Mechanisms linking the adipogenic phenotype of aging muscle to insulin resistance

衰老肌肉的脂肪形成表型与胰岛素抵抗之间的联系机制

基本信息

批准号：
7151708
负责人：
DEBORAH M MUOIO
金额：
$ 37.4万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-15 至 2011-08-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：为了响应RFA-AG-06-003，该申请提出了研究将衰老肌肉的脂肪生成表型与胰岛素抵抗发展联系起来的机制。基于我们的初步数据，我们假设增加的周围脂肪形成增加了通过与脂肪酸诱导的线粒体应激直接相关的机制，从而有助于胰岛素抵抗。因此，我们提出了研究，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以方式重塑肌肉线粒体来打击脂质浸润的不利影响，从而使这些细胞器能够更好地应对高脂质负荷。这些假设将使用两种普通的方法进行检验，该方法将基于综合的质谱法（MS）的代谢分析策略应用于体外和体内人体肌肉研究。首先，我们的计划将采用新开发的人类脂肪细胞 - 毛细胞共培养系统来研究i）脂肪细胞对邻近心肌细胞代谢功能的影响； ii）将增加脂肪形成与胰岛素作用受损的基本机制。我们预测，脂质诱导的线粒体应力将作为一个主要事件，将脂肪负担连接到葡萄糖稳态受损，此外，与年轻捐助者相比，这一事件可能会加剧这种事件。其次，使用来自Strride研究的现有数据/标本，我们将将发现从我们的体外模型转化为人类生理学。为此，我们将研究在运动训练干预的背景下，肌肉（肌肉内和周围）的脂质浸润如何与线粒体性能的胰岛素敏感性和代谢性/转录标记有关。这些目标将由杜克大学Stedman Nutrition and Nemalism Center的多学科研究团队实现。这项研究目标的完成不仅将提供有关骨骼肌肉和全身胰岛素作用之间脂质商店之间关系的机械信息，这是与肥胖，糖尿病和衰老有关的发病率的主要决定因素 - 而且还将洞悉最有效的运动处方，以防止和纠正这些条件下有缺陷的骷髅渗透胰岛素胰岛素的胰岛素动作。