Congenital muscle disorders with cores: the ryanodine receptor calcium channel paradigm

doi:10.1016/j.coph.2008.01.005

Current Opinion in Pharmacology

Volume 8, Issue 3, June 2008, Pages 319-326

https://doi.org/10.1016/j.coph.2008.01.005 Get rights and content

Dysregulation of calcium signals because of defects of the skeletal muscle sarcoplasmic reticulum calcium release channel (ryanodine receptor; RyR1) is causative of several congenital muscle disorders including malignant hyperthermia (MH; MIM #145600), central core disease (CCD; MIM #11700), specific forms of multi-minicore disease (MmD; MIM # 255320) and centronuclear myopathy (CNM). Experimental data have shown that RYR1 mutations result mainly in four types of channel defects: one class of RYR1 mutations (MH) cause the channels to become hypersensitive to activation by electrical and pharmacological stimuli. The second class of RYR1 mutations (CCD) result in leaky channels leading to depletion of Ca²⁺ from SR stores. A third class of RYR1 mutations linked to CCD causes excitation–contraction uncoupling, whereby activation of the voltage sensor Cav1.1 is unable to release calcium from the SR. The fourth class of mutations are unveiled by wild type allele silencing, and cause a decrease of mutant RyR1 channels expression on SR membranes. In this review, we discuss the classes of RYR1 mutations which have been associated with CCD, MmD and related neuromuscular phenotypes.

Introduction

Although five decades of research into the mechanisms involved in cytosolic Ca²⁺ regulation have advanced our understanding of fundamental cellular processes ranging from muscle contraction to gene expression [1], the precise impact of altered Ca²⁺ signalling on human disease has remained elusive for a long time. The discovery of genes encoding key proteins involved in Ca²⁺ homeostasis was fundamental in bridging the gap between understanding the role of Ca²⁺ in basic physiological processes and the pathophysiology of human diseases. The identification of the Ca²⁺ release channel protein (ryanodine receptor, RyR1) of striated muscle [2] and the identification of mutations in its gene, RYR1 [3], allowed for the first time a direct correlation between altered Ca²⁺ homeostasis and muscle disease (Figure 1), in particular malignant hyperthermia (MH) [4, 5, 6], central core disease (CDD) [7], specific forms of multi-minicore disease (MmD) [8, 9, 10] and centronuclear myopathy (CNM) [11] (Table 1). The overall population frequency of RYR1 mutations (about 1:50,000) is likely to have been underestimated as suggested by the finding of compound heterozygosity or homozygosity for RYR1 mutations in some patients within extensively analyzed MH and CCD pedigrees and other rare disorders including MmD [8, 9, 10], exercise-induced rhabdomyolysis [12], and some forms of exercise-induced hyperthermia [13].

Section snippets

The ryanodine receptor calcium channels

Ryanodine receptors are members of a family of intracellular Ca²⁺ release channel proteins present on ER/SR membranes [14]. Type 1 RyR is encoded by a gene on human chromosome 19q13.1 [15], and is mainly expressed in skeletal muscle and to a lower level in Purkinje cells [16], human B-lymphocytes [17, 18], and dendritic cells [19, 20, 21, 22]; this implies that mutations in the RYR1 might affect not only excitable cells but also the immune system and other tissues. The functional calcium

Conclusions

During the last few years the general understanding of congenital muscle disorders has greatly improved thanks to the identification of causative mutations in the RYR1 gene. However, the development of therapeutic treatments for affected patients has been hampered by the poor understanding of the molecular pathological mechanisms of the RyR1 defects. Understanding the mechanism(s) responsible for RYR1 allele silencing, discriminating between Ca²⁺ leak and EC uncoupling are important not only to

Acknowledgements

This work was supported by grants from Association Francaise contre les myopathies, PRIN, Swiss muscle foundation, S.N.F.N°3200B0114597, M.A.E.

