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Central Core Disease (CCD) is a congenital myopathy predominantly caused by mutations in the gene encoding ryanodine receptor type-1 (RYR1), the intracellular Ca release channel embedded in the skeletal muscle sarcoplasmic reticulum membrane. The I4898T mutation represents one of the most common RYR1 mutations associated with CCD. Unfortunately, there are no approved therapies for CCD or for other myopathies caused by mutations in this gene. This study aims to perform a top-down differential proteomic analysis on soleus muscle samples from wild-type mice (WT) and heterozygous knock-in mice carrying the I4895T (IT) mutation in RyR1, to investigate the pathogenic mechanisms and molecular pathways involved in this myopathy and to shed light on new potential biomarkers useful for future therapies. Proteomic analysis revealed 50 dysregulated protein species, and multivariate analysis showed that IT mice exhibit a distinct proteomic signature compared to WT mice, characterized by alterations in proteins associated with contractile and structural dysfunction, metabolism, and stress response. In particular, a significant increase in myosin fragments was observed in IT mice, likely due to muscle breakdown. In contrast, myotilin was downregulated, suggesting a weakening of the muscle cytoskeletal structure. There was a notable downregulation of proteins involved in glycolysis and the TCA cycle; conversely, there was an increase in proteins related to anaerobic glycolysis, suggesting a shift from aerobic to anaerobic glycolysis. Furthermore, proteins involved in fatty acid beta-oxidation and oxidative phosphorylation were also found to be upregulated in IT mice, indicating an attempt by the muscle to maximize energy production. Finally, we found a significant decrease in PGC1α, which could serve as potential therapy target and biomarker in CCD.

Ryanodine receptor type 1-related myopathies (RYR1-RM) are the most common class of congenital myopathies. Historically, RYR1-RM classification and diagnosis have been guided by histopathologic findings on muscle biopsy. Main histological subtypes of RYR1-RM include central core disease, multiminicore disease, core–rod myopathy, centronuclear myopathy, and congenital fiber-type disproportion. A range of RYR1-RM clinical phenotypes has also emerged more recently and includes King Denborough syndrome, RYR1 rhabdomyolysis-myalgia syndrome, atypical periodic paralysis, congenital neuromuscular disease with uniform type 1 fibers, and late-onset axial myopathy. This expansion of the RYR1-RM disease spectrum is due, in part, to implementation of next-generation sequencing methods, which include the entire RYR1 coding sequence rather than being restricted to hotspot regions. These methods enhance diagnostic capabilities, especially given historic limitations of histopathologic and clinical overlap across RYR1-RM. Both dominant and recessive modes of inheritance have been documented, with the latter typically associated with a more severe clinical phenotype. As with all congenital myopathies, no FDA-approved treatments exist to date. Here, we review histopathologic, clinical, imaging, and genetic diagnostic features of the main RYR1-RM subtypes. We also discuss the current state of treatments and focus on disease-modulating (nongenetic) therapeutic strategies under development for RYR1-RM. Finally, perspectives for future approaches to treatment development are broached.

RYR1 encodes the type 1 ryanodine receptor, an intracellular calcium release channel (RyR1) on the skeletal muscle sarcoplasmic reticulum (SR). Pathogenic RYR1 variations can destabilize RyR1 leading to calcium leak causing oxidative overload and myopathy. However, the effect of RyR1 leak has not been established in individuals with RYR1 -related myopathies ( RYR1 -RM), a broad spectrum of rare neuromuscular disorders. We sought to determine whether RYR1 -RM affected individuals exhibit pathologic, leaky RyR1 and whether variant location in the channel structure can predict pathogenicity. Skeletal muscle biopsies were obtained from 17 individuals with RYR1 -RM. Mutant RyR1 from these individuals exhibited pathologic SR calcium leak and increased activity of calcium-activated proteases. The increased calcium leak and protease activity were normalized by ex-vivo treatment with S107, a RyR stabilizing Rycal molecule. Using the cryo-EM structure of RyR1 and a new dataset of > 2200 suspected RYR1 -RM affected individuals we developed a method for assigning pathogenicity probabilities to RYR1 variants based on 3D co-localization of known pathogenic variants. This study provides the rationale for a clinical trial testing Rycals in RYR1 -RM affected individuals and introduces a predictive tool for investigating the pathogenicity of RYR1 variants of uncertain significance.

