Background/Purpose: Muscle weakness is a hallmark of autoimmune myositis. The mechanisms that contribute to muscle weakness are currently unknown. The observed ineffectiveness after immunomodulatory treatment suggests that the contribution of inflammatory cells to muscle weakness is likely limited. We propose that acquired deficits in ATP generating pathways within the muscle potentially contributes to muscle weakness. We hypothesize that innate immune cytokines such as type I interferon (IFN) affect mitochondria and ATP generation in myositis.

Methods: Primary muscle cells isolated from healthy control and dermatomyositis patient biopsies were subjected to type I IFN treatment. Basal oxygen consumption rate (OCR), spare respiratory capacity, proton leak, and ATP production were measured using the Seahorse XFe96 Analyzer. To assess the effect of type I IFN directly on the muscle we treated normal mice with AAV9-IFNβ under the muscle creatine kinase (MCK) promotor. Seven-week-old female C57/BL6 mice were either non-injected or injected with the AAV9-IFNβ1 vector (n=3-6/group). Daily body weight and grip strength measurement (GSM) were collected for 3 weeks. Mice then underwent a treadmill exhaustion protocol followed by in vivo torque prior to muscle and blood collection at euthanasia. Data was collected in a blinded fashion. Expression levels of IFN stimulated genes (ISG) (Mx1, IRF7, and ISG15) were measured from whole blood 3 weeks post AAV-injection.

Results: Treatment of the control myoblasts with IFNβ increased basal OCR, spare respiratory capacity, and ATP production. Treatment of DM muscle cells with IFNβ resulted in a slight increase in basal OCR, but no effects were observed in spare respiratory capacity and proton leak. However, ATP production remained high. This suggests that spare respiratory capacity is blunted in DM cells compared to control muscle cells. AAV9-IFNβ1 administration in normal female mice resulted in significantly increased fold expression of Mx1, IRF7 and ISG15, by 8.3, 7.1, and 4.2-fold, respectively. Furthermore, AAV9-IFNβ1 administration impaired various measures of muscle function as evidenced by decreased muscle strength (GSM), force (in vivo torque), and increased exhaustion (treadmill). Body weight gain was also lower throughout the experiment in AAV9-IFNβ1-injected females compared to controls.

Conclusion: Overall, these results suggest that type I IFN treatment in muscle cells increases fatty acid oxidation and oxidation phosphorylation pathways affecting de novo cholesterol and fatty acid synthesis. Together, these in vitro data suggest that type I IFN affects mitochondrial spare respiratory capacity of DM cells more profoundly than controls. Expression of type I IFN in skeletal muscle significantly worsens muscle weakness.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effect-of-type-i-ifn-on-mitochondria-and-muscle-weakness-in-myositis/