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Research to Date

How did our group become interested in Epigenetics and Muscle Memory?

During our early research, we devised two novel cellular models of skeletal muscle ageing (Sharples et al., 2010 J Cell PhysiolSharples et al., 2011 J Cell Biochem), which resulted in an ECR award (Sharples) for best oral stem cell communication at the prestigious Max Planck Institute, Berlin (2010). A novel aspect stemming from these works suggested aged muscle cells could ‘remember’ inflammatory environmental stimuli to which they were exposed in early proliferative life, a concept that we have recently defined as muscle ‘memory’ in the leading international journal Aging Cell, click for PDF.

Importantly, we were able to confirm this phenomenon, where we were the first to report a molecular mechanism for muscle ‘memory’ at the DNA level in a muscle cell model, showing aged muscle cells retained molecular ‘tags’ to their DNA (via DNA methylation) in later-life following early-life inflammatory stress. This publication (Sharples et al., 2015, Link) was the highest-scoring output from this source. Importantly, in 2016 this work resulted in a prestigious Doctoral Training Alliance UK, PhD scholarship  (R. Seaborne) and culminated in further grant success with pharma industry giant GlaxoSmithKline (GSK) to investigate the genome-wide epigenetics of muscle growth and memory in animals and humans.

At that time, in collaboration with Prof. Jarivs (LJMU) we also published a paper in international journal FASEB J (link) establishing novel epigenetic mechanisms of disuse atrophy (muscle wasting) and recovery in rodents using both transcriptomic and epigenetic analysis.

Overall, leading us to want to study epigenetics and muscle memory of both positive (exercise) and negative (disuse, inflammation, ageing) encounters.

Epigenetics and Muscle Memory of Exercise

Importantly, The Muscle Lab went on to publish a paper in Scientific Reports (Nature) (Click for PDF), identifying for the first time that human skeletal muscle possesses an epigenetic memory of previous exercise, and the discovery of novel epigenetically regulated genes across the methylome in human skeletal muscle growth.

Figure taken from Seaborne et al., Scientific Reports (Nature) DOI: 10.1038/s41598-018-20287-3

The Scientific Reports paper received international attention where the press release gathered 40,000 reads on the university webpage and was picked up by over 32 news outlets including; Science Daily, Yahoo News and Newsweek. IFLScience also published the story (25 million followers on Facebook) and it was the top story in Reddit on the day of the article (over 24,000 upvotes). The paper has now received over 1,699 tweets on social media from over 1299 different users, with an upper bound of almost 4 Million followers (Altmetric score of 1241) and has been featured on several radio, videos & podcast platforms. Including an article in the New Youk Times. The paper was the editor’s choice in epigenetics, also ranked 1st in all Cell/Molecular Biology articles (out of 664) and the 6th of ALL articles (out of 18,000) in 2018 in the Nature Journal, Scientific Reports. As a result they created a Nature video of the work on their YouTube channel DOI: 10.21203/rs.2.17320/v1, Link, that has been viewed almost 200K times on twitter. Finally, in Feb 2020 they Nature conducted an author interview with Sharples’s muscle lab to highlight how this study came to fruition (Nature website).

We also published a sister paper in Scientific Data (Nature- PDF) describing the detailed methods for the genome-wide DNA methylation analyses from human skeletal muscle after acute resistance exercise, training, detraining and retraining.

We have also extended this work to combine both transcriptome and epigenome analysis after human skeletal muscle anabolism, hypertrophy and epigenetic memory (Turner et al., Scientific Reports, 2019, PDF).

Furthermore, for Firdaus Maasar’s PhD studies in joint collaboration with Prof. Barry Drust (University of Birmingham) and international collaborators Prof Juleen Zierath and Dr. Nicolas Pillon (Karolinska Institute). We have undertake an integrative methylome and transcriptome approach to investigating the high intensity sprint exercise in human skeletal muscle (Maasar et al., 2021. Front Physiol). Overall, in this study we demonstrated that increased physiological load via change of direction sprint exercise in human skeletal muscle evokes considerable epigenetic modifications that are associated with changes in expression of genes responsible for adaptation to exercise (compared to straight line running exercise). In particular change of direction exercise evoked considerable hypomethylation in: Protein binding, MAPK, AMPK, insulin, and axon guidance pathways. Also enriched promoter hypomethylation in VEGF and NR4A1 canonical metabolic genes. These data imply that introducing changes in direction into high intensity running protocols could serve as an important modulator of a favourable epigenomic and transcriptomic landscape in response to exercise in athletes and trigger greater skeletal muscle adaptation through enhanced gene expression.

To read the most recent research in this area, check out our new book: Molecular Exercise Physiology: An Introduction (2nd edition) that includes an entire chapter on epigenetics, exercise and muscle memory  Link / Buy on Amazon.

