Myosin ATPase inhibition fails to rescue the metabolically dysregulated proteome of nebulin-deficient muscle.

Autor: Laitila J; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark., Seaborne RAE; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.; Centre of Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, UK., Ranu N; Centre of Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, UK., Kolb JS; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, MO, USA., Wallgren-Pettersson C; The Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland and Department of Medical and Clinical Genetics, Medicum, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland., Witting N; Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark., Vissing J; Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark., Vilchez JJ; Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) Spain, Valencia, Spain., Zanoteli E; Department of Neurology, Faculdade de Medicina (FMUSP), Universidade de São Paulo, São Paulo, Brazil., Palmio J; Neuromuscular Research Center, Department of Neurology, Tampere University and University Hospital, Tampere, Finland., Huovinen S; Department of Pathology, Fimlab Laboratories, Tampere University Hospital, Tampere, Finland., Granzier H; The Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland and Department of Medical and Clinical Genetics, Medicum, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland., Ochala J; Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Jazyk: angličtina
Zdroj: The Journal of physiology [J Physiol] 2024 Oct; Vol. 602 (20), pp. 5229-5245. Date of Electronic Publication: 2024 Aug 31.
DOI: 10.1113/JP286870
Abstrakt: Nemaline myopathy (NM) is a genetic muscle disease, primarily caused by mutations in the NEB gene (NEB-NM) and with muscle myosin dysfunction as a major molecular pathogenic mechanism. Recently, we have observed that the myosin biochemical super-relaxed state was significantly impaired in NEB-NM, inducing an aberrant increase in ATP consumption and remodelling of the energy proteome in diseased muscle fibres. Because the small-molecule Mavacamten is known to promote the myosin super-relaxed state and reduce the ATP demand, we tested its potency in the context of NEB-NM. We first conducted in vitro experiments in isolated single myofibres from patients and found that Mavacamten successfully reversed the myosin ATP overconsumption. Following this, we assessed its short-term in vivo effects using the conditional nebulin knockout (cNeb KO) mouse model and subsequently performing global proteomics profiling in dissected soleus myofibres. After a 4 week treatment period, we observed a remodelling of a large number of proteins in both cNeb KO mice and their wild-type siblings. Nevertheless, these changes were not related to the energy proteome, indicating that short-term Mavacamten treatment is not sufficient to properly counterbalance the metabolically dysregulated proteome of cNeb KO mice. Taken together, our findings emphasize Mavacamten potency in vitro but challenge its short-term efficacy in vivo. KEY POINTS: No cure exists for nemaline myopathy, a type of genetic skeletal muscle disease mainly derived from mutations in genes encoding myofilament proteins. Applying Mavacamten, a small molecule directly targeting the myofilaments, to isolated membrane-permeabilized muscle fibres from human patients restored myosin energetic disturbances. Treating a mouse model of nemaline myopathy in vivo with Mavacamten for 4 weeks, remodelled the skeletal muscle fibre proteome without any noticeable effects on energetic proteins. Short-term Mavacamten treatment may not be sufficient to reverse the muscle phenotype in nemaline myopathy.
(© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)
Databáze: MEDLINE
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