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Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial
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RYR1-related myopathies (RYR1-RM) are caused by pathogenic variants in the RYR1 gene which encodes the type 1 ryanodine receptor (RyR1). RyR1 is the sarcoplasmic reticulum (SR) calcium release channel that mediates excitation-contraction coupling in skeletal muscle. RyR1 sub-conductance, SR calcium leak, reduced RyR1 expression, and oxidative stress often contribute to RYR1-RM pathogenesis. Loss of RyR1-calstabin1 association, SR calcium leak, and increased RyR1 open probability were observed in 17 RYR1-RM patient skeletal muscle biopsies and improved following ex vivo treatment with Rycal compounds. Thus, we initiated a first-in-patient trial of Rycal S48168 (ARM210) in ambulatory adults with genetically confirmed RYR1-RM.
Participants received 120 mg (n = 3) or 200 mg (n = 4) S48168 (ARM210) daily for 29 days. The primary endpoint was safety and tolerability. Exploratory endpoints included S48168 (ARM210) pharmacokinetics (PK), target engagement, motor function measure (MFM)-32, hand grip and pinch strength, timed functional tests, PROMIS fatigue scale, semi-quantitative physical exam strength measurements, and oxidative stress biomarkers. The trial was registered with clinicaltrials.gov (NCT04141670) and was conducted at the National Institutes of Health Clinical Center between October 28, 2019 and December 12, 2021.
S48168 (ARM210) was well-tolerated, did not cause any serious adverse events, and exhibited a dose-dependent PK profile. Three of four participants who received the 200 mg/day dose reported improvements in PROMIS-fatigue at 28 days post-dosing, and also demonstrated improved proximal muscle strength on physical examination.
S48168 (ARM210) demonstrated favorable safety, tolerability, and PK, in RYR1-RM affected individuals. Most participants who received 200 mg/day S48168 (ARM210) reported decreased fatigue, a key symptom of RYR1-RM. These results set the foundation for a randomized, double-blind, placebo-controlled proof of concept trial to determine efficacy of S48168 (ARM210) in RYR1-RM.
NINDS and NINR Intramural Research Programs, NIH Clinical Center Bench to Bedside Award (2017-551673), ARMGO Pharma Inc., and its development partner Les Laboratoires Servier.
Drug development for the treatment of RyR1-related skeletal muscle diseases
2023, Current Opinion in Pharmacology
Type 1 ryanodine receptor (RyR1) is an intracellular Ca²⁺ release channel on the sarcoplasmic reticulum of skeletal muscle, and it plays a central role in excitation–contraction (E-C) coupling. Mutations in RyR1 are implicated in various muscle diseases including malignant hyperthermia, central core disease, and myopathies. Currently, no specific treatment exists for most of these diseases. Recently, high-throughput screening (HTS) assays have been developed for identifying potential candidates for treating RyR-related muscle diseases. Currently, two different methods, namely a FRET-based assay and an endoplasmic reticulum Ca²⁺-based assay, are available. These assays identified several compounds as novel RyR1 inhibitors. In addition, the development of a reconstituted platform permitted HTS assays for E-C coupling modulators. In this review, we will focus on recent progress in HTS assays and discuss future perspectives of these promising approaches.
Calcium channels linked to altered cellular function and disease
2020, Current Opinion in Physiology
Calcium (Ca²⁺) is one of the most diverse intracellular messengers and essential for various cellular physiological functions, including memory formation and muscle contractions. Ca²⁺ channels allow passage of Ca²⁺ ions and thus essential cellular components in enabling the strictly regulated intracellular Ca²⁺ signaling that are present in our cells. Altered Ca²⁺ channel activity is contributing to many human diseases, for example, myopathies, malignant hyperthermia, and neurological disorders such as Alzheimer’s disease, as well as different types of cancer. Here, we review established and recent studies addressing Ca²⁺ channels and their implication in human disease. We primarily focus on intracellular Ca²⁺ channels (including Ryanodine receptors, inositol trisphosphate receptors and STIM and ORAI) and diseases that affects our cognitive function and/or ability to move.
Bi-allelic expression of the RyR1 p.A4329D mutation decreases muscle strength in slow-twitch muscles in mice
2020, Journal of Biological Chemistry
Mutations in the ryanodine receptor 1 (RYR1) gene are associated with several human congenital myopathies, including the dominantly inherited central core disease and exercise-induced rhabdomyolysis, and the more severe recessive phenotypes, including multiminicore disease, centronuclear myopathy, and congenital fiber type disproportion. Within the latter group, those carrying a hypomorphic mutation in one allele and a missense mutation in the other are the most severely affected. Because of nonsense-mediated decay, most hypomorphic alleles are not expressed, resulting in homozygous expression of the missense mutation allele. This should result in 50% reduced expression of the ryanodine receptor in skeletal muscle, but its observed content is even lower. To study in more detail the biochemistry and pathophysiology of recessive RYR1 myopathies, here we investigated a mouse model we recently generated by analyzing the effect of bi-allelic versus mono-allelic expression of the RyR1 p.A4329D mutation. Our results revealed that the expression of two alleles carrying the same mutation or of one allele with the mutation in combination with a hypomorphic allele does not result in functionally equal outcomes and impacts skeletal muscles differently. In particular, the bi-allelic RyR1 p.A4329D mutation caused a milder phenotype than its mono-allelic expression, leading to changes in the biochemical properties and physiological function only of slow-twitch muscles and largely sparing fast-twitch muscles. In summary, bi-allelic expression of the RyR1 p.A4329D mutation phenotypically differs from mono-allelic expression of this mutation in a compound heterozygous carrier.
Structural development of a type-1 ryanodine receptor (RyR1) Ca<sup>2+</sup>-release channel inhibitor guided by endoplasmic reticulum Ca<sup>2+</sup> assay
2019, European Journal of Medicinal Chemistry
Citation Excerpt :
The resulting increase of cytoplasmic Ca2+ level induces skeletal muscle contraction. Genetic mutations of RyR1 are known to be associated with several muscle diseases, such as malignant hyperthermia (MH) and central core diseases (CCD) [5,6], in which over-activation of the mutated RyR1 channel causes leakage of Ca2+ from the SR store. In addition, the symptoms of several diseases, such as muscular dystrophy [7] and Alzheimer disease [8], are thought to be caused, at least in part, by over-activation of non-mutated RyR1 induced by external factors.
Type-1 ryanodine receptor (RyR1) is a calcium-release channel localized on sarcoplasmic reticulum (SR) of the skeletal muscle, and mediates muscle contraction by releasing Ca²⁺ from the SR. Genetic mutations of RyR1 are associated with skeletal muscle diseases such as malignant hyperthermia and central core diseases, in which over-activation of RyR1 causes leakage of Ca²⁺ from the SR. We recently developed an efficient high-throughput screening system based on the measurement of Ca²⁺ in endoplasmic reticulum, and used it to identify oxolinic acid (1) as a novel RyR1 channel inhibitor. Here, we designed and synthesized a series of quinolone derivatives based on 1 as a lead compound. Derivatives bearing a long alkyl chain at the nitrogen atom of the quinolone ring and having a suitable substituent at the 7-position of quinolone exhibited potent RyR1 channel-inhibitory activity. Among the synthesized compounds, 14h showed more potent activity than dantrolene, a known RyR1 inhibitor, and exhibited high RyR1 selectivity over RyR2 and RyR3. These compounds may be promising leads for clinically applicable RyR1 channel inhibitors.
Interactions among ryanodine receptor isotypes contribute to muscle fiber type development and function
2020, DMM Disease Models and Mechanisms
Mutations affecting ryanodine receptor (RyR) calcium release channels commonly underlie congenital myopathies. Although these channels are known principally for their essential roles in muscle contractility, mutations in the human RYR1 gene result in a broad spectrum of phenotypes, including muscle weakness, altered proportions of fiber types, anomalous muscle fibers with cores or centrally placed nuclei, and dysmorphic craniofacial features. Currently, it is unknown which phenotypes directly reflect requirements for RyRs and which result secondarily to aberrant muscle function. To identify biological processes requiring RyR function, skeletal muscle development was analyzed in zebrafish embryos harboring protein-null mutations. RyR channels contribute to both muscle fiber development and function. Loss of some RyRs had modest effects, altering muscle fiber-type specification in the embryo without compromising viability. In addition, each RyR-encoding gene contributed to normal swimming behavior and muscle function. The RyR channels do not function in a simple additive manner. For example, although isoform RyR1a is sufficient for muscle contraction in the absence of RyR1b, RyR1a normally attenuates the activity of the co-expressed RyR1b channel in slow muscle. RyR3 also acts to modify the functions of other RyR channels. Furthermore, diminished RyR-dependent contractility affects both muscle fiber maturation and craniofacial development. These findings help to explain some of the heterogeneity of phenotypes that accompany RyR1 mutations in humans.
Summary: Skeletal muscle fiber development and function are dependent on additive as well as combinatorial interactions among ryanodine receptor calcium release channels.

