LDHB在PGC-1a介导的肌肉线粒体能量代谢中的功能及其作用机制

Muscle mitochondria malfunction is a critical component underlying the pathogenesis of many metabolic diseases such as obesity and type 2 diabetes. PGC-1a has been identified as key regulator of skeletal muscle fuel metabolism, and has been implicated in metabolic diseases. However, the mechanisms have not been yet fully understood. We have previously found that increased expression of LDHB parallel-enhanced mitochondria metabolic capacity in mice. Our preliminary data indicated that LDHB was regulated by PGC-1a. Moreover, activation of LDHB was linked to muscle fitness in human. These results have let to the hypothesis of this proposal that, LDHB is an important downstream target of PGC-1a, LDHB could mediate the control of muscle mitochondria function by PGC-1a. We will delineate the PGC-1a/LDHB axis involved in the control of mitochondria fuel metabolism in vivo, using muscle-specific transgenic mice, and in vitro, in primary muscle cell culture. We will also investigate the relationship of LDHB with human diseases. Completion of this project will provide a novel clue for metabolic modulator therapies aimed at enhancing muscle fitness in a variety of disease states such as obesity and diabetes.

肌肉线粒体能量代谢的功能异常在肥胖症和II型糖尿病的发生发展中起着至关重要的作用。PGC-1a是肌肉线粒体能量代谢的主要调控因子，但其下游的效应分子及分子机制还不清楚。我们曾发现LDHB基因的表达与肌肉线粒体能量代谢能力正相关。本课题的前期研究表明LDHB基因的表达受PGC-1a调节，并且与人体肌肉的健康水平高度相关。因此，我们提出：LDHB可能是PGC-1a调节肌肉线粒体能量代谢的重要通路。为证实这一假设，本课题将分别从整体水平、细胞水平和线粒体亚细胞水平阐明LDHB在PGC-1a介导的线粒体能量代谢中的功能及其与代谢性疾病发生的关系，提出一个新的PGC-1a/LDHB通路对线粒体能量代谢的调节模式。本课题的完成，将为探讨代谢性疾病的防治新途径提供实验依据。

肌肉线粒体能量代谢的功能异常在肥胖症和2型糖尿病的发生发展中起着至关重要的作用。运动锻炼已被公认为预防、控制以及治疗肥胖症和2型糖尿病最有效的手段。运动锻炼不仅可以增强肌肉细胞胰岛素诱导的葡萄糖吸收，还可以通过调节肌肉线粒体能量代谢来提高葡萄糖和脂肪酸的消耗能力。PGC-1a是运动锻炼诱导肌肉线粒体能量代谢的主要调控因子，但其下游的效应分子及分子机制还不清楚。本课题我们提出：LDHB可能是PGC-1a调节肌肉线粒体能量代谢的重要通路。为证实这一假设，本课题分别从整体水平、细胞水平和线粒体亚细胞水平阐明LDHB在PGC-1a介导的肌肉线粒体能量代谢中的功能及其作用机制。我们发现，人体运动可以激活乳酸脱氢酶LDHB基因的表达。LDHB基因表达水平在运动员肌肉中明显高于常人，并且在同一个体的运动前后也发生了显著变化。此外，LDHB基因表达水平还与人体肌肉运动前后的pH变化呈显著负相关关系。这些结果提示LDHB可能是运动锻炼骨骼肌代谢重塑的重要通路。我们利用系列小鼠细胞分子实验，揭示了运动锻炼通过激活PGC-1a/ERR结合到Ldhb基因启动子上非常保守的ERR应答元件上来调控Ldhb的表达。为了研究Ldhb基因的运动代谢生理功能，我们构建了骨骼肌特异性的Ldhb转基因小鼠，发现激活Ldhb可以显著提高小鼠运动过程的耗氧能力，增强小鼠的运动耐力；这些作用很可能依赖于Ldhb过表达引起的骨骼肌线粒体代谢功能增强；进一步的体外分子细胞研究结果确证了激活Ldhb可增强线粒体氧化代谢功能。这项研究揭示了一个运动锻炼通过PGC-1a/Ldhb通路改善骨骼肌线粒体功能的分子机制，为探讨肌肉线粒体代谢相关疾病的防治新途径提供实验依据。