Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis
Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis
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DOI：
10.1152/ajpendo.2001.281.6.e1340
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发表时间：
2001-12-01
影响因子：
5.1
通讯作者：
Shulman, GI
中科院分区：
文献类型：
--
作者：
Bergeron, R;Ren, JM;Shulman, GI
骨骼肌适应运动训练或慢性能量剥夺的潜在机制在很大程度上是未知的。为了检验这个问题，给大鼠喂食含或不含β-胍基丙酸（β-GPA; 1%强化饮食）的饲料9周，已知β-胍基丙酸是一种肌酸类似物，可诱导类似于运动训练诱导的肌肉适应.与对照组大鼠相比，β-GPA喂养大鼠的肌肉磷酸肌酸、ATP和ATP/AMP比值均显著降低，并导致AMP活化蛋白激酶（AMPK）活化。在这些条件下，使用含有编码δ-氨基乙酰丙酸（ALA）合酶启动子的序列的cDNA探针测量的核呼吸因子-1（NRF-1）结合活性在β-GPA喂养的大鼠的肌肉中与对照组相比增加了约8倍。同时，肌肉ALA合成酶mRNA和细胞色素c含量也增加。与对照组相比，β-GPA喂养大鼠的趾长伸肌和滑车上肌的线粒体密度也增加了两倍以上。总之，在β-GPA补充期间慢性磷酸肌酸消耗导致肌肉AMPK的活化，其与增加的NRF-1结合活性、增加的细胞色素c含量和增加的肌肉线粒体密度相关。我们的数据表明，AMPK可能在肌肉适应慢性能量应激中发挥重要作用，它通过激活NRF-1促进线粒体生物合成和呼吸蛋白的表达。
The underlying mechanism by which skeletal muscle adapts to exercise training or chronic energy deprivation is largely unknown. To examine this question, rats were fed for 9 wk either with or without beta -guanadinopropionic acid (beta -GPA; 1% enriched diet), a creatine analog that is known to induce muscle adaptations similar to those induced by exercise training. Muscle phosphocreatine, ATP, and ATP/AMP ratios were all markedly decreased and led to the activation of AMP-activated protein kinase (AMPK) in the beta -GPA-fed rats compared with control rats. Under these conditions, nuclear respiratory factor-1 (NRF-1) binding activity, measured using a cDNA probe containing a sequence encoding for the promoter of delta -aminolevulinate (ALA) synthase, was increased by about eightfold in the muscle of beta -GPA-fed rats compared with the control group. Concomitantly, muscle ALA synthase mRNA and cytochrome c content were also increased. Mitochondrial density in both extensor digitorum longus and epitrochlearis from beta -GPA-fed rats was also increased by more than twofold compared with the control group. In conclusion, chronic phosphocreatine depletion during beta -GPA supplementation led to the activation of muscle AMPK that was associated with increased NRF-1 binding activity, increased cytochrome c content, and increased muscle mitochondrial density. Our data suggest that AMPK may play an important role in muscle adaptations to chronic energy stress and that it promotes mitochondrial biogenesis and expression of respiratory proteins through activation of NRF-1.