MR & Optical Diagnosis of Muscle Metabolism and Function

描述（由申请人提供）：本申请提出了一种磁共振（MRS）和近红外光学（NIRS）光谱学的新组合，用于研究正常和异常人体肌肉中的能量代谢。我们的目标是从能量平衡的原理及其在本基金之前的工作中开发的调节来开发人类肌肉功能的诊断程序。肌肉的代谢、能量学和功能是紧密结合的，并提供了定义正常和解释完整人体肢体中异常肌肉功能所需的关键信息。在本申请中，我们增加了小鼠肌肉研究，以测试我们的定量光谱方法的有效性和准确性。前三个具体目标利用了该基金前几年开发的综合质量和能量平衡的概念，以量化氧通量在控制氧化和糖酵解能量代谢中的作用。首先，我们问线粒体如何在氧化磷酸化中将O2与ATP通量联系起来（目的1）。我们评估磷酸化和氧化之间的耦合与实验，专注于在完整的人体肌肉细胞呼吸作为氧张力的函数。这些实验有可能建立新的观点的氧供应线粒体和细胞内的氧分压在氧化磷酸化的调节[ADP]的作用。其次，我们研究肌肉扩散电导如何将O2输送与线粒体需求联系起来（目的2）。该目的比较氧压力梯度的大小与氧摄取通量中的扩散电导。第三，我们评估了氧摄取的扩散电导对糖酵解通量和H+与乳酸流出之间的平衡的影响（目的3）。如果我们的假设得到支持，扩散电导将被发现发挥类似的功能作用的H+和乳酸平衡和氧平衡。最后，目标4显示了这种整合如何独特地解释衰老中的异常肌肉能量学。因此，该项目将控制ATP供应的能量平衡的所有主要组成部分与细胞ATP酶的需求联系起来，并以老年肌肉为例，测试这些联系及其调节的改变如何影响功能。

DESCRIPTION (provided by applicant):This application proposes a novel combination of magnetic resonance (MRS) and near infrared optical (NIRS) spectroscopy for studying energy metabolism in normal and abnormal human muscle. Our goal is to develop diagnostic procedures for human muscle function from principles of energy balances and their regulation developed by prior work on this grant. Metabolism, energetics and function of muscle are tightly integrated and provide crucial information needed to define normal and interpret abnormal muscle function in the intact human limb. In this application we add mouse muscle studies to test efficacy and accuracy of our quantitative spectroscopic methods. The first three specific aims exploit the notions of an integrative mass and energy balance developed in prior years of this grant to quantify the role of oxygen flux in the control of oxidative and glycolytic energy metabolism. First, we ask how mitochondria link O2 with ATP fluxes in oxidative phosphorylation (Aim 1). We evaluate the coupling between phosphorylation and oxidation with experiments that focus on cellular respiration in intact human muscle as a function of oxygen tension. These experiments are likely to establish new views of oxygen supply to mitochondria and the role of intracellular partial pressure of oxygen in the regulation of oxidative phosphorylation by [ADP]. Second, we examine how muscle diffusion conductance links O2 delivery with mitochondrial demand (Aim 2). This aim compares the magnitude of the oxygen pressure gradient versus the diffusive conductance in oxygen uptake flux. Third, we evaluate how much the diffusion conductance for oxygen uptake influences the balance between glycolytic flux and H+ & lactate efflux (Aim 3). If our hypothesis is supported, diffusive conductance will be found to play a similar functional role for H+ & lactate balances and for oxygen balance. Finally, Aim 4 shows how this integration uniquely accounts for abnormal muscle energetics in aging. Thus this project links all the major components of energy balance governing the supply of ATP to the demands of cellular ATPases into a coherent whole and tests how alteration of these linkages and their regulation influences function, using elderly muscle as an example.