National Heart & Lung Institute, Imperial College London
Doi
Abstract
Loss of skeletal muscle mass and function is a common co-morbidity of a number of
chronic diseases including chronic obstructive pulmonary disease (COPD) and a range
of critical illnesses as well as in ageing, affecting the quality of life of these individuals.
However, the mechanisms by which this occurs have not been completely elucidated.
Previous studies in the group identified changed in the levels of several microRNAs in
the quadriceps of COPD patients. We focused on the microRNAs that showed the
largest and most significant increased expression between patients and controls. One
of the elevated microRNAs was miR-542-3p, which was chosen after performing a
bioinformatics analysis and saw interesting predicted targets in the muscle wasting
context. MiR-542-3p was also found to be elevated in the quadriceps muscle of
sarcopenic patients. In this thesis, we aimed to determine if miR-542-5p was also
elevated in those two cohorts and if a similar pattern for miR-542-3p/-5p was seen in
critical illness such as patients with intensive care unit acquired weakness (ICUAW).
We also aimed to identify the molecular pathways by which these miRNAs contributed
to muscle impairment or dysfunction.
miR-542-3p/5p levels were found elevated in COPD and sarcopenic patients but more
markedly elevated in patients with ICUAW. In vitro, miR-542-3p decreased the
expression of mitochondrial (MRPS10) and cytoplasmic (RPS23) ribosomal proteins and
reduced 12S and 18S ribosomal RNA (rRNA) suggesting mitochondrial and cytoplasmic
ribosomal stress. miR-542-3p/-5p promoted the nuclear accumulation of phospho
SMAD2/3 and suppressed expression of SMURF1, SMAD7 and PPP2CA which are
inhibitors of the system, indicative of increased TGF-β signalling. In vivo, miR-542 over
expression caused muscle wasting in the targeted muscle, decreased mitochondrial
function, 12S rRNA and 18S rRNA levels and SMAD7 expression, consistent with the
effects of the miRNA in vitro. In patients with ICUAW similar results were observed, the
expression of 12S and 18S rRNA and SMURF1, SMAD7 and PPP2CA were reduced,
suggesting mitochondrial and cytoplasmic ribosomal stress and increased TGF-β
signalling.Open Acces