Aging muscle, epigenetics and exercise

Our research team obtained grant funding (North Staffordshire Medical & Medical Research Council EPSRC/MRC) to investigate the epigenetics of muscle tissue and muscle stem cells in elderly patients. Publishing this work in Scientific Reports, identifying a role for physical activity and HOX gene methylation in aging muscle tissue and muscle derived stem cells (Turner et al., 2020, Scientific Reports). Following this work, in collaboration with Nir Eynon and Sarah Voisin we have published in the Journal of Cachexia Sarcopenia and Muscle  (IF. 10.7 Voisin et al., 2020) developing the first aging muscle tissue epigenetic clock. Also in in the area of aging in collaboration with Prof. Mike Roberts (Auburn University, USA) we were recently able to demonstrate that resistance exercise rejuvenates the mitochondrial methylome in aged humans (Ruple et al., FASEBJ).

To read relevant review papers/chapters in epigenetics of skeletal muscle aging see (link).

Current / Future Research Focus

1. Does Aged Skeletal Muscle have an Epigenetic Memory of  Muscle Wasting? 

We have now received (2021) a Research Council Norway (RCN) Grant for 9M NOK (1M USD) for a project entitled: Does human skeletal muscle possess an epigenetic memory of wasting? Targeting UBR5 as a therapy for muscle wasting with age. With the Primary objectives of the project: 1) We will discover if human skeletal muscle possesses an epigenetic memory of muscle wasting if muscle wasting is repeated. 2) We will test a muscle gene therapy (over-expression) targeting UBR5 during recovery from muscle wasting in aged animals, and assess if this protects the muscle from a second repeated muscle wasting encounter. This is with co-investigators  Prof. Jarvis and Dr. Owens (LJMU) and Prof. Sue Bodine and Dr. David Hughes (Iowa, USA) and Prof’s Truls Raastad and Olivier Seynnes (NIH, Norway). For more detail on UBR5 see directly below!

2. UBR5, A Novel Epigenetically Regulated E3 Ubiquitin Ligase in Skeletal Muscle Remodelling and Ageing. We have recently identified that an E3 Ubiquitin Ligase, called UBR5, previously unstudied in skeletal muscle, is epigenetically regulated (via DNA methylation) with altered gene expression after human skeletal muscle loading, unloading and reloading (Seaborne et al., 2018 Sci. Reps, PDF). We have now had a paper published characterising the role of UBR5 in skeletal muscle hypertrophy, atrophy and recovery from atrophy in The Journal of Physiology (PDF). We show that UBR5 is a novel E3 Ubiquitin Ligase important for skeletal muscle hypertrophy & recovery from atrophy after disuse and injury. Also, that it has opposite roles to other well known E3 Ubiquitin Ligases, MuRF1 and MAFbx! We use several in-vivo and in-vitro approaches in human, animals, bioengineered models and cells at the genetic, DNA methylation, gene expression and protein level to characterise this newly identified ligase in the regulation of skeletal muscle mass. Check it out! PDF. We have now gone on to knock-down UBR5 in mouse muscle tissue in-vivo that causes atrophy and reduces protein synthetic/mechanotransduction cell signalling (Hughes et al., 2021, AJP – Cell Physiology). Confirming that sufficient UBR5 levels are required for maintaining muscle mass. It is important to say that to enable this UBR5 work to be produced we collaborated across international centres with Prof. Sue Bodine, Dr. David Hughes and Dr. Leslie Baehr (Iowa, USA), Prof. Jonathan Jarvis, Dr. Owens, Dr. Illdus Ahmetov (LJMU, UK) and Dr. Robert Seaborne (QMUL, UK), without whom the papers would not have come to fruition!

Figure taken from Seaborne et al., 2019. J Physiol DOI: 10.1113/JP278073

Figure above. A: UBR5 is hypomethylated and gene turned ‘on’ after resistance training and detraining in humans. B: Acutely loaded bioengineered muscle loaded in a bioreactor (Bi) demonstrates increased UBR5 gene expression similar to after acute resistance exercise in humans (Bii). C: UBR5 gene expression increased after hypertrophy in rats after  4 weeks of intermittent high frequency electrical stimulation with reductions in DNA methylation (Ci), without increases in MuRF1 and MAFbx (Cii). D: UBR5 protein abundance rapidly  increased at 3, 7, and 14 days post synergistic ablation/functional overload (FO) induced hypertrophy in mice. E: Primary human muscle derived cells differentiating over 0, 72hrs and 7 days with increased MyoD, Myogenin and MYHC I & II as well as reductions in Myf5 gene expression (Eii), corresponded with UBR5 increasing at the protein levels at 72 hrs and 7 days of human cell differentiation (Eiii).

3. Myonuclei specific methylome in skeletal muscle with exercise. 

Max Ulrich (MSc thesis) – is currently investigating the myonuclei specific methylome in human skeletal muscle with exercise.

4. Epigenetic Memory of Anabolic Steroids

Chris André Sylstad (MSc thesis) – is currently undertaking repeated testosterone dosing in skeletal muscle cells to identify retention of epigenetic information from previous steroid encounters.