The role of microRNA and oxidised microRNA-133 in muscle wasting during ageing and cachexia

miRNAs are short non-coding RNAs that play a central role in post-transcriptional gene regulation. microRNAs have been shown to play important roles in muscle development and homeostasis in adulthood. We hypothesized that microRNAs are oxidised and become pathological in muscle during ageing and cachexia, and this oxidation can alter their function. The aim of this study was to evaluate the therapeutic potential miR-133 overexpression and or inhibition of oxidised miR-133 for muscle wasting through establishing changes in grip strength, muscle mass and fiber size in mice treated with miR-133 and or antagomir to oxidised miR-133. Our data show that miR-133 and oxidised miR-133 inhibitor restore grip strength and lead to increase in fibre diameter in aged mice. Moreover, in adult mice, oxidised miR-133 led to increased abundance of mitochondrial complexes I and II in adult mice, mitochondrial biogenesis- and ER stress-related genes. In old mice, miR-133 and oxidised miR-133 inhibitor led to decrease in abundance of mitochondrial complexes I and V and modified ER stress-associated genes. Oxidised miRNAs were associated with an increase of senescence markers mainly in adult mice. Downregulation of muscle atrophy protein markers was detected with following oxo-miR-133 inhibitor treatment in aged mice. In cancer cachexia animal model, inhibitor to oxidised miR-133 led to a decrease in tumor weight in male and female mice. Cachectic male and female mice treated with inhibitor to oxidised miR-133 showed changes in p21 senescence marker, mitochondrial porin VDAC and p62 autophagy marker and mitochondrial complex I. Together, these data for the first time show functional consequences of microRNA oxidation in muscle and warrant further investigation in miR-133 overexpression and oxidised miR-133 inhibition therapeutic potential for caxechia and sarcopenia.