Background/Purpose: Dysregulation of the ER stress and interferon (IFN) pathways play a major role in the pathophysiology of autoimmune myositis. Upregulation of ER stress markers and type 1 IFN stimulated genes (an IFN ‘signature’) are present in myositis patients, and this IFN signature is related to disease activity. While the role of IFNα/β in myositis has been extensively studied, including clinical trials aimed at inhibiting type 1 IFN expression, the ER stress pathway—characterized by the accumulation of misfolded proteins and the activation of the unfolded protein response (UPR)—remains less explored. Therefore, we investigated the therapeutic efficacy of the ER stress inhibitor, 4-phenylbutyric acid (4PBA) in a myositis mouse model.

Methods: Myositis was induced in 21-day old female mice by removal of doxycycline from their water. Mice were randomized into 4 groups (n=10-17/group); Healthy controls (C57BL/6), myositis no treatment, myositis + 150 mg/kg 4PBA, and myositis + 300 mg/kg 4PBA. 4PBA was administered daily as a cherry syrup oral suspension at 150 mg/kg and 300 mg/kg body weight respectively for seven weeks. Treatment groups were evaluated based on survival time, body weight, muscle strength and function, and expression levels of ER stress markers CHOP, GADD34, Grp78, and Xbp1, and type 1 IFN stimulated genes (ISG) Ifit1, Irf7, Isg15, and Mx1.

Results: Untreated myositis mice had significantly reduced weight gain, muscle function and strength compared to BL/6 mice. 150 mg/kg 4PBA treatment resulted in an improvement in survival of myositis mice, with 76% surviving to the end of study compared to 59% and 63% for the untreated myositis and 300 mg/kg 4PBA treatment groups, respectively. Expression levels of the ER stress markers CHOP, GADD34, Grp78, and Xbp1, and type 1 IFN score, which were significantly elevated in untreated myositis mice, were noticeably decreased in skeletal muscle of 150 mg/kg 4PBA treated mice. However, significant increases in CHOP (p = 0.023) expression were observed in the higher dose treatment group compared to the untreated myositis group. Neither dose significantly improved muscle function.

Conclusion: Overall, we observed that treatment with 150 mg/kg 4PBA improved survival and showed a trend to lowering the ER stress and IFN signature, but this did not translate to functional improvement. Furthermore, 300 mg/kg did not improve any of the measures tested but instead increased the signature of selected markers. While the exact mechanisms for this dose-dependent effect are unknown, higher doses may lead to toxicity or off-target effects.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effect-of-er-stress-inhibition-with-4-phenylbutyric-acid-on-disease-phenotype-in-a-mouse-model-of-myositis/