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

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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 Unpublished genotyping studies have identified statistically significant QTL and eQTL associations of an allelic variant near ACADSB.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.