Novel microRNA regulation of skeletal and cardiac muscle mass in chronic disease

Skeletal muscle is a major tissue in the body, and, as a consequence of chronic illness or ageing, can be lost in a process known as wasting or atrophy. Muscle wasting individuals have a worse quality of life and increased mortality. The molecular mechanisms responsible for the reduction in mass are not well understood. MicroRNAs (miRNAs) are small non-coding RNAs that reduce mRNA half-life and translation. Previous work by the group identified miR-424-5p and miR-1-5p as being up-regulated and down-regulated, respectively, in a cohort of patients with chronic obstructive pulmonary disease (COPD). In this thesis, the expression of miR-424-5p was determined in cohorts of individuals who are sarcopenic and those with intensive care unit-acquired weakness (ICUAW), and found to be up-regulated compared to controls. miR-424-5p associated negatively with measures of disease severity in all cohorts, and muscle mass and function in COPD. In vitro studies revealed miR-424-5p inhibited the expression of components required to transcribe ribosomal RNA (rRNA), and reduced maximal translational capacity. Targeting of insulin-like growth factor 1 (IGF-1) by miR-424-5p was also confirmed. In vivo, overexpression of this miRNA caused atrophy in tibialis anterior (TA) muscles of mice and downregulation of mature rRNAs, suggesting that miRNA induced ribosomal stress may contribute to the atrophy. miR-424-5p expression was down-regulated in the hypertrophied right ventricle (RV) of rats with pulmonary arterial hypertension (PAH), while IGF-1 protein and rRNA was up-regulated, suggesting targets of this miRNA may promote hypertrophy following miR-424-5p downregulation. Additionally, miR-1-5p was shown to target TGF-βR1 (alk5), and these components were down-regulated and up-regulated respectively in the RV of PAH rats, suggesting another mechanism of hypertrophy propagation. Together, these data present novel mechanisms through which skeletal and cardiac muscle mass may be regulated in chronic disease and ageing.