Role of Skeletal Muscle Health on Poor LIfestyle Related Type 2 Diabetes and Cardiovascular Disease Risk

项目摘要 基于人群的研究传统上侧重于体脂(即肥胖)的测量，以评估 不良生活方式对胰岛素抵抗和心血管风险的贡献。虽然较少人认识到的是 骨骼肌在这些情况下的作用。建立在我们提出的生物行为模型的基础上，该模型结合了多个 骨骼肌健康状况的维度评估(即质量、功能、力量和肌间脂肪渗透) 及其分子转导(即肌肉因子对全身振动的反应)，这是这一研究的基本目标 建议评估骨骼肌健康在调节肥胖因素作用中的系统贡献 生活方式(即心理社会压力、不健康饮食和缺乏体力活动)对胰岛素抵抗和 心血管疾病(CVD)临床前标志物(如动脉僵硬、颈动脉内膜中层)的发展 厚度和内皮功能)。评价环境因素对血吸虫病表现的影响 生物标记、遗传影响必须加以控制。以我们的佐治亚州双胞胎研究为基础 评估了532对非洲裔美国人数量大致相同的多种族双胞胎样本 和欧洲裔美国人(EA)在15年内4次，有体力活动和心理社会压力 在这些访问中收集到的，我们将进行一次额外的后续访问(年龄范围为22-45岁)，以衡量 骨骼肌健康、胰岛素抵抗和心血管疾病的临床前标记物。具体目标是测试 假设：(1)肥胖的生活方式因素(即心理社会压力、缺乏体力活动和不健康饮食) 会共同或明显地损害骨骼肌健康，而骨骼肌健康受损将是途径 肥胖生活方式因素对胰岛素抵抗和高血压病临床前标志物的影响 心血管疾病。(2)肌细胞因子对全身振动的反应可能是分子转导分子介导的。 骨骼肌健康对胰岛素抵抗和心血管疾病临床前标志物的影响。(3)种族和性别可 修改肥胖生活方式因素对目标1和目标2的影响。次要目标是：(1)检查 骨骼肌的健康状况能否解释AAs和EAs之间在2型风险方面的健康差异 糖尿病和心血管疾病。(2)研究基因-环境相互作用对骨骼肌的潜在影响 对肥胖生活方式的反应。这一提议代表了一种范式的转变，它将重点放在 骨骼肌而不是肥胖是不良生活方式引起的代谢和血管功能障碍的原因。 这些信息不仅可以指导知识的有效传播，提高成功率 行为改变，但也有可能产生针对危重患者的新治疗策略 骨骼肌作为生存决定因素的疾病。此外，增加了对 促进AAS和EAS之间健康差距的机制将有助于发展种族-- 具体的预防策略。

Project Summary Population-based studies have traditionally focused on measurement of body fat (i.e. obesity) to assess the contribution of poor lifestyles to insulin resistance and cardiovascular risk. While much less recognized is the role of skeletal muscle in these conditions. Built on our proposed biobehavioral model which incorporates multi- dimensional evaluation of skeletal muscle health (i.e. mass, function, strength, and intermuscular fat infiltration) and its molecular transducer (i.e. myokine response to whole body vibration), the fundamental objective of this proposal is to evaluate the systemic contribution of skeletal muscle health in mediating the role of obesogenic lifestyles (i.e. psychosocial stress, unhealthy diet and physical inactivity) on insulin resistance and the development of preclinical markers of cardiovascular disease (CVD) (i.e. arterial stiffness, carotid intima media thickness and endothelial function). To evaluate the impact of environmental factors on manifestation of biological markers, genetic influences must be controlled. Building on our Georgia CV Twin Study which has evaluated a multi-ethnic twin samples of 532 twin pairs with roughly equal number of African Americans (AA) and European Americans (EA) 4 times over 15 years and has physical activity and psychosocial stress collected during these visits, we will conduct one additional follow-up visit (age range 22-45 yrs) to measure skeletal muscle health, insulin resistance and preclinical markers of CVD. The specific aims are to test the hypotheses that: (1) Obesogenic lifestyle factors (i.e. psychosocial stress, physical inactivity and unhealthy diet) will jointly or distinctively impair skeletal muscle health, and impaired skeletal muscle health will be the pathway through which obesogenic lifestyle factors exert their influence on insulin resistance and preclinical markers of CVD. (2) Myokine response to whole body vibration will be the molecular transducers mediating the effect of skeletal muscle health on insulin resistance and preclinical markers of CVD. (3) Ethnicity and gender may modify the influence of obesogenic lifestyle factors upon aim 1 and 2. The secondary aims are: (1) To examine whether skeletal muscle health can explain the health disparity between AAs and EAs in the risk of type 2 diabetes and CVD. (2) To examine the potential effects of gene-environment interactions on skeletal muscle response to obesogenic lifestyles. This proposal represents a paradigm shift by focusing on impairments in skeletal muscle rather than adiposity as a cause of poor lifestyle induced metabolic and vascular dysfunction. This information can not only guide the effective dissemination of the knowledge and increase the success rate of behavior changes, but also has the potential to generate new treatment strategies targeting the critical illness in which skeletal muscle as a determinant of survival. Furthermore, increased understanding of the mechanisms contributing to health disparities between AAs and EAs will enable the development of ethnicity- specific prevention strategies.