Characterization of pathological pathways activated in muscles of patients with congenital myopathies with disturbed Ca2+ homeostasis
Prof. Susan Treves, University of Basel
Abstract (Lay summary see below)
Congenital myopathies constitute a genetically and phenotypically broad spectrum of disorders clinically characterized by muscle weakness and atrophy, joint contractures, spinal deformities and variable cardiorespiratory involvement.
Historically, these disorders have been defined by their most predominant histopathological features namely, Central Core Disease, Multi-minicore Disease, Nemaline Myopathy, Centronuclear disease and Congenital Fibre Type Disproportion. Their severe complications require patients to receive continual medical attention, resulting in a substantial individual, familial and social disease burden. Each congenital myopathy can be caused by mutations in more than one gene and mutations in the same gene can cause different pathological phenotypes. In the past decade advances in genomics have revealed that many patients carry mutations in genes encoding proteins directly involved in Ca2+ homeostasis; nevertheless it has also become apparent that many patients harbour mutations in genes encoding for proteins not directly involved in Ca2+ regulation such as SEPN1, MTM1 and KBTBD13. More detailed investigations into the latter group of patients have nevertheless revealed that muscles from such patients show profound alterations of calcium regulation and that these may be the cause of the profound muscle weakness. Such findings highlight the fact that the link between the primary effect(s) of the mutation(s) and the secondary changes in Ca2+ homeostasis is still missing.
The overall aim of this project is to identify such a link. We hypothesise that common pathophysiological pathways are activated in muscles of patients with different congenital myopathies who share as a common feature disturbed Ca2+ homeostasis. In such patients muscle function is severely disturbed not only because of a direct effect of the mutations on protein function, but also because the presence of mutations leads to the activation of secondary pathogenic events which result in the transcriptional down-regulation of muscle specific genes involved in excitation-contraction coupling. The identification of a common molecular pathway downstream from the primary mutation is critical in order to develop therapeutical strategies aimed at improving muscle function and thus the quality of life of these patients
Lay summary
Caratterizzazione dei meccanismi patologici attivati nei muscoli di pazienti affetti da miopatie congenite caratterizzate da alterazioni dell’omeostasi del Ca2+ intracellulare.
Le miopatie congenite comprendono un ampio spettro di malattie fenotipicamente e genotipicamente diverse, caratterizzate da debolezza muscolare, atrofia, contratture articolari, scoliosi con la presenza o l’assenza di coinvolgimento cardiorespiratorio. Storicamente queste malattie sono state definite dalle loro caratteristiche istopatologiche come ad esempio, la malattia Central Core, la malattia Multi-minicore, la miopatia Nemaline, la malattia Centronuclear etc. 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 nell’omeostasi del calcio. Tuttavia si è anche scoperto che una parte dei pazienti è portatore di mutazioni in geni codificanti proteine non direttamente coinvolte nell’omeostasi del calcio come ad esempio SEPN1, MTM1 e KBTBD13. Ricerche più approfondite hanno pero dimostrato che i muscoli di questi ultimi pazienti mostrano comunque cambiamenti nella regolazione del Ca2+ intracellulare e che questi cambiamenti nell’omeostasi del calcio potrebbero essere la causa della debolezza muscolare. Questi risultati evidenziano anche il fatto che manca ancora un nesso tra l’effetto primario della mutazione e i cambiamenti secondari nell’omeostasi del Ca2+.
Lo scopo principale di questo progetto è di identificare questo nesso. La nostra ipotesi di base è che meccanismi patologici comuni sono attivati nei muscoli di pazienti affetti d miopatie congenite che hanno come caratteristica un’alterazione dell’omeostasi intracellulare del Ca2+. In questi pazienti la funzionalità muscolare è disturbata non solo perché le mutazioni hanno un effetto sulla funzionalità proteica, ma anche perché la presenza di mutazioni causa l’attivazione di eventi patologici secondari, che portano alla diminuita espressione di geni muscolo-specifici che sono coinvolti nell’eccitazione-contrazione. L’identificazione di questi pathways molecolari a valle della mutazione primaria, è fondamentale al fine di sviluppare terapia farmacologiche mirate a migliorare la funzionalità muscolare e dunque la qualità della vita di questi pazienti.
Projets
- Nouveaux projets de recherche dès 2024
- L'importance de la recherche
- Projets financés
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- Molecular mechanisms of complement activation and neuromuscular disruption by combinations of autoantibodies from patients with Myasthenia Gravis
- From the investigation of the role of SRSF1 in ALS/FTD to its targeting as a therapeutic strategy
- Molecular crosstalk between muscles and motor neurons and its role in neuromuscular circuit formation
- Molecular Diagnosis and Coping Mechanisms in Mitochondrial Myopathies
- IPRIMYO: Immune-privileged, immortal, myogenic stem cells for gene therapy of Muscular Dystrophy
- Effect of RYR1 mutations on muscle spindle function and their impact on the musculoskeletal system
- Therapeutic potential of human myogenic reserve cells in Duchenne Muscular Dystrophy
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- Targeting protein s-acylation during Tubular Aggregate Myopathy
- Aggravating the phenotype of dystrophic mice for improving preclinical research and clinical translation for Duchenne muscular dystrophy
- Characterization of autoreactive T cells in Guillain-Barré syndrome
- A vascularized human muscle-on-a-chip to elucidate the contribution of endothelial-mesenchymal transition on the progression of muscular dystrophies
- Characterization of a novel form of ALS associated with changes in the sphingolipid metabolism
- Pre-clinical treatment of mouse models carrying recessive Ryr1 mutations with HDAC/DNA methyltransferase inhibitors.
