Dysregulated Muscle Lipid Metabolism in African-Americans

非裔美国人肌肉脂质代谢失调

• 批准号: 6676419
• 负责人: RONALD CORTRIGHT
• 金额: $ 13.95万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6676419
• 关键词: African American; acyl coA; biopsy; carbon dioxide; caucasian American; clinical research; disease /disorder proneness /risk; electron microscopy; enzyme activity; exercise; fatty acid metabolism; female; human subject; insulin sensitivity /resistance; light microscopy; long chain fatty acid; menstrual cycle; mitochondrial membrane; noninsulin dependent diabetes mellitus; obesity; oxidation; racial /ethnic difference; striated muscles; thin layer chromatography; women's health

DESCRIPTION (provided by applicant): The prevalence of obesity and diabetes is greater among African-American (AAW) than Caucasian women (CW) in the United States. Although environmental factors may be influential, obese AAW have been shown to possess inherent metabolic defects that suppress lipid oxidation by skeletal muscle. More startling however, is the emerging evidence that these defects may pre-exist in non-obese AAW, predisposing this racial group toward a more rapid onset of fat gain vs. CW. This is fundamentally important because the resultant increase in intramuscular lipid content is strongly linked with insulin resistance and diabetes. Despite the significance of these findings, the cellular mechanisms to explain this racial/ethnic specific metabolic dysfunction remain undefined. Our primary hypothesis is that pre-obese/diabetic AAW possess skeletal muscle with an inherent impairment in the capacity to oxidize long-chain fatty acids (LCFA), leading to a cytotoxic accumulation of bioactive lipids, and precipitation of insulin resistance and diabetes. However, in lean CW, endurance exercise training (EET) stimulates mitochondrial biogenesis, elevating the muscles capacity to oxidize LCFA. Our secondary hypothesis is that AAW will respond to EET by increasing the capacity of skeletal muscle to oxidize lipids, thus reducing the propensity toward developing obesity and diabetes. The aims of the present investigation are 1) to identify the pre-existing cellular site(s) of dysfunction in skeletal muscle LCFA oxidation in lean AAW and 2) to determine whether AAW are responsive to EET. To accomplish our aims, we will investigate 12 sedentary, lean AAW and CW matched for age, BMI (< 25 kg/m2), and menstrual status. Obese subjects from both races will be assessed for comparisons. Skeletal muscle LCFA oxidative capacity will be measured by trapping labeled 14CO2 derived from oxidation by intact muscle strips and homogenates (rectus abdominus) in order to identify the specific cellular defects in lipid metabolism as being due to 1) pre-mitochondrial events 2) mitochondrial activation of LCFA to acyl-CoA 3) the transport of LCFA across the mitochondrial membrane and/or 4) the post-transport mitochondrial oxidative system. Measures of whole body insulin sensitivity will be made to determine the strength of association between the status of skeletal muscle lipid metabolism and insulin action. A subset of subjects from aim 1 and new recruits will undergo 7 days and 8 weeks of EET (cycling) to determine the impact of chronic muscle activity (vastus lateralis) on mitochondrial biogenesis, oxidation of LCFA, and insulin action in AAW. Our findings will be used for subsequent RO1 applications to achieve our Iong-term objective of understanding the mechanism(s) that underlie the greater morbidity and mortality associated with obesity and diabetes in AAW.

描述（由申请人提供）：非裔美国人（AAW）的肥胖和糖尿病患病率要比美国的白种妇女（CW）更大。尽管环境因素可能具有影响力，但肥胖的AAW已被证明具有固有的代谢缺陷，可抑制骨骼肌的脂质氧化。然而，更令人震惊的是，新兴的证据表明这些缺陷可能在非肥胖AAW中曾经存在，这使这个种族群体倾向于更快地发作脂肪增益与CW。这在根本上很重要，因为肌内脂质含量的增加与胰岛素抵抗和糖尿病密切相关。尽管这些发现具有重要意义，但解释这种种族/种族特异性代谢功能障碍的细胞机制仍然不确定。我们的主要假设是，肥胖/糖尿病前AAW具有骨骼肌的骨骼肌肉，其固有的损害可氧化长链脂肪酸（LCFA），从而导致生物活性脂质的细胞毒性积累，以及胰岛素抵抗和胰岛素抵抗和糖尿病的沉淀。但是，在瘦肉CW中，耐力运动训练（EET）刺激了线粒体生物发生，从而提高了氧化LCFA的肌肉能力。我们的次要假设是，AAW将通过增加骨骼肌氧化脂质的能力来对EET做出反应，从而减少肥胖和糖尿病的倾向。本研究的目的是1）确定骨骼肌LCFA氧化中液体功能障碍的预先存在的细胞部位，以确定AAW是否对EET响应。为了实现我们的目标，我们将调查12个久坐的，瘦的AAW和CW年龄，BMI（<25 kg/m2）和月经状态。将评估来自两个种族的肥胖受试者进行比较。 Skeletal muscle LCFA oxidative capacity will be measured by trapping labeled 14CO2 derived from oxidation by intact muscle strips and homogenates (rectus abdominus) in order to identify the specific cellular defects in lipid metabolism as being due to 1) pre-mitochondrial events 2) mitochondrial activation of LCFA to acyl-CoA 3) the transport of LCFA across the线粒体膜和/或4）传输后线粒体氧化系统。将采取全身胰岛素敏感性的度量，以确定骨骼肌脂质代谢和胰岛素作用的状态之间的关联强度。来自AIM 1和新兵的受试者子集将经历7天和8周的EET（骑行），以确定慢性肌肉活性（股外侧）对线粒体生物发生，LCFA的氧化以及AAW中的胰岛素作用的影响。我们的发现将用于随后的RO1应用，以实现我们了解与AAW中肥胖和糖尿病相关的发病率和死亡率更大的机制的IONG期限目标。