Intermittent exogenous ketosis during exercise and training: exploring the role of de novo angiogenesis and epigenetic regulation in muscular adaptation

We recently demonstrated intermittent exogenous ketosis (IEK) by oral ketone ester intake to stimulate angiogenesis during muscular overload. IEK also inhibited muscle deterioration in a mouse model of cancer cachexia. This project aims to investigate the role of angiogenesis and epigenetic modification in the effects of IEK on exercise-induced muscular remodeling. In vitro experiments involve incubation of myoblasts and endothelial cells with ketones. Furthermore, healthy volunteers undergo controlled exercise training and/or muscular unloading protocols to cause rapid muscular adaptation, in the absence or presence of IEK. Muscle and endothelial cells from the in vitro and in vivo experiments are analyzed by bulk RNAseq, targeted bisulfite sequencing, ChIP-qPCR, and ATACseq to assess the effect of ketones on gene expression, methylation, acetylation, and open chromatin. Targetted RNA- and ATAC-sequencing at single cell level is used to characterize the impact of ketones on regulation of muscular angiogenesis, and anabolic/catabolic pathways. We expect this project to improve the understanding of the role of ketones in muscular adaptation during catabolic stress.