Molecular Mechanisms of Exercise Benefits to Insulin Resistant People

项目摘要/摘要 确定运动益处的分子调节点具有高度的国家优先事项，因为 有机会开发有针对性的新疗法，使患有无运动相关健康的人群受益 问题，包括2型糖尿病和糖尿病前期，以胰岛素抵抗(IR)为特征。IR在以下方面最为普遍 与骨质疏松症相关的老年人口。我们提出了PGC-1α4(α4)的新的代谢调节作用， 一种肥大基因，通过抗阻运动(RE)增强。根据大量的初步数据，我们 假设α4与PPARβ(Rβ)协同促进肌肉糖酵解和胰岛素敏感性(IS) 以及增加肌肉质量和表现。根据我们新的初步数据，我们还将调查 无论是通过糖酵解蛋白的脱乙酰基，RE都能增强肌肉的糖酵解能力。Rβ也减少了 氧化应激不仅会增强IS，而且还有助于其他健康益处。基于信使核糖核酸的新数据 表明稀土减少了蛋白质的降解，这将在当前的提案中进行研究。我们会 确定3个月的RE训练是否提高了胰岛素敏感性以及肌肉性能和体重 IR患者通过糖酵解增强、糖酵解蛋白脱乙酰化还原蛋白的途径 降解和促进合成，改善氧化应激。我们将研究48名50-75岁的IR人群 在3个月前和3个月后进行每周4次抗阻训练或久坐不动，并与 瘦身就是人。我们将在一场急性运动之前和之后收集股外侧肌活检样本。 并在混合餐后测量糖酵解、能量代谢物、糖原合成酶、 糖原含量、α-4、R-β、胰岛素信号蛋白和蛋白质组分析。我们还将测量标志物 氧化应激包括8-OXO-dG(DNA损伤的测量)、对蛋白质的氧化损伤以及随后的 肌肉蛋白质的降解，我们假设是通过增加Rβ和RE的抗氧化作用来减少的 训练。我们还将利用稳定同位素标记示踪剂对特定肌肉蛋白进行活体标记 确定α4诱导的肌肉肥大是否不仅通过减少降解，而且还通过 增强收缩蛋白的合成。尽管我们的初步细胞系研究提供了支持数据 α-4和R-β对IS和糖酵解的直接作用以及R-β的抗氧化作用 决定我们结果的基因不能在人类身上获得。因此，我们将在小鼠模型中进行研究 与高脂饮食诱导的IR表明，α4增强IS和糖酵解，而Rβ降低氧化应激。我们 还将沉默小鼠肌肉的α4和Rβ，以证实我们基于细胞的结果显示，收缩诱导 更改取决于α4和Rβ。这些人类和动物研究将共同提供必要的 稀土如何增强IS、糖酵解、降低氧化应激和促进肌肉的机制解释 IR人群的表现和质量，因此对他们的健康和寿命有很大贡献。

PROJECT SUMMARY/ABSTRACT Identification of the molecular regulatory points of exercise benefits is of high national priority because of the opportunity to develop targeted novel therapeutics benefiting populations suffering from inactivity-related health problems, including T2DM and pre-diabetes, characterized by insulin resistance (IR). IR is most prevalent in the older population associated with sarcopenia. We propose novel metabolic regulatory role of PGC-1α4 (α4), a hypertrophy gene, enhanced by resistance exercise (RE). Based on substantial preliminary data, we hypothesize that α4, in cooperation with PPARβ (Rβ), promotes muscle glycolysis and insulin sensitivity (IS) as well as increasing muscle mass and performance. Based on our novel preliminary data we will also investigate whether by deacetylation of glycolytic proteins, RE enhances muscle glycolytic capacity. Rβ also reduces oxidative stress that not only enhances IS but also contributes to other health benefits. New mRNA based data indicates that RE reduces protein degradation which will be investigated in the current proposal. We will determine whether 3 months of RE training enhances insulin sensitivity and muscle performance and mass in IR people through pathways of enhanced glycolysis, deacetylation of glycolytic proteins reducing protein degradation and enhancing synthesis and ameliorating oxidative stress. We will study 48 IR people 50-75 yrs before and after 3 months of either 4-times/week resistance training or sedentary life and compare them with lean IS people. We will collect vastus lateralis muscle biopsy samples before and after an acute exercise bout and following a mixed meal to measure markers of glycolysis, energy metabolites, glycogen synthase, glycogen content, α4, Rβ, insulin signaling proteins and proteome analysis. We will also measure markers of oxidative stress including 8-OXO-dg (measure of DNA damage), oxidative damage to proteins and subsequent muscle protein degradation, which we hypothesize is reduced by increased anti-oxidant effect of Rβ with RE training. We also will use in vivo labeling of specific muscle proteins utilizing stable isotope labeled tracers to determine whether α4 induced muscle hypertrophy occurs not only by reducing degradation but also by enhancing contractile protein synthesis. Although our preliminary cell line studies provide supporting data on direct effects of α4 and Rβ on IS and glycolysis and on the anti-oxidant effect of Rβ, direct effects of these genes on our outcomes cannot be obtained in humans. Therefore we will perform studies in a mouse model with high-fat diet-induced IR to show that α4 enhances IS and glycolysis and Rβ reduces oxidative stress. We also will silence α4 and Rβ of mouse muscle to confirm our cell based results showing that contraction-induced changes are dependent on α4 and Rβ. Together these human and animal studies will render the necessary mechanistic explanation on how RE enhances IS, glycolysis, reduces oxidative stress and promote muscle performance and mass in IR people, thus substantially contributing to their health and life spans.