Quadriceps miR-542-3p and -5p are elevated in COPD and reduce function by inhibiting ribosomal and protein synthesis.

Roser Farre-Garros,Michael I Polkey,Paul R Kemp,Martin Connolly,Cyrus Cooper,Avan A Sayer,S Amanda Natanek,Jen Y Lee,Harnish Patel

doi:10.1152/japplphysiol.00882.2018

Abstract

Reduced physical performance reduces quality of life in patients with chronic obstructive pulmonary disease (COPD). Impaired physical performance is, in part, a consequence of reduced muscle mass and function, which is accompanied by mitochondrial dysfunction. We recently showed that miR-542-3p and miR-542-5p were elevated in a small cohort of COPD patients and more markedly in critical care patients. In mice, these microRNAs (miRNAs) promoted mitochondrial dysfunction suggesting that they would affect physical performance in patients with COPD, but we did not explore the association of these miRNAs with disease severity or physical performance further. We therefore quantified miR-542-3p/5p and mitochondrial rRNA expression in RNA extracted from quadriceps muscle of patients with COPD and determined their association with physical performance. As miR-542-3p inhibits ribosomal protein synthesis its ability to inhibit protein synthesis was also determined in vitro. Both miR-542-3p expression and -5p expression were elevated in patients with COPD (5-fold P < 0.001) and the degree of elevation associated with impaired lung function (transfer capacity of the lung for CO in % and forced expiratory volume in 1 s in %) and physical performance (6-min walk distance in %). In COPD patients, the ratio of 12S rRNA to 16S rRNA was suppressed suggesting mitochondrial ribosomal stress and mitochondrial dysfunction and miR-542-3p/5p expression was inversely associated with mitochondrial gene expression and positively associated with p53 activity. miR-542-3p suppressed RPS23 expression and maximal protein synthesis in vitro. Our data show that miR-542-3p and -5p expression is elevated in COPD patients and may suppress physical performance at least in part by inhibiting mitochondrial and cytoplasmic ribosome synthesis and suppressing protein synthesis.NEW & NOTEWORTHY miR-542-3p and -5p are elevated in the quadriceps muscle of patients with chronic obstructive pulmonary disease (COPD) in proportion to the severity of their lung disease. These microRNAs inhibit mitochondrial and cytoplasmic protein synthesis suggesting that they contribute to impaired exercise performance in COPD.

Highlights

A reduction in muscle mass and strength occurs both in response to chronic disease and as part of normal human aging [9], and loss of muscle function reduces quality of life by limiting ability to perform normal daily tasks and is associated with increased mortality [7, 36]
We recently showed that the microRNA miR-542-3p inhibited the expression of mitochondrial ribosomal proteins, reduced mitochondrial rRNA in particular the 12S rRNA leading to a reduction in the 12S:16S mitochondrial rRNA ratio, and reduced mitochondrial membrane potential [11]
The data presented here show that increased expression of miR-542-3p and miR-542-5p is associated with muscle dysfunction in chronic obstructive pulmonary disease (COPD) patients

Summary

Introduction

A reduction in muscle mass and strength occurs both in response to chronic disease and as part of normal human aging [9], and loss of muscle function reduces quality of life by limiting ability to perform normal daily tasks and is associated with increased mortality [7, 36]. One chronic disease for which skeletal muscle wasting is a common comorbidity is chronic obstructive pulmonary disease (COPD) [19], and in this condition, wasting and reduced muscle function are associated with poorer quality of life and increased mortality [8, 35]. In COPD patients, there is a reduction in both muscle mass [33] and mitochondrial oxidative capacity [13, 20]. The loss of muscle mass arises from an imbalance in protein turnover with a relative increase in protein breakdown compared with protein synthesis, and diverse studies have reported changes in components of both degradative and synthetic pathways, but, taken together, these data do not convey a consistent conclusion suggesting that there are multiple factors that regulate mass [15]

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