Introduction: DNA damage accumulation is a classical hallmark of ageing often culminating in replicative senescence. In cells such as cardiac myocytes, which do not replicate, downstream mechanisms resulting in functional decline are less well understood. The stochastic model of DNA damage accumulation states that long genes are more susceptible to DNA damage induced lesions than shorter genes. Dystrophin is large structural protein encoded by one of the longest genes in the genome, DMD. Loss of function mutations result in profound skeletal and cardiac muscle disease and age-related reductions in protein have been observed. Therefore, we hypothesised that DNA damage would confer a loss of dystrophin in cardiac muscle. 

Methods: In line with local regulations regarding the use of animals in research we dissected cardiac tissues from 3 male and 3 female 17-week old Ercc1Δ/- mice, a well-established model to investigate the pathophysiological effects of DNA damage in vivo. We used an antibody directed to the C-terminus of the dystrophin protein to perform Western blotting on these tissues and compared abundance with a panel of proteins from cardiac genes of short and medium lengths known to play an important role in cardiac physiology and health.  

Results: We discovered that Ercc1Δ/- mouse hearts exhibited a substantial decline in protein abundance of the 427kDa isoform of dystrophin in both male and females when compared with wildtype littermate controls (P<0.05, Mann-Whitney U test). Modest reductions were also observed in proteins of cardiac genes, these however, were not found to be statistically significant. 

Conclusion: Our preliminary investigation supports the hypothesis that dystrophin abundance is highly susceptible to DNA damage. Future research will seek to understand the precise DNA/RNA signatures leading to dystrophin deficiency, how these can be measured in humans and how important this mechanism is to functional outcomes in ageing.