ACADSB-dependent skeletal muscle gene expression in relation to cardiorespiratory fitness

ACADSB 依赖性骨骼肌基因表达与心肺健康的关系

基本信息

批准号：
10311258
负责人：
Johanna Fleischman
金额：
$ 3.96万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10311258
关键词：
Acetylation Affect Aftercare Age Animals Branched-Chain Amino Acids Breeding CCRL2 gene Cardiometabolic Disease Cell Respiration Chromatin Contralateral DNA cassette Data Dependovirus Disease Enzymes Fatty Acids Future Generations Gene Expression Generations Genes Genetic Genetic Transcription Genetic study Genotype Global Change Harvest Health Healthcare Systems Heritability Heterogeneity Histone Deacetylase Histone Deacetylase Inhibitor Histones Human Immunoprecipitation Individual Injections Intervention Isoleucine Knowledge Leucine Limb structure Link Lipids Longevity Meta-Analysis Metabolic Metabolic Diseases Metabolism Mitochondria Modeling Molecular Muscle Muscle Mitochondria Obesity Onset of illness Oxidative Phosphorylation Pathway interactions Patients Pharmacology Phenocopy Phenotype Play Post-Translational Protein Processing Propionates Protein Isoforms Proteins Quality of life Quantitative Trait Loci RNA Splicing RNA analysis Rattus Regulation Risk Role Rotation Running Skeletal Muscle Sodium Butyrate Sodium propionate Sprague-Dawley Rats Testing Thinness Tissue-Specific Gene Expression Transcriptional Regulation Up-Regulation Valine Variant Viral Volatile Fatty Acids Water Western Blotting Work acyl-CoA dehydrogenase amino acid metabolism branched chain fatty acid cardiorespiratory fitness dietary disorder risk experience fatty acid metabolism fitness genetic association genetic variant improved in vivo insulin sensitivity metabolomics mitochondrial dysfunction mitochondrial metabolism molecular phenotype mortality overexpression oxidation prevent propionyl-coenzyme A trait transcriptome sequencing transcriptomics vector

项目摘要

ABSTRACT Individuals with higher cardiorespiratory fitness (CRF) experience decreased rates of obesity and cardiometabolic disease and show significantly lower age-adjusted and disease-adjusted mortality. Given the increasing rates of obesity and cardiometabolic disease and the negative consequences of these diseases on quality of life and the healthcare system, there is a need to understand the intrinsic molecular mechanisms that contribute to the higher fitness phenotype. Although it is predicted that CRF is highly genetically heritable, it is unknown how the inheritance of specific genes contributes to the health and longevity associated with CRF. To study the genetic heritability of CRF, our lab has been characterizing a rat bred for high (HCR) and low (LCR) CRF via generational selective breeding for fitness which originated from a genetically heterogeneous stock. HCR rats phenocopy high-CRF traits in humans including leanness, longevity, and increased expression of genes related to mitochondrial oxidative phosphorylation, fatty acid (FA) metabolism, and branch chain amino acid (BCAA) metabolism in the skeletal muscle. Genetic and phenotypic heterogeneity is conserved within the HCR and LCR lines through rotational breeding, such that the interaction between genes and phenotype can be studied. One of the most highly and consistently upregulated genes in the skeletal muscle of HCR rats is ACADSB, a BCAA and short-chain FA catabolic enzyme whose key end metabolic product is propionate. Unpublished genotyping studies have identified statistically significant QTL and eQTL associations of an allelic variant near ACADSB. We hypothesize that ACADSB regulates the expression of genes related to oxidative metabolism and reduced disease risk in part by increased generation of propionate, an HDAC- inhibitor, in skeletal muscle. Specifically, HCR rats more highly express a shorter splice variant of ACADSB, raising the question of whether the HCR-associated isoform, or the total ACADSB concentration, potentially leads to differential gene expression. My project will test this hypothesis by (1) overexpressing LCR and HCR- associated splice variants of ACADSB in the skeletal muscle of both HCR and LCR rats, assessing the global changes in skeletal muscle gene expression with RNA-Seq, and observing the changes in metabolic flux through ACADSB, and (2) supplementing HCR and LCR rats with propionate to assess global transcriptional regulation and changes in chromatin histone post-translational modifications.

抽象的心肺健康 (CRF) 较高的个体肥胖率较低，并且心脏代谢疾病，并显示出显着较低的年龄调整死亡率和疾病调整死亡率。鉴于肥胖和心脏代谢疾病的发病率不断增加，以及这些疾病对人的负面影响生活质量和医疗保健系统，有必要了解内在的分子机制有助于更高的适应度表型。尽管预测 CRF 具有高度遗传性，但目前尚不清楚特定基因的遗传如何促进与 CRF 相关的健康和长寿。为了研究 CRF 的遗传性，我们的实验室对高 (HCR) 和低 (HCR) 培育的大鼠进行了表征。 (LCR) CRF 通过世代选择性育种来适应，源自遗传异质性库存。 HCR 大鼠的表型与人类高 CRF 特征相似，包括瘦、长寿和表达增加与线粒体氧化磷酸化、脂肪酸 (FA) 代谢和支链相关的基因骨骼肌中的氨基酸（BCAA）代谢。遗传和表型异质性是保守的通过轮换育种，在 HCR 和 LCR 品系中，基因和可以研究表型。骨骼肌中最高度且持续上调的基因之一 HCR 大鼠是 ACADSB，一种 BCAA 和短链 FA 分解代谢酶，其关键最终代谢产物是丙酸盐。未发表的基因分型研究已确定具有统计显着性的 QTL 和 eQTL 关联 ACADSB 附近的等位基因变异。我们假设 ACADSB 调节相关基因的表达氧化代谢和降低疾病风险部分是通过增加丙酸盐（一种 HDAC-）的生成来实现的。抑制剂，存在于骨骼肌中。具体来说，HCR 大鼠更高程度地表达 ACADSB 的较短剪接变体，提出这样的问题：HCR 相关亚型或 ACADSB 总浓度是否可能导致基因表达差异。我的项目将通过 (1) 过度表达 LCR 和 HCR 来测试这个假设 - HCR 和 LCR 大鼠骨骼肌中 ACADSB 的相关剪接变异，评估整体通过RNA-Seq观察骨骼肌基因表达的变化，并观察代谢通量的变化通过 ACADSB，以及 (2) 向 HCR 和 LCR 大鼠补充丙酸盐以评估整体转录染色质组蛋白翻译后修饰的调节和变化。