolism during exercise. Therefore, we investigated the involvement of Angptl4 in exercise-induced AMPK activation in skeletal muscle. Angptl4 protein and mRNA expression levels were significantly increased in the gastrocnemius and soleus muscles of mice following a 50-min running bout. Treatment of C2C12 myotubes with Angptl4 increased phosphorylation of AMPK and acetyl-CoA carboxylase (ACC), which were markers of AMPK activation, and the mitochondrial maximum respiratory capacity. Treadmill exercise increased AMPK and ACC phosphorylation in the gastrocnemius of normal mice; this phosphorylation increase was attenuated in mice lacking Angptl4. Endurance to swimming and hanging was also reduced in Angptl4 knockout mice. Taken together, our current data demonstrate that exercise-induced upregulation of skeletal muscle Angptl4 is critical for AMPK activation and exercise tolerance. These findings unveil a new role for skeletal muscle Angptl4 in exercise physiology. NEW & NOTEWORTHY 1) Angiopoietin-like protein 4 (Angptl4) treatment activates AMP-activated protein kinase (AMPK) signaling in skeletal muscle cells. 2) Angptl4 increases the maximum mitochondrial oxidative capacity through AMPK activation in skeletal muscle cells. 3) Lack of Angptl4 mitigates exercise-induced skeletal muscle AMPK activation. 4) Angptl4-deficient mice show a lower endurance to exercise.
血管生成素样蛋白 4（Angptl4）/禁食诱导脂肪因子（Fiaf）的表达水平可通过运动在骨骼肌中增加。我们之前已经表明，Angptl4 通过调节下丘脑 AMP 激活的蛋白激酶（AMPK）活性来调节摄食和能量消耗。AMPK 是一种重要的信号分子，可整合运动过程中的骨骼肌代谢。因此，我们研究了 Angptl4 在运动诱导的骨骼肌 AMPK 激活中的作用。在经过 50 分钟的跑步运动后，小鼠的比目鱼肌和跖肌中的 Angptl4 蛋白和 mRNA 表达水平显著增加。Angptl4 处理 C2C12 肌管增加了 AMPK 和乙酰辅酶 A 羧化酶（ACC）的磷酸化，这是 AMPK 激活的标志物，以及线粒体最大呼吸能力。跑步机运动增加了正常小鼠比目鱼肌中的 AMPK 和 ACC 磷酸化；在缺乏 Angptl4 的小鼠中，这种磷酸化增加减弱了。Angptl4 敲除小鼠的游泳和悬挂耐力也降低了。总之，我们目前的数据表明，运动诱导的骨骼肌 Angptl4 上调对于 AMPK 激活和运动耐受力至关重要。这些发现揭示了骨骼肌 Angptl4 在运动生理学中的新作用。新的和值得注意的是：1）血管生成素样蛋白 4（Angptl4）处理可激活骨骼肌细胞中的 AMP 激活的蛋白激酶（AMPK）信号。2）Angptl4 通过激活骨骼肌细胞中的 AMPK 增加最大线粒体氧化能力。3）缺乏 Angptl4 可减轻运动诱导的骨骼肌 AMPK 激活。4）Angptl4 缺乏的小鼠表现出较低的运动耐力。
