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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.

摘要