Abstract Typical central core disease (CCD) is characterized pathologically by the presence of a core and is accompanied by type 1 fiber uniformity. Congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) is characterized pathologically by the presence of type 1 fiber uniformity but without the abnormal structural changes in muscle fibers. Interestingly, typical CCD and 40% of CNMDU1 cases are caused by the same mutations in RYR1, and thus CNMDU1 has been considered an early precursor to CCD. To better understand the nature of CNMDU1, we re-evaluated muscle biopsies from 16 patients with CNMDU1 using immunohistochemistry to RYR1, triadin and TOM20, and compared this to muscle biopsies from 36 typical CCD patients. In CCD, RYR1, and triadin were present in the core regions, while TOM20 was absent in the core regions. Interestingly, in 5 CNMDU1 cases with the RYR1 mutation, RYR1, and triadin were similarly present in core-like areas, while TOM20 was absent in the subsarcolemmal region. Furthermore, there was a correlation between the core position and the disease duration or progression—the older patients in more advanced stages had more centralized cores. Our results indicate that CNMDU1 due to RYR1 mutation is a de facto core myopathy.

In this review, we focus on congenital myopathies, which are a genetically heterogeneous group of hereditary muscle diseases with slow or minimal progression. They are mainly defined and classified according to pathological features, with the major subtypes being core myopathy (central core disease), nemaline myopathy, myotubular/centronuclear myopathy, and congenital fiber-type disproportion myopathy. Recent advances in molecular genetics, especially next-generation sequencing technology, have rapidly increased the number of known causative genes for congenital myopathies; however, most of the diseases related to the novel causative genes are extremely rare. There remains no cure for congenital myopathies. However, there have been recent promising findings that could inform the development of therapy for several types of congenital myopathies, including myotubular myopathy, which indicates the importance of prompt and correct diagnosis. This review discusses the major causative genes (NEB, ACTA1, ADSSL1, RYR1, SELENON, MTM1, DNM2, and TPM3) for each subtype of congenital myopathies and the relevant latest findings.

The RYR1 gene encodes the skeletal muscle isoform ryanodine receptor and is fundamental to the process of excitation–contraction coupling and skeletal muscle calcium homeostasis. Mapping to chromosome 19q13.2, the gene comprises 106 exons and encodes a protein of 5,038 amino acids. Mutations in the gene have been found in association with several diseases: the pharmacogenetic disorder, malignant hyperthermia (MH); and three congenital myopathies, including central core disease (CCD), multiminicore disease (MmD), and in an isolated case of a congenital myopathy characterized on histology by cores and rods. The majority of gene mutations reported are missense changes identified in cases of MH and CCD. In vitro analysis has confirmed that alteration of normal calcium homeostasis is a functional consequence of some of these changes. Genotype–phenotype correlation studies performed using data from MH and CCD patients have also suggested that mutations may be associated with a range of disease severity phenotypes. This review aims to summarize the current understanding of RYR1 mutations reported in association with MH and CCD and the present viewpoint on the use of mutation data to aid clinical diagnosis of these conditions. Hum Mutat 27(10), 977–989, 2006. © 2006 Wiley‐Liss, Inc.

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.

