AMPK Activation of Muscle Autophagy Prevents Fasting-Induced Hypoglycemia and Myopathy during Aging
AMPK Activation of Muscle Autophagy Prevents Fasting-Induced Hypoglycemia and Myopathy during Aging
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DOI：
10.1016/j.cmet.2015.05.016
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发表时间：
2015-06-02
期刊：
影响因子：
29
通讯作者：
Steinberg, Gregory R.
中科院分区：
文献类型：
--
作者：
Bujak, Adam L.;Crane, Justin D.;Steinberg, Gregory R.
AMP激活的蛋白激酶（AMPK）激活自噬，但其在衰老和禁食诱导的肌肉功能中的作用尚未确定。在这里，我们报告了缺乏骨骼肌AMPK（AMPK-MKO）的禁食小鼠导致低血糖和高酮症。这不是由于有缺陷的脂肪酸氧化，而是与肌肉蛋白水解的阻断有关，导致丙氨酸的循环水平降低，丙氨酸是一种维生素E生成所需的必需氨基酸。肌肉自噬的标志物包括Ulk 1 Ser 555和Ser 757的磷酸化以及RFP-LC 3斑点的聚集受损。与受损的自噬一致，老年AMPKMKO小鼠具有显著的肌病，其特征在于肌肉功能降低、线粒体疾病和自噬/线粒体自噬蛋白p62和Parkin的积累。这些发现确立了骨骼肌AMPK介导的自噬在长时间禁食期间保持血糖水平以及在衰老期间保持肌肉完整性和线粒体功能的基本要求。
The AMP-activated protein kinase (AMPK) activates autophagy, but its role in aging and fasting-induced muscle function has not been defined. Here we report that fasting mice lacking skeletal muscle AMPK (AMPK-MKO) results in hypoglycemia and hyperketosis. This is not due to defective fatty acid oxidation, but instead is related to a block in muscle proteolysis that leads to reduced circulating levels of alanine, an essential amino acid required for gluconeogenesis. Markers of muscle autophagy including phosphorylation of Ulk1 Ser555 and Ser757 and aggregation of RFP-LC3 puncta are impaired. Consistent with impaired autophagy, aged AMPKMKO mice possess a significant myopathy characterized by reduced muscle function, mitochondrial disease, and accumulation of the autophagy/mitophagy proteins p62 and Parkin. These findings establish an essential requirement for skeletal muscle AMPK-mediated autophagy in preserving blood glucose levels during prolonged fasting as well as maintaining muscle integrity and mitochondrial function during aging.