Inhibition of myogenic MicroRNAs-1, 133, and 206 by inflammatory cytokines links inflammation and muscle degeneration in adult inflammatory myopathies.

Objective: The molecular basis of inflammatory myopathies such as dermatomyositis, 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. In order to identify possible new targets for drug development, this study explored the mechanism by which inflammation may play a role in inflammatory myopathy pathology. Methods: We compared expression levels of inflammatory cytokines and microRNAs (miRs) between muscle biopsies from inflammatory myopathy patients and non-myositic muscle donors. In vitro human and mouse model systems where then used to characterize the role of these cytokines and miRs on myoblast-to-myocyte differentiation. Results: We observed increased expression of inflammatory cytokines including TNFα, IFNα, IFNβ, and IL1β in different subtypes of inflammatory myopathies. In all subtypes evaluated, we observed decreased expression of miRs miR-1, 133a, and 133b, as well as decreased miR-206 in DM; these miRs are essential for adult skeletal muscle differentiation and maintenance. TNFα was significantly inversely correlated with decreased myogenic miR expression in inflammatory myopathy subtypes. In mechanistic studies, TNFα inhibited expression of myogenic miRs and suppressed differentiation of C2C12 myoblasts to myocytes/myotubes in an NF-ĸB dependent manner. This block in differentiation by TNFα was relieved by overexpression of miR-1, miR-206, or miR-133a/b. Conclusions: Taken together, these results provide a new mechanistic link between pro-inflammatory cytokine action and the degenerative pathology of inflammatory myopathies, and suggest therapeutic approaches for these diseases. © 2013 American College of Rheumatology.