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的主要因素疾病的发病率和死亡率。瘦体重和肌肉活力的丧失不仅会损害活动能力，还会损害导致各种全身性疾病结果的恶化。环境暴露于砷全球数百万个个体的心血管和代谢疾病密切相关。然而，这些增加的风险的基本致病机制相对尚不清楚。提议研究试图通过研究砷会损害肌肉祖先的假设来填补这一知识差距细胞功能和差异化以促进肌肉质量和成分的下降，并破坏健康肌肉代谢与全身器官的交流。我们发现低到中等环境暴露于饮用水中的砷可通过破坏肌肉来促进骨骼肌肉的下降组成和结构，以及损伤线粒体并改变线粒体生物能学。在此外，我们发现类似于Myosteatosis（主要危险因素）的肌肉的纤维化重塑。用于人类的心血管死亡率和2型糖尿病。从机械上讲，干细胞线粒体靶向通过砷促进致病祖细胞表型和分化的表观遗传诱导。这是解决功能失调的线粒体和核表观遗传学的机制很重要为了确定恢复正常肌肉代谢的策略。朝着这个目标，研究特定目标1将检验以下假设：功能失调的线粒体通信驱动致病性祖细胞的代谢和表型变化及其利基市场决定肌肉维持和肥胖。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恢复了正常的表观遗传调节，干细胞表型和肌肉代谢。特定目的2中研究的目的是检验以下假设：适应不良的线粒体表型驱动致病性旁分泌和全身交流。这些研究着重于功能失调由miRNA货物介导的旁分泌和全身信号传导，在砷中释放的细胞外囊泡中暴露的肌肉祖细胞和骨骼肌。我们将确定砷对 miRNA货物并确定这种变化的轮廓是否会影响全身器官的新陈代谢，例如肝。与AIM 1一样，我们将干预线粒体保护剂，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上与临床相关的，可立即提取的策略，以逆转致病性肌肉维持和丧失慢性砷暴露的再生能力。更大的影响将是确定减少砷对代谢和心血管全球负担的贡献的策略疾病，对衰老人群的不断增长。