Inhibition of Myogenic MicroRNAs 1, 133, and 206 by Inflammatory Cytokines Links Inflammation and Muscle Degeneration in Adult Inflammatory Myopathies
ABSTRACT The molecular basis of inflammatory myopathies such as dermatomyositis (DM), polymyositis, and inclusion body myositis, which share the characteristics of chronic muscle inflammation and skeletal muscle wasting, are poorly understood. As such, effective targeted treatments for these diseases are lacking, resulting in critical unmet medical needs for these devastating diseases. The purpose of this study was to identify possible new targets for drug development by exploring the mechanism by which inflammation may play a role in the pathology of the inflammatory myopathies.
We compared expression levels of inflammatory cytokines and microRNAs (miRNAs) between muscle biopsy samples from patients with inflammatory myopathies and those from donors without myositis. In vitro human and mouse model systems were then used to characterize the role of these cytokines and microRNAs on myoblast-to-myocyte differentiation.
We observed increased expression of inflammatory cytokines, including tumor necrosis factor α (TNFα), interferon-α (IFNα), IFNβ, and interleukin-1β, in different subtypes of inflammatory myopathies. We observed decreased expression of microRNA-1 (miR-1), miR-133a, and miR-133b in all of the inflammatory myopathy subtypes we evaluated, as well as decreased expression of miR-206 in DM; these miRNAs are essential for adult skeletal muscle differentiation and maintenance. TNFα was significantly inversely correlated with decreased myogenic miRNA expression in the inflammatory myopathy subtypes. In mechanistic studies, TNFα inhibited the expression of myogenic miRNAs and suppressed the differentiation of C2C12 myoblasts to myocytes/myotubes in an NF-κB-dependent manner. This block in differentiation by TNFα was relieved by overexpression of miR-1, miR-206, or miR-133a/b.
Taken together, these results provide a new mechanistic link between the action of proinflammatory cytokines and the degenerative pathology of inflammatory myopathies, and suggest therapeutic approaches for these diseases.
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ABSTRACT: MicroRNAs (miRNAs) are non-coding RNAs that can regulate the expression of mRNAs and proteins by degrading mRNA molecules or by inhibiting their translation. It has been predicted that miRNAs regulate approximately 60% of protein-coding genes that could be involved in a wide range of biological processes. Research over the last 5 years suggests that miRNAs play important roles in skeletal muscle function and several miRNAs have been identified as modulators of myogenesis, muscle mass, and nutrient metabolism in physiological and pathological states. In addition, some miRNAs can be incorporated into intracellular vesicles, released into the circulation, transported to other cells, and possibly function in other organs in an endocrine manner. This phenomenon might explain the interactions between skeletal muscles and other organs. Thus, far, several muscle-secreted miRNAs have been identified and their involvement in muscle biology has been debated. Based on the recent understanding, this perspective article describes the potential valuable role of miRNAs in skeletal muscle function, delineates its limitations, and outlines its future perspectives.Frontiers in Physiology 01/2014; 5:495. DOI:10.3389/fphys.2014.00495
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ABSTRACT: The molecular mechanisms underlying the muscle atrophy of intensive care unit-acquired weakness (ICUAW) are poorly understood. We hypothesised that increased circulating and muscle growth and differentiation factor-15 (GDF-15) causes atrophy in ICUAW by changing expression of key microRNAs. To investigate GDF-15 and microRNA expression in patients with ICUAW and to elucidate possible mechanisms by which they cause muscle atrophy in vivo and in vitro. In an observational study, 20 patients with ICUAW and seven elective surgical patients (controls) underwent rectus femoris muscle biopsy and blood sampling. mRNA and microRNA expression of target genes were examined in muscle specimens and GDF-15 protein concentration quantified in plasma. The effects of GDF-15 on C2C12 myotubes in vitro were examined. Compared with controls, GDF-15 protein was elevated in plasma (median 7239 vs 2454 pg/mL, p=0.001) and GDF-15 mRNA in the muscle (median twofold increase p=0.006) of patients with ICUAW. The expression of microRNAs involved in muscle homeostasis was significantly lower in the muscle of patients with ICUAW. GDF-15 treatment of C2C12 myotubes significantly elevated expression of muscle atrophy-related genes and down-regulated the expression of muscle microRNAs. miR-181a suppressed transforming growth factor-β (TGF-β) responses in C2C12 cells, suggesting increased sensitivity to TGF-β in ICUAW muscle. Consistent with this suggestion, nuclear phospho-small mothers against decapentaplegic (SMAD) 2/3 was increased in ICUAW muscle. GDF-15 may increase sensitivity to TGF-β signalling by suppressing the expression of muscle microRNAs, thereby promoting muscle atrophy in ICUAW. This study identifies both GDF-15 and associated microRNA as potential therapeutic targets. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.Thorax 12/2014; 70(3). DOI:10.1136/thoraxjnl-2014-206225 · 8.56 Impact Factor
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ABSTRACT: Sporadic inclusion body myositis (IBM) is an acquired muscle disorder associated with ageing, for which there is no effective treatment. Ongoing developments include: genetic studies that may provide insights regarding the pathogenesis of IBM, improved histopathological markers, the description of a new IBM autoantibody, scrutiny of the diagnostic utility of clinical features and biomarkers, the refinement of diagnostic criteria, the emerging use of MRI as a diagnostic and monitoring tool, and new pathogenic insights that have led to novel therapeutic approaches being trialled for IBM, including treatments with the objective of restoring protein homeostasis and myostatin blockers. The effect of exercise in IBM continues to be investigated. However, despite these ongoing developments, the aetiopathogenesis of IBM remains uncertain. A translational and multidisciplinary collaborative approach is critical to improve the diagnosis, treatment, and care of patients with IBM.Current Rheumatology Reports 12/2014; 16(12):477. DOI:10.1007/s11926-014-0477-9 · 2.45 Impact Factor