Journal Article

RYR1-Related Myopathies Involve More than Calcium Dysregulation: Insights from Transcriptomic Profiling

Romualdi, Chiara, Vedovelli, Luca, Szabadkai, Gyorgy, Vianello, Sara, Minervini, Giovanni, Sorarù, Gianni, Gorgoglione, Domenico, Pennuto, Maria, Sabbatini, Daniele, Fusto, Aurora, Pegoraro, Elena, Marchioretti, Caterina, Bello, Luca, Capece, Giuliana, Suman, Matteo

2025

Overview

Ryanodine receptor 1-related myopathies (RYR1-RM) are caused by RYR1 gene variants and comprise a wide spectrum of histopathological manifestations. Here, we focus on patients carrying RYR1 variants and muscle histopathology consistent with central core disease (CCD) or multi-minicore disease (MmD). RNA-sequencing analyses of skeletal muscle biopsies obtained from both CCD and MmD patients and from healthy controls were performed to better understand the molecular pathways activated by RYR1 variants. Our analyses revealed that, beyond the well-established role of RYR1 in calcium homeostasis, broader cellular pathways are implicated. In CCD, differentially expressed genes were enriched for pathways related to oxidative stress response, SMAD signalling, and apoptosis, consistent with the role of intracellular calcium dysregulation in promoting mitochondrial dysfunction and cell death. In contrast, MmD patients exhibited enrichment of pathways related to immune activation. This was corroborated by the upregulation of GTPase-regulating genes and the down-regulation of transcriptional repressors such as ZFP36 and ATN1. When considering all RYR1-RM patients collectively, Wnt signalling, immune-related pathways, and oxidative phosphorylation emerged as shared enriched pathways, indicating possible convergent mechanisms across histopathological phenotypes. Our study suggests that complex gene regulation driven by RYR1 variants may be a unifying feature in CCD and MmD, offering new insight into potential therapeutic targets.

• Publisher: MDPI AG
• Subject: Adult / Age groups / Amino acids / Apoptosis / Binomial distribution / Biopsy / Calcium (intracellular) / Calcium (mitochondrial) / Calcium - metabolism / Calcium homeostasis / CCD / Cell death / Cellular stress response / Central core disease / Congenital diseases / Down-regulation / Female / Gene Expression Profiling / Gene Expression Regulation / Gene regulation / Genes / Genetic transcription / Genomes / Homeostasis / Humans / Hypotheses / Immune response / Intracellular signalling / Male / Middle Aged / MmD / Muscle, Skeletal - metabolism / Muscle, Skeletal - pathology / Muscles / Muscular Diseases - genetics / Muscular Diseases - metabolism / Muscular Diseases - pathology / Musculoskeletal system / Myopathy, Central Core - genetics / Myopathy, Central Core - metabolism / Myopathy, Central Core - pathology / Oxidative phosphorylation / Oxidative stress / Pediatrics / Phenotypes / Phosphorylation / Proteins / Repressors / RNA / RNASeq / Ryanodine Receptor Calcium Release Channel - genetics / Ryanodine Receptor Calcium Release Channel - metabolism / Ryanodine receptors / RYR1 / RYR1-RM / Signal transduction / Skeletal muscle / skeletal muscle diseases / Therapeutic targets / Transcription factors / Transcriptome / Transcriptomics / Wnt protein