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Dysfunctional skeletal muscle communication in arsenic-promoted cardiometabolic disease

砷促进的心脏代谢疾病中骨骼肌通讯功能障碍

基本信息

批准号：
10315229
负责人：
Aaron Barchowsky
金额：
$ 53.8万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-23 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10315229
关键词：
Acute Affect Aging Arsenic Autocrine Communication Bioenergetics Cancer Burden Cardiometabolic Disease Cardiovascular Diseases Cardiovascular system Cell Communication Cell Differentiation process Cells Choristoma Chronic Communication Disease Disease Outcome Environmental Exposure Epigenetic Process Exposure to Functional disorder Generations Goals Homeostasis Human Impairment Individual Injury Insulin Resistance Intervention Investigation Knowledge Liver Liver diseases Maintenance Malignant neoplasm of liver Mediating Memory Metabolic Metabolic Diseases Metabolism MicroRNAs Mitochondria Morbidity - disease rate Mus Muscle Muscle Mitochondria Muscle function Muscle satellite cell Muscular Atrophy Myopathy Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity Organ Paracrine Communication Pathogenesis Pathogenicity Pathway interactions Peptides Phenotype Population Process Protective Agents Reactive Oxygen Species Regenerative capacity Risk Severities Signal Transduction Skeletal Muscle Structure Systemic disease Testing Thinness Tissues Toxic Environmental Substances Translating Work autocrine bisulfite sequencing burden of illness cancer survival cardiovascular disorder risk cardiovascular risk factor clinically relevant disorder risk drinking water epidemiology study epigenetic regulation extracellular vesicles in utero in vivo insulin sensitivity intercellular communication lean body mass metabolic phenotype mortality muscle form muscle metabolism muscle regeneration novel paracrine prevent progenitor receptor repaired response skeletal muscle metabolism stem cell function stem cells tissue regeneration transcriptome sequencing vesicular release whole genome young adult

项目摘要

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.

项目描述/摘要肌肉质量下降和代谢受损是心血管疾病的主要因素。疾病发病率和死亡率。瘦体重和肌肉活力的丧失不仅会损害活动能力，导致大范围全身性疾病结局恶化。环境砷暴露与全球数百万人的心血管和代谢疾病密切相关。然而，在这方面，这些风险增加的潜在致病机制相对未知。拟议研究试图通过调查砷损害肌肉祖细胞的假设来填补这一知识空白。细胞功能和分化，以促进肌肉质量和组成的下降，以及破坏健康肌肉代谢与全身器官的沟通。我们发现低到中度的环境暴露于饮用水中的砷通过破坏肌肉促进骨骼肌衰退这可能导致线粒体的组成和结构以及损伤线粒体和改变线粒体生物能量学。在此外，我们发现肌肉的纤维脂肪形成性重塑类似于肌肉脂肪变性，这是一个主要的危险因素，心血管疾病死亡率和2型糖尿病。从机制上讲，干细胞线粒体靶向通过砷促进表观遗传诱导致病祖细胞表型和分化。是解决线粒体和核表观遗传通讯功能失调的机制很重要以确定恢复正常肌肉代谢的策略。为了实现这一目标，具体目标1将检验线粒体通讯功能障碍驱动致病性祖细胞及其生态位的代谢和表型变化决定了肌肉的维持，肥胖症重要的是，我们将使用线粒体保护肽来确定是否逆转了砷的线粒体效应恢复了正常的表观遗传调节、干细胞表型和肌肉新陈代谢.具体目标2中的研究目的是检验适应不良的线粒体表型驱动致病性旁分泌和系统性交流。这些研究集中在功能失调的由砷释放的细胞外囊泡中的miRNA货物介导的旁分泌和系统信号传导- 暴露的肌肉祖细胞和骨骼肌。我们将确定砷的影响， miRNA货物，并确定这种改变的概况是否会影响全身器官的代谢，如肝脏与目标1一样，我们将用线粒体保护剂干预，以确定miRNA是否货物概况和器官代谢可以恢复正常。如果成功，这些研究将确定临床相关的和立即驯服的策略，以扭转致病性肌肉维持和损失，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疾病负担的贡献的战略疾病，这是老龄化人口日益关注的问题。