RyR1 protein content is reduced in inflammatory and mitochondrial myopathies and induces ER stress

Abstract

AbstractDecreased ryanodine receptor type 1 (RyR1) protein is a hallmark of recessiveRYR1-related myopathies (RyR1-RM), which are caused by recessive mutations in theRYR1gene. It is not clear how the decrease in the RyR1 protein triggers muscular disorders. Furthermore, it is a hot topic whether a decrease in RyR1 protein levels can also occur during non-RYR1-related myopathies. In this study, we first show that reducedRYR1transcripts are associated with various human myopathies, and that RyR1 protein levels are significantly decreased in muscle samples analysed in inflammatory myopathies (IM) and mitochondrial myopathies (MM), both of which are non-RYR1-RM. Secondly, proteomic data show that exclusive depletion of RyR1 proteinin vitrorecapitulates the common altered molecular pathways observed during myopathies. RyR1 protein depletion impairs ER-mitochondria tethering and Ca2+transfer to mitochondria, decreases mitophagy genes and induces an accumulation of dysfunctional mitochondria. This phenomenon is also associated with altered lipid homeostasis with an increase in deleterious sphingolipid species. Finally, decreased RyR1 protein levels lead to an increase in the ER stress markers GRP78-Bip and CHOP in muscle cellin vitro, and in mouse and human muscles. Overall, our results indicate an important role of RyR1 protein depletion and ER stress in the pathogenesis of myopathies.