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Congenital muscle disorders with cores: the ryanodine receptor calcium channel paradigm

Introduction

Section snippets

The ryanodine receptor calcium channels

Conclusions

Acknowledgements

Neuromuscul Disord

Br J Anaesth

Cell Calcium

Genomics

J Biol Chem

J Biol Chem

FEBS Lett

Biochem Biophys Res Commun

Structure

Neuromuscul Disord

Biophys J

Biochemical Pharmacol

Neuromuscul Disord

Am J Hum Gen

Neuromuscul Disord

J Biol Chem

Am J Hum Genet

Eur J Paediat Neurol

Neuromuscul Disord

Unlocking the secrets of cell signalling

Annu Rev Physiol

Purification and reconstitution of the calcium release channel from skeletal muscle

Nature

Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia

Science

Malignant hyperthermia orphanet

J Rare Dis

Mutations in RYR1 in malignant hyperthermia and central core disease

Hum Mutat

Novel regulators of RyR Ca2+ release channels: insight into molecular changes in genetically linked myopathies

J Muscle Res Cell Motil

Central core disease orphanet

J Rare Dis

Multi-minicore disease orphanet

J Rare Dis

Multiminicore myopathy, central core disease, malignant hyperthermia susceptibility, and RYR1 mutations: one disease with many faces?

Arch Neurol

Functional effects of mutations identified in patients with multiminicore disease

IUBMB Life

Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis

Anesthesiology

Junctophilin-mediated channel crosstalk essential for cerebellar synaptic plasticity

EMBO J

Uncoupling of ATP-mediated calcium signaling and dysregulated interleukin-6 secretion in dendritic cells by nanomolar thimerosal

Environ Health Perspect

Ca2+ signaling through ryanodine receptor 1 enhances maturation and activation of human dendritic cells

J Cell Sci

Internal structure and visualization of transmembrane domains of the RyR1 calcium release channel by cryo-EM

Nat Struct Molec Biol

Novel regulators of RyR Ca²⁺ release channels: insight into molecular changes in genetically linked myopathies

Ca²⁺ signaling through ryanodine receptor 1 enhances maturation and activation of human dendritic cells