Effect of endurance exercise on microRNAs in myositis skeletal muscle-A randomized controlled study.

Jessica F Boehler,Matthew D Barberio,Marshall W Hogarth,Ingela Loell,Kanneboyina Nagaraju,James S Novak,Ingrid E Lundberg,Yi-Wen Chen,Li Alemo Munters,Kristy J Brown,Svetlana Ghimbovschi,Helene Alexanderson,Heather Gordish-Dressman,Elena Cavarretta

doi:10.1371/journal.pone.0183292

Abstract

ObjectiveTo identify changes in skeletal muscle microRNA expression after endurance exercise and associate the identified microRNAs with mRNA and protein expression to disease-specific pathways in polymyositis (PM) and dermatomyositis (DM) patients.MethodsFollowing a parallel clinical trial design, patients with probable PM or DM, exercising less than once a week, and on stable medication for at least one month were randomized into two groups at Karolinska University Hospital: a 12-week endurance exercise group (n = 12) or a non-exercised control group (n = 11). Using an Affymetrix microarray, microRNA expression was determined in paired muscle biopsies taken before and after the exercise intervention from 3 patients in each group. Ingenuity pathway analysis with a microRNA target filter was used to identify microRNA transcript targets. These targets were investigated at the mRNA (microarray) and protein (mass spectrometry) levels in patients.ResultsEndurance exercise altered 39 microRNAs. The microRNAs with increased expression were predicted to target transcripts involved in inflammatory processes, metabolism, and muscle atrophy. Further, these target transcripts had an associated decrease in mRNA expression in exercised patients. In particular, a decrease in the NF-κB regulator IKBKB was associated with an increase in its target microRNA (miR-196b). At the protein level, there was an increase in mitochondrial proteins (AK3, HIBADH), which were associated with a decrease in microRNAs that were predicted to regulate their expression.ConclusionImprovement in disease phenotype after exercise is associated with increasing microRNAs that target and downregulate immune processes at the transcript level, as well as decreasing microRNAs that target and upregulate mitochondrial content at the protein level. Therefore, microRNAs may improve disease by decreasing immune responses and increasing mitochondrial biogenesis.Trial registrationClinicalTrials.gov NCT01184625

Highlights

Inflammatory myopathies, collectively known as myositis, are a group of heterogeneous rheumatic disorders characterized by chronic muscle weakness and fatigue [1, 2]
The microRNAs with increased expression were predicted to target transcripts involved in inflammatory processes, metabolism, and muscle atrophy. These target transcripts had an associated decrease in mRNA expression in exercised patients
The pathology is characterized by extensive inflammation and includes signs of skeletal muscle damage such as central nucleation, variation in fiber size, fibrosis, and fiber atrophy

Summary

Introduction

Inflammatory myopathies, collectively known as myositis, are a group of heterogeneous rheumatic disorders characterized by chronic muscle weakness and fatigue [1, 2]. Its underlying cause is currently unknown, myositis is thought to be autoimmune in origin, given the presence of autoantibodies in more than 50% of patients [3]. Since these disorders involve both muscle and immune responses, anti-inflammatory and immunosuppressive drugs are currently used for treatment. Glucocorticoids are an effective treatment because they target both the muscles and the immune system [4] They have substantial side effects, such as muscle fiber atrophy, that can lead to further muscle damage when taken in large doses or for extended periods of time [5]

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