Muscle velocity recovery cycles: A new tool for early diagnosis of critical illness myopathy
Dr. Werner Z'Graggen, Inselspital Bern
Abstract (Lay summary see below)
Critical illness myopathy (CIM) is associated with prolonged stay on mechanical ventilation and in the ICU, need for weeks to months of rehabilitation, worse outcome and increased resource use. While several risk factors have been described, the exact pathophysiology of the disease is unknown. There is some evidence that systemic inflammation, oxidative stress, mitochondrial dysfunction, impaired microcirculation, hyperglycemia, inactivation of sodium channels and immobility with neuromuscular deconditioning contribute to the disease. We have shown in pigs that muscle membrane dysfunction occurs within 6 hours of sepsis. In patients with probable CIM, we found similar muscle membrane dysfunction and provided evidence that membrane depolarization and/or sodium channel inactivation occurred. The aim of the present project is twofold:
1), to prospectively evaluate the evolution and pathophysiologic characteristics of muscular abnormalities in a porcine model of sepsis from the early phase of sepsis until the definite diagnosis of CIM according to the current criteria. We hypothesize that structural damage is preceded by muscle membrane depolarization and that diagnosis of membrane depolarization is one of the first signs of CIM.
2), to validate muscle excitability testing as a surrogate for absolute muscle membrane potential. The assessment of the latter is not routinely possible in patients.
If our hypotheses can be confirmed, the conditions leading to CIM can be diagnosed very early with the possibility to implement therapeutic steps to attenuate its course.
Lay summary
Muskelfaserexzitabilitätsmessungen: eine neue Methode für die Frühdiagnose der critical illness-Myopathie
Die geltenden Diagnosekriterien erlauben die Diagnosestellung frühestens am Ende der ersten Woche nach Eintritt des Patienten auf die Intensivstation zu einem Zeitpunkt, wenn sich die Erkrankung schon entwickelt hat und die Muskelschädigung bereits aufgetreten ist. In eigenen tierexperimentellen Studien konnten wir mit einer durch unsere Forschungsgruppe entwickelten elektrophysiologischen Methode zeigen, dass in der frühen Phase einer schweren Infektion (Sepsis) eine Störung der elektrischen Eigenschaften der Muskelfaser-Membran besteht. Unbekannt ist aktuell, ob diese Veränderungen das erste messbare Zeichen der „critical illness“-Myopathie sind und eine Frühdiagnose vor der definitiven Schädigung der Muskelfasern erlauben.
In diesem Projekt werden die Eigenschaften von Muskelfaser-Membranen von Beginn einer Sepsis bis zum Auftreten der „critical illness“-Myopathie nach geltenden diagnostischen Kriterien im Tierexperiment untersucht. Die verwendete Methode ist auch im Menschen anwendbar. Eine Untersuchung dauert ca. 15 - 20 Minuten und ist für den Patienten wenig belastend. In klinischen Studien konnte diese neue Methode bereits bei gesunden Probanden und bei verschiedenen Muskelerkrankungen erfolgreich angewendet werden.
Das Projekt will dazu beitragen die Ursache der „critical illness“-Myopathie besser zu verstehen und eine Frühdiagnose zu ermöglichen. Es sollte uns erlauben, neue Strategien für die Prävention dieser Erkrankungen zu entwickeln und damit die Auftreten dieser schweren Komplikation der modernen intensivmedizinischen Behandlung zu senken.
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
- Glutamine metabolism as a potential target for Duchenne Muscular Dystrophy
- 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
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