Dysfunctional skeletal muscle communication in arsenic-promoted cardiometabolic disease

项目说明/摘要 肌肉质量下降和代谢受损是导致心血管疾病的主要因素 疾病发病率和死亡率。精瘦的身体质量和肌肉活力的丧失不仅会损害行动能力，还会 导致大范围系统性疾病后果的恶化。环境暴露于砷 它与全球数百万人的心血管和代谢性疾病密切相关。然而， 这些风险增加的潜在致病机制相对未知。建议数 研究试图通过调查砷损害肌肉祖细胞的假说来填补这一知识空白 细胞功能和分化，促进肌肉质量和组成的下降，以及破坏 健康的肌肉代谢与全身器官的沟通。我们发现低到中等 环境暴露于饮用水中的砷通过破坏肌肉而促进骨骼肌衰退 组成和结构，以及损伤线粒体和改变线粒体生物能量学。在……里面 此外，我们发现类似于肌骨瘤病的肌肉成纤维脂肪重塑是一个主要的危险因素。 用于人类的心血管死亡率和2型糖尿病。从机制上讲，干细胞线粒体是靶向的 通过砷促进表观遗传诱导致病祖细胞表型和分化。它是 对解决线粒体和核表观遗传通讯障碍机制的重要意义 以确定恢复正常肌肉新陈代谢的策略。为了实现这一目标，中国的研究 特定目标1将检验线粒体通讯功能障碍导致致病的假说 祖细胞及其生态位的代谢和表型变化决定了肌肉的维持和 肥胖症。重要的是，我们将使用线粒体保护肽来确定逆转 砷对线粒体的作用可恢复正常的表观遗传调节、干细胞表型和肌肉 新陈代谢。《特定目标2》的研究目的是检验一种假说，即不适应的线粒体 表型驱动致病旁分泌和系统沟通。这些研究的重点是功能障碍 砷释放的胞外小泡中miRNA Cargo介导的旁分泌和系统信号转导 暴露的肌肉祖细胞和骨骼肌。我们将确定砷对人体的影响。 并确定这种改变是否会影响系统器官的新陈代谢，如 肝脏。与目标1一样，我们将使用线粒体保护剂进行干预，以确定miRNA是否 货物轮廓和器官代谢可恢复正常。如果成功，这些研究将确定 临床相关和立即可处理的逆转致病肌肉维持和丢失的策略 慢性砷暴露的再生能力。更大的影响将是确定 减少砷对全球代谢和心血管负担的贡献的战略 疾病，这是老龄化人口中日益令人担忧的问题。

PROJECT DESCRIPTION / ABSTRACT Declines in muscle quality and impaired metabolism are major contributing factors to cardiovascular disease morbidity and mortality. Loss of lean body mass and muscle vitality not only impairs mobility, but also contributes to worsening of a large range of systemic disease outcomes. Environmental exposure to arsenic is strongly associated with cardiovascular and metabolic disease in millions of individuals globally. However, the underlying pathogenic mechanisms for these increased risks are relatively unknown. The proposed studies seek to fill this knowledge gap by investigating the hypothesis that arsenic impairs muscle progenitor cell function and differentiation to promote declines in muscle quality and composition, as well as disrupt communication of healthy muscle metabolism with systemic organs. We find that low to moderate environmental exposure to arsenic in drinking water promotes skeletal muscle decline by disrupting muscle composition and structure, as well as injuring mitochondria and altering mitochondrial bioenergetics. In addition, we find fibroadipogenic remodeling of the muscle that resembles myosteatosis, a major risk factor for cardiovascular mortality and type 2 diabetes in humans. Mechanistically, stem cell mitochondria targeted by arsenic promote epigenetic induction of pathogenic progenitor cell phenotypes and differentiation. It is important to resolve the mechanisms for dysfunctional mitochondrial and nuclear epigenetic communication in order to identify strategies that restore normal muscle metabolism. Towards this goal, the studies in specific Aim 1 will test the hypothesis that dysfunctional mitochondrial communication drives pathogenic metabolic and phenotypic changes in progenitor cells and their niche that dictate muscle maintenance and adiposity. Importantly, we will use a mitochondrial protective peptide to determine whether reversing the mitochondrial effects of arsenic restores normal epigenetic regulation, stem cell phenotypes, and muscle metabolism. The goal of the studies in specific Aim 2 is to test the hypothesis that maladaptive mitochondrial phenotypes drive pathogenic paracrine and systemic communication. These studies focus on dysfunctional paracrine and systemic signaling mediated by miRNA cargo in extracellular vesicles released from arsenic- exposed muscle progenitor cells and skeletal muscles. We will identify the effects of arsenic on the profile of miRNA cargo and determine whether this altered profile affects metabolism in systemic organs, such as the liver. As in Aim 1, we will intervene with mitochondrial protective agents to determine whether the miRNA cargo profiles and organ metabolism can be restored to normal. If successful, these studies will identify clinically-relevant and immediately-tractable strategies to reverse pathogenic muscle maintenance and loss of regenerative capacity from chronic arsenic exposures. The greater impact will be the identification of strategies to reduce the contribution of arsenic to the global burden of metabolic and cardiovascular diseases, an ever-increasing concern in aging populations.