Oxidised microRNAs: novel regulators of muscle wasting

Katarzyna Goljanek-Whysall, Raul Gonzalez-Ojeda, Gibran Pedraza-Vazquez, Brian McDonagh
& Physiology, Human Biology Building 3031, School of Medicine, University of Galway, University Road, Galway, Ireland

There is currently a disproportionate increase in age-related health issues, with one of the major problems being the age-related loss of muscle mass and function – sarcopenia. Redox and epigenetic factors are key regulatory pathways associated with ageing. MicroRNAs, stable RNAs with half-life >24h, regulate muscle homeostasis posttranscriptionally. Oxidative modification of microRNAs could result in the regulation of non-native targets. Redox balance is disrupted during ageing and the accumulation of oxidised, most likely pathogenic, microRNAs in muscle leads to their disrupted specificity for regulating protein content.
We have validated microRNAs/mRNAs/proteins networks affected by ageing in muscle and have shown that modifying microRNA expression improves muscle function, but there is currently no research into the function of oxidised microRNAs in ageing. Integrating omics and functional approaches, we have demonstrated oxidised microRNAs enriched in muscle of older people. Moreover, we have shown that microRNAs oxidised in muscle of mice and humans during ageing and disease regulate muscle mass and function. Using omics approaches, we demonstrated a shift in target regulation of oxidised microRNAs. Finally, our data show that inhibiting oxidised miR-378 in old mice positively affects myofibre size and muscle strength.