Mechanisms linking the adipogenic phenotype of aging muscle to insulin resistance

描述（由申请人提供）： 作为对RFA-AG-06-003的响应，本申请提出研究将衰老肌肉的脂肪形成表型与胰岛素抵抗的发生联系起来的机制。基于我们的初步数据，我们假设肌周脂肪生成增加通过与脂肪酸诱导的线粒体应激直接相关的机制导致胰岛素抵抗。因此，我们提出了研究，以确定骨骼肌纤维内和之间的脂质沉积如何影响线粒体的性能，胰岛素敏感性和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，使这些细胞器能够更好地科普高脂质负荷，从而对抗脂质浸润的不利影响。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，我们的计划将采用新开发的人脂肪细胞-肌细胞共培养系统来研究i）脂肪细胞对邻近肌细胞代谢功能的影响;和ii）将增加脂肪形成与受损的胰岛素作用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一个主要的事件，连接成脂负担受损的葡萄糖稳态，而且，这一事件可能会加剧从老年人相比，年轻的捐助者的肌细胞。其次，使用STRRIDE研究的现有数据/样本，我们将把体外模型的发现转化为人体生理学。为此，我们将研究如何脂质浸润的肌肉（肌内和肌周）与胰岛素敏感性和线粒体性能的代谢/转录标志物，在运动训练干预的背景下。这些目标将由来自杜克大学斯特德曼营养和代谢中心的多学科研究小组完成。本研究目的的完成不仅将提供有关骨骼肌内和周围的脂质储存与全身胰岛素作用之间关系的机械信息-肥胖，糖尿病和衰老相关发病率的主要决定因素-而且还将提供对预防和纠正这些条件下骨骼肌胰岛素作用不足的最有效运动处方的见解。

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.