Mechanisms linking the adipogenic phenotype of aging muscle to insulin resistance

描述（由申请人提供）：针对RFA-AG-06-003，本申请提出研究衰老肌肉的脂肪形成表型与胰岛素抵抗发展之间的联系机制。基于我们的初步数据，我们假设肌周脂肪生成的增加通过与脂肪酸诱导的线粒体应激直接相关的机制有助于胰岛素抵抗。因此，我们建议进行研究，以确定骨骼肌纤维内部和之间的脂质沉积如何影响线粒体性能、胰岛素敏感性以及这两个功能终点之间的相互作用。我们进一步假设，习惯性运动通过重塑肌肉线粒体来对抗脂质浸润的不利影响，使这些细胞器能够更好地应对高脂质负荷。这些假设将使用双管齐下的方法进行测试，该方法将基于综合质谱（MS）的代谢分析策略应用于人体肌肉的体外和体内研究。首先，我们的计划将采用一种新开发的人类脂肪细胞-肌细胞共培养系统来研究：(1)脂肪细胞对邻近肌细胞代谢功能的影响；ii)将脂肪生成增加与胰岛素作用受损联系起来的潜在机制。我们预测，脂质诱导的线粒体应激将成为将脂肪生成负担与葡萄糖稳态受损联系起来的主要事件，此外，与年轻供体相比，老年供体的肌细胞可能会加剧这一事件。其次，利用STRRIDE研究的现有数据/标本，我们将把体外模型的发现转化为人体生理学。为此，我们将在运动训练干预的背景下研究肌肉脂质浸润（肌肉内和肌肉周围）与胰岛素敏感性和线粒体性能的代谢/转录标记物之间的关系。这些目标将由杜克大学斯特德曼营养与代谢中心的一个多学科研究小组完成。完成这项研究的目的不仅将提供关于骨骼肌内和周围脂质储存与全身胰岛素作用之间关系的机制信息-这是与肥胖，糖尿病和衰老相关的发病率的主要决定因素-而且还将提供最有效的运动处方，以预防和纠正这些情况下骨骼肌胰岛素作用不足。

DESCRIPTION (provided by applicant): In response to RFA-AG-06-003, this application proposes to investigate mechanisms that link the adipogenic phenotype of aging muscle to the development of insulin resistance. Based on our preliminary data, we hypothesize that increased perimuscular adipogenesis contributes to insulin resistance via mechanisms that link directly to fatty acid-induced mitochondrial stress. We have therefore proposed studies to determine how lipid deposits within and between skeletal myofibers impact mitochondrial performance, insulin sensitivity and the interplay between these two functional endpoints. We further hypothesize that habitual exercise combats the adverse effects of lipid infiltration by remodeling muscle mitochondria in manner that enables these organelles to better cope with a high lipid load. These hypotheses will be tested using a two-pronged approach that applies comprehensive mass-spectrometry (MS) based metabolic profiling strategies to both in vitro and in vivo studies of human muscle. First, our plan will employ a newly developed human adipocyte-myocyte co-culture system to investigate i) the impact of adipocytes on the metabolic function of neighboring myocytes; and ii) the underlying mechanisms that link increasing adipogenesis to impaired insulin action. We predict that lipid-induced mitochondrial stress will emerge as a primary event that connects adipogenic burden to impaired glucose homeostasis, and moreover, that this event might be exacerbated in myocytes from aged compared to young donors. Second, using existing data/specimens from the STRRIDE study we will translate findings from our in vitro model to human physiology. To this end, we will examine how lipid infiltration of muscle (both intramuscular and perimuscular) relates to both insulin sensitivity and metabolic/transcriptional markers of mitochondrial performance, in the context of an exercise training intervention. These goals will be accomplished by a multidisciplinary research team from the Duke University Stedman Nutrition and Metabolism Center. Completion of the aims of this study will not only provide mechanistic information about the relationship between lipid stores in and around skeletal muscle and whole body insulin action - a major determinant of morbidity related to obesity, diabetes and aging - but will also provide insight into the most efficacious exercise prescription for preventing and correcting deficient skeletal muscle insulin action in these conditions.