p53 improves aerobic exercise capacity and augments skeletal muscle mitochondrial DNA content.
p53 improves aerobic exercise capacity and augments skeletal muscle mitochondrial DNA content.
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DOI：
10.1161/circresaha.109.205310
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发表时间：
2009-09-25
影响因子：
20.1
通讯作者：
Hwang PM
中科院分区：
文献类型：
--
作者：
Park JY;Wang PY;Matsumoto T;Sung HJ;Ma W;Choi JW;Anderson SA;Leary SC;Balaban RS;Kang JG;Hwang PM
运动能力是一种与心血管和全因死亡保护相关的生理特征。p53调节线粒体功能，其缺失会显著降低运动能力，但其潜在的遗传机制尚不清楚。了解p53如何提高运动能力的生物学可能为改善心血管和一般健康提供有用的见解。了解p53调控有氧运动能力的遗传机制。使用各种生理，代谢和分子技术，我们进一步表征了最大运动能力和训练的效果，测量了运动能力的各种非线粒体和线粒体决定因素，并检查了线粒体生物发生的假定调节因子。由于p53不影响基线心脏功能或正性肌力储备，我们专注于骨骼肌的参与，现在报告了p53在调节骨骼肌线粒体功能中的更广泛作用。p53与线粒体转录因子A（TFAM）相互作用，TFAM是一种对线粒体DNA（mtDNA）转录和维持重要的核编码基因，并调节mtDNA含量。与p53−/−小鼠相比，p53 +/+小鼠的mtDNA增加在有氧骨骼肌组与糖酵解骨骼肌组中更为明显，心脏组织无显著变化。这些体内观察结果进一步得到体外研究的支持，体外研究显示小鼠成肌细胞中p53的过度表达增加TFAM和mtDNA水平，而shRNA耗尽TFAM降低mtDNA含量。我们目前的研究结果表明，p53促进有氧代谢和运动能力，通过利用不同的线粒体基因和机制，在组织特异性的方式。
Exercise capacity is a physiological characteristic associated with protection from both cardiovascular and all-cause mortality. p53 regulates mitochondrial function and its deletion markedly diminishes exercise capacity, but the underlying genetic mechanism orchestrating this is unclear. Understanding the biology of how p53 improves exercise capacity may provide useful insights for improving both cardiovascular as well as general health. To understand the genetic mechanism by which p53 regulates aerobic exercise capacity. Using a variety of physiological, metabolic and molecular techniques, we further characterized maximum exercise capacity and the effects of training, measured various non-mitochondrial and mitochondrial determinants of exercise capacity, and examined putative regulators of mitochondrial biogenesis. As p53 did not affect baseline cardiac function or inotropic reserve, we focused on the involvement of skeletal muscle and now report a wider role for p53 in modulating skeletal muscle mitochondrial function. p53 interacts with Mitochondrial Transcription Factor A (TFAM), a nuclear-encoded gene important for mitochondrial DNA (mtDNA) transcription and maintenance, and regulates mtDNA content. The increased mtDNA in p53+/+ compared to p53−/− mice was more marked in aerobic versus glycolytic skeletal muscle groups with no significant changes in cardiac tissue. These in vivo observations were further supported by in vitro studies showing over-expression of p53 in mouse myoblasts increases both TFAM and mtDNA levels while depletion of TFAM by shRNA decreases mtDNA content. Our current findings indicate that p53 promotes aerobic metabolism and exercise capacity by utilizing different mitochondrial genes and mechanisms in a tissue-specific manner.