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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：
10620274
负责人：
Aaron Barchowsky
金额：
$ 49.4万
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/10620274
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 Relative Risks 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 cardiometabolism 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 mortality muscle form muscle metabolism muscle regeneration novel paracrine prevent progenitor programs 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新陈代谢受损是心血管疾病的主要原因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行动能力，还会影响身体健康。导致多种全身性疾病结果恶化。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，这些风险增加的潜在致病机制相对未知。拟议的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，促进肌肉质量和成分下降，以及破坏健康的肌肉代谢与全身器官的沟通。我们发现低到中等饮用水中砷的环境暴露会破坏肌肉，从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。在此外，我们发现类似于肌脂肪变性的肌肉纤维脂肪形成重塑，这是一个主要危险因素人类心血管死亡率和 2 型糖尿病。从机制上讲，干细胞线粒体靶向砷可促进表观遗传诱导致病祖细胞表型和分化。这是对于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。为实现这一目标，研究具体目标 1 将检验线粒体通讯功能失调导致致病的假设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。重要的是，我们将使用线粒体保护肽来确定是否逆转砷的线粒体作用可恢复正常的表观遗传调节、干细胞表型和肌肉代谢。具体目标 2 中的研究目标是检验以下假设：适应不良的线粒体表型驱动致病性旁分泌和全身通讯。这些研究重点关注功能失调由砷释放的细胞外囊泡中的 miRNA 货物介导的旁分泌和全身信号传导暴露的肌肉祖细胞和骨骼肌。我们将确定砷对剖面的影响 miRNA 货物并确定这种改变的特征是否影响全身器官的代谢，例如肝。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 是否货物特征和器官代谢可以恢复正常。如果成功的话，这些研究将确定临床相关且可立即处理的策略，以逆转致病性肌肉维持和丧失慢性砷暴露的再生能力。更大的影响将是识别减少砷对全球代谢和心血管负担的影响的策略疾病，是人口老龄化日益严重的问题。