ArticleActa neuropathologica communications2022
NEB mutations disrupt the super-relaxed state of myosin and remodel the muscle metabolic proteome in nemaline myopathy.
Article in Acta neuropathologica communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 39 citations in OpenAlex.
- Changes in cardiac myosin acetylation disrupt the super-relaxed state in genotype-negative hypertrophic cardiomyopathy with type 2 diabetes.Cardiovascular diabetology · 2026Article
- The D2.B10-DmdThe American journal of pathology · 2026Article
- Myosin inhibition partially rescues the myofiber proteome in X-linked myotubular myopathy.JCI insight · 2025Article
- A homozygous single-nucleotide variant inJournal of neuromuscular diseases · 2025Article
- Sex-dependent and muscle-specific progression of the MYBPC1 E248K Myotrem myopathy in response to aging.JCI insight · 2025Article
- Dysregulated skeletal muscle myosin super-relaxation and energetics in male participants with type 2 diabetes mellitus.Diabetologia · 2025Article
- Integrated single-cell functional-proteomic profiling reveals a shift in myofibre specificity in human nemaline myopathy: A proof-of-principle study.The Journal of physiology · 2025Article
- Myosin relaxation states in skeletal muscle fibers of rats and mice: Effects of sex and adiposity.Physiological reports · 2025Article
- Review: Utility of mass spectrometry in rare disease research and diagnosis.NPJ genomic medicine · 2025Review
- Human skeletal muscle fiber heterogeneity beyond myosin heavy chains.Nature communications · 2025Article
- Congenital myopathies: pathophysiological mechanisms and promising therapies.Journal of translational medicine · 2024Review
- Aberrant myonuclear domains and impaired myofiber contractility despite marked hypertrophy in MYMK-related, Carey-Fineman-Ziter Syndrome.Acta neuropathologica communications · 2024Article
- Article
- A therapeutic leap: how myosin inhibitors moved from cardiac interventions to skeletal muscle myopathy solutions.The Journal of clinical investigation · 2024Article
- The structural OFF and ON states of myosin can be decoupled from the biochemical super- and disordered-relaxed states.PNAS nexus · 2024Article
- The structural OFF and ON states of myosin can be decoupled from the biochemical super-relaxed and disordered-relaxed states.bioRxiv : the preprint server for biology · 2023Article
- Pharmacological Inhibition of Myostatin in a Mouse Model of Typical Nemaline Myopathy Increases Muscle Size and Force.International journal of molecular sciences · 2023Article
- Different Mouse Models of Nemaline Myopathy Harboring Acta1 Mutations Display Differing Abnormalities Related to Mitochondrial Biology.The American journal of pathology · 2023Article
- Aberrations in Energetic Metabolism and Stress-Related Pathways Contribute to Pathophysiology in the Neb Conditional Knockout Mouse Model of Nemaline Myopathy.The American journal of pathology · 2023Article
- Predominant myosin superrelaxed state in canine myocardium with naturally occurring dilated cardiomyopathy.American journal of physiology. Heart and circulatory physiology · 2023Article
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Authors and funding
23 authors at 16 institutions in 9 countries.
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Abstract
Nemaline myopathy (NM) is one of the most common non-dystrophic genetic muscle disorders. NM is often associated with mutations in the NEB gene. Even though the exact NEB-NM pathophysiological mechanisms remain unclear, histological analyses of patients' muscle biopsies often reveal unexplained accumulation of glycogen and abnormally shaped mitochondria. Hence, the aim of the present study was to define the exact molecular and cellular cascade of events that would lead to potential changes in muscle energetics in NEB-NM. For that, we applied a wide range of biophysical and cell biology assays on skeletal muscle fibres from NM patients as well as untargeted proteomics analyses on isolated myofibres from a muscle-specific nebulin-deficient mouse model. Unexpectedly, we found that the myosin stabilizing conformational state, known as super-relaxed state, was significantly impaired, inducing an increase in the energy (ATP) consumption of resting muscle fibres from NEB-NM patients when compared with controls or with other forms of genetic/rare, acquired NM. This destabilization of the myosin super-relaxed state had dynamic consequences as we observed a remodeling of the metabolic proteome in muscle fibres from nebulin-deficient mice. Altogether, our findings explain some of the hitherto obscure hallmarks of NM, including the appearance of abnormal energy proteins and suggest potential beneficial effects of drugs targeting myosin activity/conformations for NEB-NM.
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