Excitation-Contraction Coupling Alterations in Myopathies

Marty, Isabelle; Fauré, Julien

doi:10.3233/jnd-160172

Cited by 25 publications

(15 citation statements)

References 81 publications

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“…The IVCT requires an open biopsy to obtain sufficient fresh skeletal muscle tissue and may yield false-negative results [25]. Approximately 50% of MH-susceptible individuals exhibit cores on biopsy whereas others, without a history of myopathy prior to an MH episode (MH trait only), do not [8, 26, 27]. It is therefore challenging to rule out MH susceptibility in individuals with pathogenic RYR1 missense variants, and this is compounded by the fact that susceptible individuals do not always exhibit symptoms following initial exposure(s) to triggering agents.…”

Section: Genetic Etiologymentioning

confidence: 99%

“…Nevertheless, collectively, there is no ideal in vivo RYR1 -RM animal model, but work is underway to develop a model that better resembles this spectrum of diseases as a whole. Caution must also be taken when comparing results across different model systems [26].…”

Section: Ryr1-rm Therapeutic Approachesmentioning

confidence: 99%

“…However, studies of patient-derived myotubes with the corresponding human mutation, p.Ile4898Thr, show a differing phenotype of minimal leak. To this point, Marty and Faure discuss the difficulty of identifying exact pathophysiologic mechanisms while differing preclinical models are used for the same variant, and they consequently surmise that actual insults are likely more complex than our current understanding [26].…”

Section: Ryr1-rm Therapeutic Approachesmentioning

confidence: 99%

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Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches

2018

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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.

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Section: Genetic Etiologymentioning

confidence: 99%

Section: Ryr1-rm Therapeutic Approachesmentioning

confidence: 99%

Section: Ryr1-rm Therapeutic Approachesmentioning

confidence: 99%

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Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches

2018

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“…The impact of RYR1 mutations are either an alteration of the RyR1 calcium channel function (gain-or loss-of-function), a modification of the RyR1-DHPR coupling, or the reduction in the amount of RyR1 protein. In all cases, the consequence is a reduction in the amplitude of calcium release upon stimulation, resulting in muscle weakness [3][4][5][6][7][8]. To explore the various pathophysiology mechanisms associated with RYR1 mutations, different mouse models have been created.…”

Section: Introductionmentioning

confidence: 99%

In vivo RyR1 reduction in muscle triggers a core-like myopathy

Pelletier

Petiot

Brocard

et al. 2020

acta neuropathol commun

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Mutations in the RYR1 gene, encoding the skeletal muscle calcium channel RyR1, lead to congenital myopathies, through expression of a channel with abnormal permeability and/or in reduced amount, but the direct functional whole organism consequences of exclusive reduction in RyR1 amount have never been studied. We have developed and characterized a mouse model with inducible muscle specific RYR1 deletion. Tamoxifen-induced recombination in the RYR1 gene at adult age resulted in a progressive reduction in the protein amount reaching a stable level of 50% of the initial amount, and was associated with a progressive muscle weakness and atrophy. Measurement of calcium fluxes in isolated muscle fibers demonstrated a reduction in the amplitude of RyR1-related calcium release mirroring the reduction in the protein amount. Alterations in the muscle structure were observed, with fibers atrophy, abnormal mitochondria distribution and membrane remodeling. An increase in the expression level of many proteins was observed, as well as an inhibition of the autophagy process. This model demonstrates that RyR1 reduction is sufficient to recapitulate most features of Central Core Disease, and accordingly similar alterations were observed in muscle biopsies from Dusty Core Disease patients (a subtype of Central Core Disease), pointing to common pathophysiological mechanisms related to RyR1 reduction.

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“…Many lines of evidence suggest that certain inherited human myopathies originate from the expression of overactive or leaky RyR1s (reviewed recently by Fauré et al, [89] and Marty et al, [90]). Remarkably, Andronache and coworkers (2009) found that the altered gating of one of these RyR1 mutant proteins (Y522S) also exerts a retrograde influence on the function of Ca V 1.1 [91].…”

Section: Retrograde Signaling In Skeletal Musclementioning

confidence: 99%

Ca2+ Channels Mediate Bidirectional Signaling between Sarcolemma and Sarcoplasmic Reticulum in Muscle Cells

Ávila

Rosa

Monsalvo-Villegas

et al. 2019

Cells

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The skeletal muscle and myocardial cells present highly specialized structures; for example, the close interaction between the sarcoplasmic reticulum (SR) and mitochondria—responsible for excitation-metabolism coupling—and the junction that connects the SR with T-tubules, critical for excitation-contraction (EC) coupling. The mechanisms that underlie EC coupling in these two cell types, however, are fundamentally distinct. They involve the differential expression of Ca2+ channel subtypes: CaV1.1 and RyR1 (skeletal), vs. CaV1.2 and RyR2 (cardiac). The CaV channels transform action potentials into elevations of cytosolic Ca2+, by activating RyRs and thus promoting SR Ca2+ release. The high levels of Ca2+, in turn, stimulate not only the contractile machinery but also the generation of mitochondrial reactive oxygen species (ROS). This forward signaling is reciprocally regulated by the following feedback mechanisms: Ca2+-dependent inactivation (of Ca2+ channels), the recruitment of Na+/Ca2+ exchanger activity, and oxidative changes in ion channels and transporters. Here, we summarize both well-established concepts and recent advances that have contributed to a better understanding of the molecular mechanisms involved in this bidirectional signaling.

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Excitation-Contraction Coupling Alterations in Myopathies

Cited by 25 publications

References 81 publications

Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches

Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches

In vivo RyR1 reduction in muscle triggers a core-like myopathy

Ca2+ Channels Mediate Bidirectional Signaling between Sarcolemma and Sarcoplasmic Reticulum in Muscle Cells

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