Background/Purpose: The Idiopathic Inflammatory Myopathies (IIM) is a heterogeneous group of acquired autoimmune disorders, characterised by symmetrical muscle weakness. Whilst immune cells clearly play a role in muscle weakness induction in IIM, the correlation between inflammatory cell loads and the degree of muscle weakness is poor, while muscle weakness is detectable prior to inflammatory cell infiltrations. It is thus accepted that non-immune mechanisms, such as ER stress induction, are also key contributors to muscle weakness induction in IIM (Lightfoot et al. 2015). However, the mechanisms which regulate ER stress pathway activation here are poorly understood. MicroRNAs are short, non-coding RNAs whose primary role is to post-transcriptionally regulate gene expression. MicroRNAs have been described to regulate a plethora of biological processes, and dysregulation of microRNA expression has been reported in several diseases (Goljanek-Whysall et al. 2012). A study examining various myopathies reported that the expression of multiple microRNAs was dysregulated (Eisenberg et al. 2007). More recently a study examining miRNA expression in the muscle of PM, DM and IBM patients identified that expression of micro-RNA 133a was significantly downregulated in all subtypes of IIM (Georgantas et al. 2007). However, the mechanistic implication of microRNA regulation in the context of IIM remains unelucidated. Micro-RNA 133a is a muscle-specific microRNA, or “myomiR” and is predicted to regulate several genes associated with ER stress pathways. We hypothesise that, given the importance of ER stress pathway activation in IIM and the dysregulation of miR-133a in the muscle of IIM patients, microRNAs may play an important pathogenic role in IIM. Specifically, miR-133a may contribute to chronic ER stress pathway activation here, and thus represent a potential future therapeutic target to minimise non-immune cell mediated muscle weakness. Methods: C57Bl6 mice (6-10 months) were treated with a miR-133a mimic, a miR-133a inhibitor or a scrambled miR-133a control. The anterior tibialis was excised and RNA isolated and purified using standard TRizol extraction. qPCR and SDS-PAGE was used to examine changes in miR-133a and ER stress pathway gene expressions. C2C12 myotubes overexpressing MHC I was used as an experimental model of ER stress pathway activation to validate our miR-133a findings. Results: Our data demonstrate that downregulation of a muscle specific microRNA, i.e miR-133a, resulted in the activation of a specific arm of the ER stress pathway, as demonstrated by upregulation of expression of the ER stress receptor IRE1, and activation of the downstream transcription factor X-box binding protein 1 (XBP-1). Additionally, inhibition of miR-133a resulted in downregulation of the ER stress chaperone Grp78. Conclusion: These data suggest that miR-133a may be a key regulator of ER stress pathway activation in skeletal muscle, and which may have implications in the chronic ER stress pathway activation demonstrable in IIM patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/investigating-the-pathogenic-role-of-er-stress-pathways-in-the-idiopathic-inflammatory-myopathies-iim-interrogating-the-role-of-micro-rna-133a-as-an-important-regulator-of-er-stress-activation/