The role of DNA methylation in the regulation of skeletal muscle atrophy, hypertrophy and epigenetic 'memory'

Skeletal muscle mass is vitally important for the maintenance of health and quality of life into old age, with a plethora of disorders and diseases linked to the loss of this tissue. As a consequence, molecular biologists have extensively investigated both atrophying and hypertrophying skeletal muscle, in order to understand the molecular pathways that are induced to evoke both loss and growth of skeletal muscle. Despite huge progressions in the field, a full understanding of the molecular mechanisms that orchestrate growth and loss in skeletal muscle, remain elusive. In this regard, epigenetics, referring to alterations in gene expression via structural modifications of DNA without fundamental alterations of the DNA code, have recently become a promising area of research, specifically for its role in modulating genetic expression. However, the field of skeletal muscle epigenetics is in its infancy, and as such, there is currently a distinct paucity of research investigating this biological phenomenon. Herein, a genomic approach was utilised to examine the role DNA methylation plays in modulating the response, at both a genetic and phenotypic level, of mammalian skeletal muscle. The methodological and analytical approaches utilised in this thesis identify a number of important, novel and impactful findings. Firstly, it is identified that DNA methylation displays a distinct inverse relationship with gene expression during both muscular atrophy and hypertrophy, these findings are furthered by work identifying that DNA methylation alterations may precede functional changes in gene expression during skeletal muscle hypertrophy. This thesis also elucidated that skeletal muscle possesses an epigenetic memory that creates an enhanced adaptive response to resistance load induced hypertrophy, when the same stimulus was previously encountered. Finally, in human subjects, a number of novel and previously unstudied gene transcripts were identified that display significantly positive correlations with changes in skeletal muscle mass, as evoked by resistance training. The data in this thesis demonstrates an important role for DNA methylation in regulating skeletal muscle mass during periods of both muscle atrophy and hypertrophy, respectively. The work presented here may allow for further work to be conducted, expanding our understanding of epigenetics in skeletal muscle and best facilitating the development of therapeutics that may alleviate the detrimental effects observed during periods of skeletal muscle atrophy.