AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation
AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation
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DOI：
10.1073/pnas.252625599
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发表时间：
2002-12-10
影响因子：
11.1
通讯作者：
Shulman, GI
中科院分区：
文献类型：
--
作者：
Zong, HH;Ren, JM;Shulman, GI
线粒体的生物发生是对慢性能量缺乏的一种关键的适应，然而负责这一反应的信号机制却知之甚少。AMPK是一种进化保守的燃料感受器，为了研究AMPK在线粒体生物发生中的作用，我们研究了在肌肉中表达AMPK显性-负性突变体的转基因小鼠(dN-AMPK)。DN-AMPK和WT小鼠都接受了肌酸类似物--β-胍基丙酸(GPA)的治疗，这导致了肌肉中ATP/AMP比率和磷酸肌酸浓度的相似降低。在WT小鼠中，GPA处理导致肌肉AMPK的激活和线粒体的生物发生。然而，同样的GPA处理对糖尿病肾病-AMPK小鼠的AMPK活性和线粒体含量没有影响。此外，AMPK失活抑制了GPA诱导的过氧化物酶体增殖物激活受体γ共激活因子1α和钙/钙调蛋白依赖的蛋白激酶IV的表达增加(这两种蛋白都是线粒体生物发生的主要调节因子)。这些数据表明，通过感知肌肉细胞的能量状态，AMPK是启动线粒体生物发生的关键调节因子。
Mitochondrial biogenesis is a critical adaptation to chronic energy deprivation, yet the signaling mechanisms responsible for this response are poorly understood. To examine the role of AMP-activated protein kinase (AMPK), an evolutionarily conserved fuel sensor, in mitochondrial biogenesis we studied transgenic mice expressing a dominant-negative mutant of AMPK in muscle (DN-AMPK). Both DN-AMPK and WT mice were treated with beta-guanidinopropionic acid (GPA), a creatine analog, which led to similar reductions in the intramuscular ATP/AMP ratio and phosphocreatine concentrations. In WT mice, GPA treatment resulted in activation of muscle AMPK and mitochondrial biogenesis. However, the same GPA treatment in DN-AMPK mice had no effect on AMPK activity or mitochondrial content. Furthermore, AMPK inactivation abrogated GPA-induced increases in the expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha and calcium/calmodulin-dependent protein kinase IV (both master regulators of mitochondrial biogenesis). These data demonstrate that by sensing the energy status of the muscle cell, AMPK is a critical regulator involved in initiating mitochondrial biogenesis.