Ryanodine receptors (RyRs) are main regulators of intracellular Ca2+ release and muscle contraction. The Y522S mutation of RyR1 causes central core disease, a weakening myopathy, and malignant hyperthermia, a sudden and potentially fatal response to anesthetics or heat. Y522 is in the core of the N-terminal subdomain C of RyR1 and the mechanism of how this mutation orchestrates malfunction is unpredictable for this 2-MDa ion channel, which has four identical subunits composed of 15 distinct cytoplasmic domains each. We expressed and purified the RyR1 rabbit homolog, Y523S, from HEK293 cells and reconstituted it in nanodiscs under closed and open states. The high-resolution cryogenic electron microscopic (cryo-EM) three-dimensional (3D) structures show that the phenyl ring of Tyr functions in a manner analogous to a “spacer” within an α-helical bundle. Mutation to the much smaller Ser alters the hydrophobic network within the bundle, triggering rearrangement of its α-helices with repercussions in the orientation of most cytoplasmic domains. Examining the mutation-induced readjustments exposed a series of connected α-helices acting as an ∼100 Å-long lever: One end protrudes toward the dihydropyridine receptor, its molecular activator (akin to an antenna), while the other end reaches the Ca2+ activation site. The Y523S mutation elicits channel preactivation in the absence of any activator and full opening at 1.5 μM free Ca2+, increasing by ∼20-fold the potency of Ca2+ to activate the channel compared with RyR1 wild type (WT). This study identified a preactivated pathological state of RyR1 and a long-range lever that may work as a molecular switch to open the channel.

Skeletal muscle contraction relies on both high-fidelity calcium (Ca2+) signals and robust capacity for adenosine triphosphate (ATP) generation. Ca2+ release units (CRUs) are highly organized junctions between the terminal cisternae of the sarcoplasmic reticulum (SR) and the transverse tubule (T-tubule). CRUs provide the structural framework for rapid elevations in myoplasmic Ca2+ during excitation–contraction (EC) coupling, the process whereby depolarization of the T-tubule membrane triggers SR Ca2+ release through ryanodine receptor-1 (RyR1) channels. Under conditions of local or global depletion of SR Ca2+ stores, store-operated Ca2+ entry (SOCE) provides an additional source of Ca2+ that originates from the extracellular space. In addition to Ca2+, skeletal muscle also requires ATP to both produce force and to replenish SR Ca2+ stores. Mitochondria are the principal intracellular organelles responsible for ATP production via aerobic respiration. This review provides a broad overview of the literature supporting a role for impaired Ca2+ handling, dysfunctional Ca2+-dependent production of reactive oxygen/nitrogen species (ROS/RNS), and structural/functional alterations in CRUs and mitochondria in the loss of muscle mass, reduction in muscle contractility, and increase in muscle damage in sarcopenia and a wide range of muscle disorders including muscular dystrophy, rhabdomyolysis, central core disease, and disuse atrophy. Understanding the impact of these processes on normal muscle function will provide important insights into potential therapeutic targets designed to prevent or reverse muscle dysfunction during aging and disease.

Background and purpose Pathogenic variants in the RYR1 gene have been associated with a variety of conditions, ranging from congenital myopathy to adult manifestations. Our aim was to characterize the p.Leu2286Val variant in 17 Basque patients, to accurately determine its correlation with clinical features and to explore the possible founder effect of the variant. Methods Families harbouring the p.Leu2286 RYR1 variant underwent a detailed clinical evaluation, including muscle magnetic resonance imaging, electromyography and muscle biopsy. Haplotypes were analysed in available patients and their relatives. Results Individuals carrying the p.Leu2286Val shared a common haplotype, suggesting a founder event in the Basque Country population. The most prevalent features were exertional myalgia, high creatine kinase (CK) levels, cramps and muscle hypertrophy. None of the patients carrying only the p.Leu2286Val showed progression to severe muscle weakness and muscle magnetic resonance imaging showed a heterogeneous muscle involvement. Muscle biopsy revealed non‐specific findings in two patients and features associated with central core disease in one patient carrying only the p.Leu2286Val and two patients harbouring an additional RYR1 variant. Three individuals carrying an in trans RYR1 variant presented with an earlier onset and more severe phenotype. Conclusion Here, it is shown that the dominantly inherited p.Leu2286Val RYR1 founder variant is associated with a milder phenotype of exercise intolerance, myalgia and hyperCKemia.