Does skeletal muscle have an epigenetic memory?

Recently, a group of researchers from the United Kingdom undertook a study aimed at the  identification of  possible epigenetic memory in skeletal muscle by hypertrophy [1].

Their aim was to know how the muscle was influenced by induced environmental stimuli.  They also studied how muscle hypetrophy influenced gene expression to get more information or details in the hope of identification useful therapies to improve the quality of life in situations where muscular regression is present such as senescence [2],  injuries, and pathologies. To this end the researchers subjected a group of male individuals to a period of experimentation by monitoring the muscular conditions  on three phases :   an initial period of resistance training, followed by a period of absolute rest, followed by a second training period. Then    the y measured the presence of an epigenetic memory induced by muscle hypertrophy. What is epigenetic memory? How much and how is it going to be useful for future generations to have a control on it?

Epigenetic memory means the ability of the tissue to respond differently to environmental stimuli, in an adaptive or maladaptive way. It has been clear for many years  that there is an epigenetic memory,  which  is influenced by the surrounding environment and it can stimulate a positive gene expression (muscle growth and healthy maintenance for life) or negative (loss muscle in old age). The starting point of the British researchers was based on the scientific evidence showing the consequences of a previous exposure to negative environmental stimuli and a consequent epigenetic response modification, which has been “remembered” over time. One of the most influential modifications in epigenetic regulation is the methylation of particular CpG DNA sites; through the methylation or demethylation of these areas it is possible, respectively, to induce expression or repression of the genes closed into these. To confirm this evidence, there are several studies, including the one carried out on individuals born in the period of the Dutch famine of 1943. These individuals showed various pathologies arised from malnutrition in the prenatal period including cardiovascular diseases, hypertension, obesity, raised lipids and reduced glucose tolerance in adult life. Subsequent analysis of the CpG sites of these individuals has been noted an excessive methylation of DNA, which has led to a correlation with the occurrence of these  [3]. Further examples of studies, performed on mice, showed how a status of reduced caloric intake in the nutrition of mothers, led to a reduction in the number of muscle fibers in the progeny, correlated to a high methylation of CpG sites[4]. Therefore, if these hypermethylations are related with negative environmental events, the research group assumed that positive environmental events could induce hypomethylation. In particular, the researchers decided to undertake studies to verify this hypothesis, starting from the study about human skeletal muscle. The experiment, which involved the participation of 8 male individuals, consisted on submitting them to 7 weeks of intense muscular effort, followed by 7 weeks of absolute rest to conclude with other 7 weeks of muscle reloading, all preceded by a week of familiarization with the exercises. From the analysis of the samples of muscle tissue, obtained through biopsies carried out immediately after the end of each of the 7 weeks, the researchers obtained results, highlighting particular gene clusters that showed interesting activities following the activity carried out during the experimentation. In particular, two clusters, named as CLUSTER A and CLUSTER B, showed methylations of the respective CpG sites correlated with what we define as epigenetic memory. Cluster A was hypomethylated, compared to baseline, after the loading phase, which corresponds to an increase in gene expression; it was re-methylated during the rest period where has been noticed a decrease in gene expression and finally it was hypomethylated after reloading with consequent gene overexpression. Cluster B also showed a higher hypomethyl status in the first 500 CpG sites than other ones as a consequence of load-induced hypertrophy. As in the case of Cluster A, Cluster B genes were methylated at baseline and have become hypomethylated after initial loading. Unlike Cluster A, Cluster B remained hypomethylated with the discharge, even when the muscle returned to baseline levels, and this hypomethylation was recalled after the induced hypertrophy by recharging (Figure 2).