Different tissues have unique genome-organisation patterns that fine-tune gene expression, e.g. by enhancing gene silencing through nuclear envelope (NE)-association. However, tissues only achieve their optimal pattern in ~60-70% of cells. Nonetheless, these patterns are important as their disruption yields many disorders. Schirmer found mutations in muscle NE genome-organising proteins cause Emery-Dreifuss muscular dystrophy (EDMD) with metabolic genes strongly disrupted in patients while Galloway and Hall identified muscle metabolic changes in athletes, the elderly, and with exercise.

Hypothesis: Just as metabolic genome organisation is disrupted in EDMD patients, it may be further optimised in athletes. We propose that drugs targeting metabolic pathways disrupted in EDMD may improve muscle function in both muscular dystrophy and ageing. Moreover, metabolic changes during exercise might contribute epigenetic regulation to this nexus to further optimise muscle performance.

Aim1. Relate exercise metabolic changes to genome organisation

The student will compare Galloway/Hall-generated lists of metabolites/metabolic pathways altered during exercise to Schirmer-generated lists of metabolic genes under NE-genome regulation. Where correlations are observed, gene positioning will be determined in muscle from EDMD patients, healthy controls, and athletes before and after exercise using fluorescence-in-situ-hybridisation (FISH). As many NE-regulated genes undergo release and retention, we predict such genes will undergo rapid repositioning. As this should affect enhancer interactions, 4C will also be performed.

Aim2. Test metabolic drugs for improving muscle function

Our pilot data shows metabolic drug treatment of a tissue culture EDMD model yields improvement in myotube fusion, alignment, and nuclear distribution. Control myotubes also improve with this treatment. The student will test more drug combinations/concentrations using tissue culture myogenesis assays, delivering quantitative data on myotube fusion/alignment, nuclear distribution/genome organisation (FISH), and metabolism (Seahorse metabolic analyser). Depending on the success of future funding applications the student might also test these in mice and/or patient/athlete biopsies.

Aim3. Do muscle metabolites alter the epigenetic landscape of metabolic genes?

Some muscle metabolites can be used in pathways adding epigenetic marks to genes. The student will perform ChIP on these genes will determine if changes occur in epigenetic marks in biopsy material and/or in vitro myogenesis assays using patient/athlete cells. Cells treated with metabolites upregulated in exercise will determine if they can change the epigenetic profile of metabolic genes.

Further reading: PMID:27264872, PMID:36282542, PMID:31862442, PMID:28655718, PMID:37253386, PMID:37987178, PMID:35466785, PMID:38908902, PMID:27200088, PMID:28424353, PMID:28214269