Exercise Inducible Lactate Dehydrogenase B Regulates Mitochondrial Function in Skeletal Muscle
Exercise Inducible Lactate Dehydrogenase B Regulates Mitochondrial Function in Skeletal Muscle
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运动诱导型乳酸脱氢酶 B 调节骨骼肌线粒体功能。
DOI：
10.1074/jbc.m116.749424
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发表时间：
2016-12-02
影响因子：
4.8
通讯作者：
Gan, Zhenji
中科院分区：
文献类型：
--
作者：
Liang, Xijun;Liu, Lin;Gan, Zhenji
乳酸脱氢酶（LDH）催化丙酮酸和乳酸的相互转化，这是骨骼肌的关键燃料代谢产物，特别是在运动过程中。然而，LDH的生理相关性仍然知之甚少。在这里，我们发现Ldhb的表达是由人体肌肉运动诱导的，并且在等长运动期间与肌肉内pH值（乳酸生成的标志）的变化呈负相关。我们发现Ldhb的表达受运动诱导的过氧化物酶体增殖物激活受体共激活因子1 （PGC-1）的调节。Ldhb基因启动子报告基因研究表明，PGC-1通过多个保守的雌激素相关受体（ERR）和肌细胞增强因子2 （MEF2）结合位点激活Ldhb基因表达。在肌肉中过度表达Ldhb（肌酸激酶(MCK)-Ldhb）的转基因小鼠在运动中表现出更高的运动表现和更高的耗氧量。MCK-Ldhb肌肉显示线粒体酶活性增强，线粒体基因表达增加，提示适应性氧化肌肉转化。此外，MCK-Ldhb培养的骨骼肌管线粒体呼吸能力增加，乳酸产量降低。总之，这些结果确定了先前未被识别的ldhb驱动的肌肉线粒体功能改变，并提出了运动训练诱导的适应性代谢反应的机制。
Lactate dehydrogenase (LDH) catalyzes the interconversion of pyruvate and lactate, which are critical fuel metabolites of skeletal muscle particularly during exercise. However, the physiological relevance of LDH remains poorly understood. Here we show that Ldhb expression is induced by exercise in human muscle and negatively correlated with changes in intramuscular pH levels, a marker of lactate production, during isometric exercise. We found that the expression of Ldhb is regulated by exercise-induced peroxisome proliferator-activated receptor coactivator 1 (PGC-1). Ldhb gene promoter reporter studies demonstrated that PGC-1 activates Ldhb gene expression through multiple conserved estrogen-related receptor (ERR) and myocyte enhancer factor 2 (MEF2) binding sites. Transgenic mice overexpressing Ldhb in muscle (muscle creatine kinase (MCK)-Ldhb) exhibited increased exercise performance and enhanced oxygen consumption during exercise. MCK-Ldhb muscle was shown to have enhanced mitochondrial enzyme activity and increased mitochondrial gene expression, suggesting an adaptive oxidative muscle transformation. In addition, mitochondrial respiration capacity was increased and lactate production decreased in MCK-Ldhb skeletal myotubes in culture. Together, these results identified a previously unrecognized Ldhb-driven alteration in muscle mitochondrial function and suggested a mechanism for the adaptive metabolic response induced by exercise training.