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

项目概要 基于人群的研究传统上侧重于测量身体脂肪（即肥胖）来评估 不良生活方式导致胰岛素抵抗和心血管风险。虽然不太被认可的是 骨骼肌在这些条件下的作用。基于我们提出的生物行为模型，该模型结合了多种 骨骼肌健康的维度评估（即质量、功能、力量和肌间脂肪浸润） 及其分子传感器（即肌因子对全身振动的反应），这个的基本目标 提议是评估骨骼肌健康在介导肥胖作用中的系统贡献 生活方式（即社会心理压力、不健康饮食和缺乏身体活动）对胰岛素抵抗和 心血管疾病 (CVD) 临床前标志物的开发（即动脉僵硬度、颈动脉内膜中层 厚度和内皮功能）。评估环境因素对表现的影响 生物标记、遗传影响必须得到控制。以我们的乔治亚州 CV 双胞胎研究为基础，该研究已 评估了 532 对双胞胎的多种族双胞胎样本，其中非洲裔美国人 (AA) 的数量大致相等 和欧洲美国人 (EA) 在 15 年内 4 次并且有体力活动和社会心理压力 在这些访问期间收集的信息，我们将进行一次额外的后续访问（年龄范围 22-45 岁）来衡量 骨骼肌健康、胰岛素抵抗和 CVD 临床前标志物。具体目的是测试 假设：（1）导致肥胖的生活方式因素（即社会心理压力、缺乏身体活动和不健康饮食） 将共同或明显损害骨骼肌健康，而骨骼肌健康受损将是途径 导致肥胖的生活方式因素对胰岛素抵抗和胰岛素抵抗的临床前标志物产生影响 化学气相沉积。 (2) 肌动蛋白对全身振动的反应将是介导以下效应的分子传感器 骨骼肌健康对胰岛素抵抗和 CVD 临床前标志物的影响。 (3) 种族和性别可能 改变肥胖生活方式因素对目标 1 和 2 的影响。次要目标是：（1）检查 骨骼肌健康是否可以解释 AA 和 EA 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。该提案代表了一种范式转变，重点关注以下方面的损害： 骨骼肌而不是肥胖是不良生活方式引起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并提高成功率 行为改变，但也有可能针对关键的行为产生新的治疗策略 在这种疾病中，骨骼肌是生存的决定因素。此外，加深了对 造成 AA 和 EA 之间健康差异的机制将促进族裔群体的发展 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.