CHOP/ERO1A pathway of Unfolded Protein Response in RYR1 and SEPN1-Related myopathies

RYR1 and SEPN1 are proteins involved in calcium homeostasis of the endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR). Genetic mutations in RYR1 and SEPN1 impair their respective activity, leading to neuromuscular disorders known as RYR1 and SEPN1-related myopathies (-RM), which, due to their low incidence in the population, are classified as rare diseases. An incomplete understanding of their molecular mechanisms and the absence of biomarkers have limited the development of any effective treatment. The overlap in clinical signs and histological features between SEPN1 and RYR1-RM suggests a potential common underlying pathological mechanism. Previous studies have demonstrated the involvement of ER stress and Unfolded Protein Response (UPR) in these myopathies. Here, I proceeded with a genomic and a pharmacological approach to better understand the involvement of ER stress/UPR branches in the pathogenesis of these two diseases and identify potential new targets for therapy. I crossed a mouse model carrying the RYR1 I4895T mutation, the homologous mutation of one of the most common RYR1 mutations in humans, with a mouse model deleted for the gene encoding for the pro-apoptotic factor CHOP. RYR1I4895T mice showed increased ER stress and UPR and, even if CHOP deletion attenuated these conditions in skeletal muscles, protecting from apoptosis, it did not rescue the receptor function nor the perinatal lethality. Furthermore, I crossed a SEPN1 knock-out mouse model with a mouse model devoid of ERO1. ER stress and UPR markers were significantly decreased in double knock-out mice, and muscle function was rescued. To tackle the suitability of pharmacological treatment in SEPN1 knock-out mice, I tried TUDCA, a pan-ER stress inhibitor. TUDCA was beneficial in SEPN1 knock-out muscles, mirroring the effects of ERO1 loss. These findings in mouse models of RYR1-RM and SEPN1-RM identify ER stress and UPR as important disease pathways and pave the way for treatment.