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Epigenetics & Muscle ‘Memory’

Research to Date

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 confirmed 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) in Biogerontology has had over almost 4000 downloads on researchgate/ the publisher’s website, where at the time it 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 (Illumina EPIC BeadChip arrays) of muscle growth and memory in animals and humans.

From these studies, in collaboration with Prof. Jarivs (LJMU) we have published a paper in international journal FASEB J (link) establishing novel epigenetic mechanisms in muscle wasting and recovery in rodents using both transcriptomic and epigenetic analysis (microarrays and pyrosequencing respectively). Importantly, The Muscle Lab has recently published 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 skeletal muscle growth.

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

This article received international attention where the paper released by our universities press office received 39,000 reads on the university webpage, was picked up by over 20 media/news outlets including; Science Daily, Yahoo News and Newsweek. The story was also published by IFLScience with 25 million followers on Facebook and was the top story in Reddit on the day of the article with over 24,000 upvotes. The paper has now received 849 tweets on social media from 654 different users, with an upper bound of 1,372,784 followers, and was featured on ABC radio in Australia.

We have also recently had a paper accepted 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. Furthermore, we have recently published a book chapter for international publisher Elsevier, entitled: Epigenetics of skeletal muscle aging (link). We have also just received another grant from North Staffordshire Medical Institute (NSMI), UK to investigate the epigenetics of sarcopenia and muscle disuse after falling injury and surgery in elderly patients. Finally, we are currently writing an invited book chapter for Elsevier that will be included in a series called ‘Epigenetics in Exercise Science’ in the book Sports, Exercise, and Nutritional Genomics. This should be published late 2018/early 2019, so stay tuned here for the link!

Current / Future Research Focus

1. A Novel Epigenetically Regulated E3 Ubiquitin Ligase in Skeletal Muscle Remodelling and Ageing. We have recently identified that an E3 Ubiquitin Ligase, 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). As part of our future research program we aim to further investigate the role of this E3 ligase in skeletal muscle atrophy, recovery from atrophy and hypertrophy with age. We currently have exciting new data suggesting that this novel ligase is important in remodelling muscle mass and decreased in aging muscle using animal, human and bioengineered skeletal muscle models. The lab is currently collaborating across international centres for these studies with Prof. Jarvis (LJMU, UK), Prof. Sue Bodine, Dr. David Hughes and Dr. Leslie Baehr (Iowa, USA), Dr. Owens (LJMU, UK) and Dr. Robert Seaborne (QMUL, UK).

The figure above, A: Demonstrates, in humans, that the identified E3 Ubiquitin Ligase is hypomethylated during loading (chronic resistance exercise) induced muscle hypertrophy where gene expression is also increased. During unloading (complete cessation of exercise) where muscle returns to baseline size (pre-exercise size) the ligase is hypermethylated and gene expression returns to baseline levels. Upon reloading (retraining induced hypertrophy) the gene is hypomethylated to the greatest extent and is associated with the largest increase in gene expression and lean muscle mass. B: After hypertrophy in rats, post chronic electrical stimulation, the E3 ligase is hypomethylated and gene expression increased. C: During TTX induced denervation of the peroneal nerve, evoking atrophy of the left hindlimb, the E3 ligase is hypomethylated and gene expression increased at 3 & 7 days and returns towards baseline at 14 days of atrophy. Hypomethylation is also maintained during recovery of muscle and the ligase’s gene expression is increased once more. We are currently undertaking analyses at the protein level and evoking muscle specific knock-down of the ligase during atrophy and recovery of muscle in collaboration with Prof. Sue Bodine, Dr. David Hughes and Dr. Leslie Baehr (Iowa, USA), and protein localisation studies with Dr. Daniel Owens (LJMU, UK).

2. Does Aged Skeletal Muscle have an Epigenetic Memory of Disuse Atrophy? Given that our work has now demonstrated that healthy adult human skeletal muscle has an epigenetic memory of muscle hypertrophy after earlier exercise. We wish to extend these findings and develop our exciting studies with Prof. Jarvis and Dr. Owens (LJMU), and undertake studies to investigate if aged skeletal muscle has an epigenetic memory of disuse atrophy.

3. Do Muscle Cells have an Memory of the Hypertrophic Niche? Role of Epigenetics: We also derived muscle cells from our recent human study and are looking to see if these cells retain a memory of the exercise trained niche from which they were derived. Then, we aim to investigate if these ‘previously trained cells’ respond more advantageously to hypertrophic factors once isolated in-vitro and the underlying epigenetics of this process. This work is in collaboration with Dr. Daniel Owens (LJMU) and Dr. Robert Seaborne (QMUL).

4. Andreas Kasper  is currently isolating cells from human anabolic steroid users/bodybuilders vs.  non-steriod using natural body builders and trying to identify if there is a memory of the in-vivo steriod environment once isolated in culture. The ultimate aim is to develop epigenetic tests can be used to identify steroid abuse in elite athletes. Both these studies are in collaboration with Professor Claire Stewart and Dr. Daniel Owens (LJMU, UK)