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）：在美国，非裔美国人（AAW）的肥胖和糖尿病患病率高于白人女性（CW）。虽然环境因素可能是有影响的，肥胖AAW已被证明具有固有的代谢缺陷，抑制骨骼肌的脂质氧化。然而，更令人吃惊的是，新出现的证据表明，这些缺陷可能预先存在于非肥胖的AAW中，使这个种族群体比CW更快地开始脂肪增加。这非常重要，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。尽管这些发现的意义，细胞机制来解释这种种族/民族特异性代谢功能障碍仍然不明确。我们的主要假设是，前肥胖/糖尿病AAW具有骨骼肌，其氧化长链脂肪酸（LCFA）的能力存在固有损伤，导致生物活性脂质的细胞毒性积累，以及胰岛素抵抗和糖尿病的沉淀。然而，在瘦CW中，耐力运动训练（EET）刺激线粒体生物合成，提高肌肉氧化LCFA的能力。我们的第二个假设是，AAW将通过增加骨骼肌氧化脂质的能力对EET作出反应，从而降低肥胖和糖尿病的倾向。本研究的目的是：1）确定瘦AAW中骨骼肌LCFA氧化功能障碍的预先存在的细胞部位; 2）确定AAW是否对EET有反应。为了实现我们的目标，我们将调查12名久坐、瘦的AAW和CW，年龄、BMI（< 25 kg/m2）和月经状态相匹配。将对来自两个种族的肥胖受试者进行评估以进行比较。将通过捕获来自完整肌肉条和匀浆氧化的标记14 CO2来测量骨骼肌LCFA氧化能力（腹直肌），以鉴定脂质代谢中的特定细胞缺陷是由于1）线粒体前事件，2）LCFA向酰基-CoA的线粒体活化，3）LCFA跨线粒体膜的转运和/或4）线粒体后活化。运输线粒体氧化系统。将测量全身胰岛素敏感性，以确定骨骼肌脂质代谢状态与胰岛素作用之间的关联强度。来自目标1和新招募的受试者亚组将接受7天和8周的EET（骑自行车），以确定慢性肌肉活动（股外侧肌）对AAW中线粒体生物合成、LCFA氧化和胰岛素作用的影响。我们的研究结果将用于随后的RO 1应用，以实现我们的长期目标，即了解AAW中与肥胖和糖尿病相关的更高发病率和死亡率的机制。