- New aspects of TGFβ signaling in muscle homeostasis and regeneration
- Inhibition of sphingolipid synthesis as a treatment strategy for Duchenne muscular dystrophy
- Tamoxifen in Duchenne muscular dystrophy (TAMDMD)
- DNA aptamers against the DUX4 protein reveal novel therapeutic implications for FSHD
- Facilitating diagnosis of critical illness myopathy using muscle excitability testing
- Rapid Exploratory Imaging for High-resolution and Whole Extremity Coverage in MR Neurography
- Deciphering novel mechanisms and effectors contributing to muscle dysfunction in Myotonic Dystrophy Type I
- Can HDAC/DNA methyltransferase inhibitors improve muscle function in a congenital myopathy caused by recessive RYR1 mutations?
- Identification of the critical regulators of protein synthesis and degradation in human muscle atrophy
- Exploring peripheral B-cell-helper T cell phenotypes in the blood of patients with Myasthenia gravis using mass cytometry (CyTOF)
- Molecular signature, metabolic profile and therapeutic potential of human myogenic reserve cells
- A multicenter cross-sectional and longitudinal study of the Swiss cohort of Merosin-negative congenital muscular dystrophy
- Targeting NADPH oxidase 4 in models of Duchenne muscular dystrophy
- Characterizing the role of ER stress in C9orf72-linked ALS pathology
- Inducing mitophagy with Urolithin A to restore mitochondrial and muscle function in muscular dystrophy
- Motor unit action potentials analysis in patients with myopathies with a new wireless portable and multichannel Surface EMG device (WPM-SEMG)
- Role and therapeutic potential of PLIN3 in neuromuscular diseases
- Changes in ventilation distribution in children with neuromuscular disease using the insufflator/exsufflator technique: An observational study
- Mechanism and function of genome organization in muscle development and integrity
- Role and therapeutic potential of NADPH oxidases in a mouse model of Duchenne Muscular Dystrophy
- Characterization of pathological pathways activated in muscles of patients with congenital myopathies with disturbed Ca2+ homeostasis
- Creation of a study team to conduct an SMA 1-clinical trial at the Centre for Neuromuscular Diseases of the University Children's Hospital Basel (UKBB)
- Novel treatment to stop progressive neuropathy and muscle weakness in multifocal motor neuropathy
- Understanding the pathomechanisms leading to muscle alterations in Myotonic Dystrophy type I
- Automated volumetry and quantitative MRI to diagnose peripheral nerve lesions – translational proposal for a new clinical diagnostic imaging tool
- Novel approaches against Spinal Muscular Atrophy by targeting splicing regulators
- Protective effects and mechanisms of action of tamoxifen in mice with severe muscular diseases
- Role of the receptor FgfrL1 in the development of slow muscle fibers
- Muscle velocity recovery cycles: A new tool for early diagnosis of critical illness myopathy
- Generation of uncommitted human IPSC derived muscle stem cells for therapeutic applications
- Transposable vectors for dystrophin-expression in a murine model for muscular dystrophy
- Cardiac involvement in patients with Duchenne/Becker Muscular Dystrophy; an observational study
- Deciphering the pathogenic mechanisms of C9ORF72 ALS
- Enhancing estrogenic signalling to fight muscular dystrophies: Mechanisms of action and repurposing clinically approved drugs
- Mechanisms and therapeutic potential of modulating PGC‐1α to alter neuromuscular junction morphology and function
- Triggering human myoblast differentiation: from EGFR to myogenic transcription factors
- Improving cellular therapies of muscle dystrophies by uncovering epigenetic and signaling pathways of muscle formation
- Protein engineering in an attempt to increase the mechanical, integrin dependent cytoskeleton-matrix linkage in muscle fibers
- Muscle velocity recovery cycles: a new tool for characterization of muscle disease in vivo
- Excessive neurotrypsin activation and agrin cleavage-a pathogenic condition leading to sarcopenia-like muscle atrophy?
- Evaluation of novel treatment strategies for dyspherlinopathies in mouse models
- Cell therapy of LGMD2D by donor HLA-characterized human mesoangioblasts (hMABs) produced in GMP conditions
- In search of small molecules targeting protein-RNA complex: a novel approach against Spinal Muscular Atrophy
- Restoration of autophagy as a new strategy for the treatment of congenital muscular dystrophies
- Development of magnetic resonance methods for functional imaging of the skeletal muscle
- Targeting ER stress response: a potential mechanism for neuroprotection in Amyotrophic Lateral Sclerosis
- Generation of uncommitted human IPSC derived muscle stem cells for therapeutic applications
- Brochure décrivant les projets
- SEAL Therapeutics AG
- Rencontres et séminaires
- Participation à des associations faîtières
- Les registres de patients
- Le réseau Myosuisse
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