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 (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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
MedImmune, LLC, Gaithersburg, Maryland.
Robert W
RW
Georgantas
Katie
K
Streicher
Steven A
SA
Greenberg
Lydia M
LM
Greenlees
Wei
W
Zhu
Philip Z
PZ
Brohawn
Brandon W
BW
Higgs
Meggan
M
Czapiga
Christopher A
CA
Morehouse
Anthony
A
Amato
Laura
L
Richman
Bahija
B
Jallal
Yihong
Y
Yao
Koustubh
K
Ranade
D000328:Adult; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology; D009220:Myositis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism
D016207:Cytokines; C544547:MIRN1 microRNA, human; C548234:MIRN133 microRNA, human; C546087:MIRN206 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B