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.
[Show abstract][Hide abstract] 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 · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A large body of evidence indicates modified expression of protein-coding genes in response to different kinds of physical activity. Recent years have exposed another level of regulation of cellular processes mediated by non-coding RNAs. MicroRNAs (miRNAs) are one of the largest families of non-coding RNAs. MiRNAs mediate post-transcriptional regulation of gene expression. The amount of data supporting the key role of miRNAs in the adaptation of the immune and other body systems to exercise steadily grows. MiRNAs change their expression profiles after exercise and seem to be involved in regulation of exercise-responsive genes in immune and other cell types. Here we discuss existing data and future directions in the field.
[Show abstract][Hide abstract] ABSTRACT: The idiopathic inflammatory myopathies are a heterogeneous group of disorders characterised by diffuse muscle weakness and inflammation. A common immunopathogenic mechanism is the cytokine driven infiltration of immune cells into the muscle tissue. Recent studies have dissected further the inflammatory cell types and associated cytokines involved in the immune-mediated myopathies and other chronic inflammatory and autoimmune disorders. In this review we outline the current knowledge of cytokine expression profiles and cellular sources in the major forms of inflammatory myopathy and detail the known mechanistic functions of these cytokines in the context of inflammatory myositis. Furthermore, we discuss how the application of this knowledge may lead to new therapeutic strategies for the treatment of the inflammatory myopathies, in particular for cases resistant to conventional forms of therapy.
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