Can HDAC/DNA methyltransferase inhibitors improve muscle function in a congenital myopathy caused by recessive RYR1 mutations?
Prof. Francesco Zorzato and Prof. Susan Treves, University Hospital Basel
Abstract (Lay summary see below)
Defects of the calcium release channel (ryanodine receptor; RyR1) are causative of several congenital muscle disorders including malignant hyperthermia (MH; MIM #145600), central core disease (CCD; MIM #11700), certain forms of multi-minicore disease (MmD; MIM # 255320) and centronuclear myopathy (CNM; MIM # 255320). Experimental results indicate that RYR1 mutations mainly cause four types of channel defects: one class (linked to MH) causes the channels to become hypersensitive to activation by electrical and pharmacological stimuli. The second class (linked to CCD) results in leaky channels leading to depletion of Ca2+ from sarcoplasmic reticulum (SR) stores. The third class (also linked to CCD) causes excitation–contraction uncoupling, whereby activation of the voltage sensor Cav1.1 is unable to cause release of calcium from the SR. The fourth class linked to recessive mutations, is associated with a decrease of mutant RyR1 channels content on SR membranes. However, the pathological mechanism leading to reduced RyR1 expression and content is presently unknown.
Our working hypothesis is that the presence of recessive RYR1 mutations (as well as recessive mutations in other genes associated with congenital myopathies including SELENON) activates an epigenetic loop leading to a reduced expression of RyR1. Indeed, muscles of patients with recessive RYR1 mutations exhibit striking changes at the level of protein and mRNA expression, including increased content of HDAC-4 and HDAC-5, depletion of muscle specific miR-1 and -133, as well as depletion of miR-22 and -124 two miRs that specifically bind to the 3’UTR of the human RYR1. Additionally, the increased content of HDAC-4 and -5 correlates with a hyper methylation of internal RYR1 CpG islands. The combination of these epigenetic modifications could be responsible for the depletion of RyR1 seen in muscles of these patients.
The main aim of this project is to understand (i) why recessive RYR1 mutations are accompanied by epigenetic modifications, (ii) whether the epigenetic machinery represents a pharmacological target. In order to answer these questions we will use a mouse model we have developed carrying recessive RYR1 mutations isogenic with RYR1 mutations found in a severely affected MmD patient. We think that this project is important not only because it will help elucidate the pathophysiology of diseases linked to recessive mutations but also because it will help develop pharmacological therapies to improve the quality of life of patients with disorders leading to a decrease of RyR1 expression in skeletal muscle sarcoplasmic reticulum.
Lay summary
Le miopatie congenite comprendono un ampio spettro di malattie fenotipicamente e genotipicamente diverse, caratterizzate da debolezza muscolare, atrofia, contratture articolari, scogliosi con la presenza o l’assenza di coinvolgimento cardiorespiratorio. Queste malattie sono state definite dalle loro caratteristiche istopatologiche come ad esempio, la malattia Central Core (o CCD), la malattia Multi-minicore (o MmD), la miopatia Nemaline, la malattia Centronuclear (o CNM). Ogni malattia congenita può essere causata da mutazioni in più geni e mutazioni all’interno dello stesso gene possono causare malattie fenotipicamente e patologicamente diverse. Negli ultimi anni avanzamenti nelle metodiche di sequenziamento del DNA hanno dimostrato che molti pazienti affetti da malattie congenite muscolari hanno mutazioni nei geni codificanti proteine coinvolte nel metabolismo del calcio, tra cui mutazioni nel RYR1, il gene codificante il recettore della rianodina (RyR1), il canale del calcio del muscolo scheletrico. Risultati sperimentali hanno dimostrato come molte delle mutazioni dominanti nel RYR1 alterano le proprietà biofisiche del canale, alterando la quantità di calcio rilasciata. Questo ha un impatto notevole sulle capacità dei muscoli di contrarsi e/o di rilassarsi. Pochi studi fino ad ora si sono focalizzati sul meccanismo fisiopatologico delle mutazioni recessive nel RYR1. I muscoli dei pazienti affetti da MmD e portatori di mutazioni nel RYR1 mostrano una significativa diminuzione nella quantità di proteina RyR1, un aumento delle istoni de-acetilasi HDAC-4 e HDAC-5, deplezione di alcuni micro-RNA muscoli specifici ed ipermetilazione del gene RYR1. Questi risultati ci hanno portato a formulare l’ipotesi che questi eventi epigenetici giocano un ruolo fondamentale nel meccanismo fisiopatologico delle malattie congenite muscolari dovute a mutazioni recessive nel RYR1.
Lo scopo di questo progetto di ricerca è di capire: (i) perché mutazioni recessive nel RYR1 sono accompagnate da questi importanti fenomeni epigenetici; (ii) se questi meccanismi epigenetici rappresentano un bersaglio farmacologico. Per rispondere a queste domande abbiamo creato un modello animale in cui abbiamo inserito due mutazioni nel RYR1 isogeniche a quelle trovate in un paziente affetto da MmD. Questo modello animale verrà utilizzato per capire il meccanismo fisiopatologico della malattia MmD e per testare farmaci tra cui gli inibitori delle istoni de-acetilasi e dei DNA metiltransferasi.
Projekte
- Neue Forschungsprojekte ab 2024
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