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Application of new isotope methods: Two interventions in insulin resistant rodent models.

机译：新同位素方法的应用：胰岛素抵抗性啮齿动物模型的两种干预措施。

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摘要

A 2H2O labeling method is applied to the measurement of mitochondrial biogenesis, represented by mitochondrial (mt) DNA synthesis, in vivo in voluntary exercised healthy and insulin resistant rodents. A time course study revealed a transient induction of mitochondrial biogenesis in voluntary exercised female Sprague Dawley (SD) rats. Voluntary exercised female rats reached steady running distances of ∼10,000 m/day by the third week. MtDNA fractional synthesis from the red portion of the gastrocnemius was increased 3.7-fold after 1 week of voluntary wheel running, but returned to baseline after the third week. No significant increase in cytochrome C oxidase activity was observed.; The influence of biological sex on voluntary wheel running behavior and on associated mitochondrial adaptations was also investigated. Female rats ran 3.6-fold fold farther per day than age matched male rats after 2 weeks of access to running wheels; no increase in mtDNA fractional synthesis was observed in male rats. High fat feeding did not affect wheel running or the associated stimulation of mtDNA fractional synthesis in female rats. Two insulin resistant rodent models, Zucker Diabetic Fatty (ZDF) and Zucker Fatty (fa/fa) female rats, were tested for spontaneous running and associated changes in mtDNA synthesis. Female ZDF rats ran 6250 m/day during the second week of access to wheel running and mtDNA fractional synthesis was significantly elevated in the red (1.7-fold), but not white gastrocnemius muscle. In contrast, non-diabetic female Zucker Fatty (fa/fa) rats ran only 1550 m/day, with large variability in distance run. A significant correlation between distance run and mtDNA synthesis was observed in the red portion of the gastrocnemius of fa/fa rats (r2 = 0.88, p 0.05).; Rosiglitazone, a PPAR-gamma agonist commonly used for the treatment of insulin resistance, was administered to male ZDF pre-diabetic rats. Four weeks of oral rosiglitazone treatment (3mg/kg/day) decreased fractional synthesis of mtDNA to 65% of the rate of the control group in both the red and white portions of the gastrocnemius. Two weeks of pre-treatment with rosiglitazone reduced spontaneous wheel running distance by 90%. The reduced wheel running behavior was sufficient to ablate the decrease in mtDNA fractional synthesis induced by rosiglitazone treatment in the red, but not the white portions of the gastrocnemius.; In summary, changes in mtDNA synthesis can be measured by D2O labeling. Voluntary wheel running causes a transient increase in mtDNA fractional synthesis and these changes in mtDNA synthesis are more sensitive than changes in mitochondrial enzyme activity. The mitochondrial biogenic response to voluntary exercise is running dependent. Animals with high innate wheel running behavior (female SD, female ZDF, and male ZDF) show increased mtDNA synthesis in response to exercise, while the response is absent in animals with low innate running behavior (male SD and female fa/fa). A PPAR-gamma agonist (rosiglitazone) reduces voluntary exercise and mtDNA synthesis. We conclude that measurement of mtDNA synthesis by D2O is a very sensitive biomarker of mitochondrial plasticity in skeletal muscle in response to wheel running, and use of this approach allows subtle influences on mitochondrial biogenesis to be detected, including the effects of sex, genetic strain, distance run, and pharmacologic agents.
机译：2H2O标记方法适用于在自愿运动的健康和胰岛素抵抗性啮齿动物体内体内以线粒体（mt）DNA合成为代表的线粒体生物发生的测量。一项时程研究显示，在自愿运动的雌性Sprague Dawley（SD）大鼠中短暂诱导线粒体生物发生。到第三周，自愿运动的雌性大鼠达到稳定的跑步距离〜10,000 m / day。腓肠肌红色部分的MtDNA分数合成在自愿轮转运行1周后增加了3.7倍，但在第三周后恢复到基线。没有观察到细胞色素C氧化酶活性的显着增加。还研究了生物性别对自愿轮转行为和相关线粒体适应性的影响。进入跑轮2周后，雌性大鼠每天的运行距离是成年雄性大鼠的3.6倍。在雄性大鼠中未观察到mtDNA分数合成的增加。高脂喂养不会影响轮转或雌性大鼠的mtDNA分数合成的相关刺激。测试了两只胰岛素抵抗性啮齿动物模型，即Zucker糖尿病脂肪（ZDF）和Zucker Fatty（fa / fa）雌性大鼠的自发运行和相关的mtDNA合成变化。雌性ZDF大鼠在进行滚轮运动的第二周跑了6250 m /天，红色（1.7倍），但腓肠肌白色肌肉的mtDNA分数合成显着提高。相比之下，非糖尿病雌性Zucker Fatty（fa / fa）大鼠仅以1550 m /天的速度奔跑，远距离奔跑变化很大。在fa / fa大鼠腓肠肌红色部分观察到距离游动与mtDNA合成之间的显着相关性（r2 = 0.88，p <0.05）。罗格列酮（一种通常用于治疗胰岛素抵抗的PPAR-γ激动剂）已施用于ZDF前糖尿病大鼠。口服罗格列酮治疗4周（3mg / kg /天）使腓肠肌红色和白色部分的mtDNA合成比例降低至对照组的65％。罗格列酮预处理两周可将自发车轮的行驶距离降低90％。降低的车轮行驶行为足以消除由罗格列酮治疗引起的红色（而非腓肠肌的白色部分）引起的mtDNA分数合成的降低。总之，可以通过D2O标记来测量mtDNA合成中的变化。自愿性轮转导致mtDNA分数合成的瞬时增加，并且mtDNA合成的这些变化比线粒体酶活性的变化更敏感。自愿锻炼的线粒体生物反应是依赖于跑步的。具有高先天跑动行为的动物（雌性SD，雌性ZDF和雄性ZDF）显示出对运动的响应增加的线粒体DNA合成，而在具有低先天运动行为的动物（雄性SD和雌性fa / fa）中则没有这种反应。 PPAR-γ激动剂（罗格列酮）可减少自愿运动和mtDNA合成。我们得出的结论是，D2O对mtDNA合成的测量是骨骼肌线粒体可塑性在响应车轮行驶时的非常敏感的生物标记，使用这种方法可以检测到对线粒体生物发生的细微影响，包括性别，遗传株系，长跑和药理代理。

著录项

  • 作者

    Thomas, Tiffany Adriana.;

  • 作者单位

    University of California, Berkeley.;

  • 授予单位 University of California, Berkeley.;
  • 学科 Chemistry Biochemistry.; Health Sciences Nutrition.; Biology Physiology.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 152 p.
  • 总页数 152
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;预防医学、卫生学;
  • 关键词

  • 入库时间 2022-08-17 11:39:02

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