ArticleJournal of medical genetics2013
Troponin activator augments muscle force in nemaline myopathy patients with nebulin mutations.
Article in Journal of medical genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 49 citations in OpenAlex.
- Retrospective Cohort Analysis of Clinical, Molecular, and Histopathologic Characteristics of 275 Patients With Nemaline Myopathy.Neurology. Genetics · 2025Article
- Comprehensive phenotypic characterization of an allelic series of zebrafish models of NEB-related nemaline myopathy.Human molecular genetics · 2024Article
- Characterization of NEB pathogenic variants in patients reveals novel nemaline myopathy disease mechanisms and omecamtiv mecarbil force effects.Acta neuropathologica · 2024Article
- Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy.The Journal of general physiology · 2024Article
- 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
- Small molecule drugs to improve sarcomere function in those with acquired and inherited myopathies.American journal of physiology. Cell physiology · 2023Review
- NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy.Human molecular genetics · 2023Article
- Troponin Variants in Congenital Myopathies: How They Affect Skeletal Muscle Mechanics.International journal of molecular sciences · 2021Review
- Acute and chronic tirasemtiv treatment improves in vivo and in vitro muscle performance in actin-based nemaline myopathy mice.Human molecular genetics · 2021Article
- Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium.The Journal of clinical investigation · 2021Article
- Preserved single muscle fiber specific force in facioscapulohumeral muscular dystrophy.Neurology · 2020Article
- Nebulin: big protein with big responsibilities.Journal of muscle research and cell motility · 2020Review
- In vivo characterization of skeletal muscle function in nebulin-deficient mice.Muscle & nerve · 2020Article
- Expressing a Z-disk nebulin fragment in nebulin-deficient mouse muscle: effects on muscle structure and function.Skeletal muscle · 2020Article
- Failure to identify modifiers ofBiology open · 2019Article
- Small molecule studies: the fourth wave of muscle research.Journal of muscle research and cell motility · 2019Article
- Deleting nebulin's C-terminus reveals its importance to sarcomeric structure and function and is sufficient to invoke nemaline myopathy.Human molecular genetics · 2019Article
- Treating pediatric neuromuscular disorders: The future is now.American journal of medical genetics. Part A · 2018Review
- Congenital myopathies: disorders of excitation-contraction coupling and muscle contraction.Nature reviews. Neurology · 2018Review
- Dysfunctional sarcomere contractility contributes to muscle weakness in ACTA1-related nemaline myopathy (NEM3).Annals of neurology · 2018Article
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Authors and funding
11 authors at 6 institutions in 3 countries.
Funding
Abstract
backgroundNemaline myopathy-the most common non-dystrophic congenital myopathy-is caused by mutations in thin filament genes, of which the nebulin gene is the most frequently affected one. The nebulin gene codes for the giant sarcomeric protein nebulin, which plays a crucial role in skeletal muscle contractile performance. Muscle weakness is a hallmark feature of nemaline myopathy patients with nebulin mutations, and is caused by changes in contractile protein function, including a lower calcium-sensitivity of force generation. To date no therapy exists to treat muscle weakness in nemaline myopathy. Here, we studied the ability of the novel fast skeletal muscle troponin activator, CK-2066260, to augment force generation at submaximal calcium levels in muscle cells from nemaline myopathy patients with nebulin mutations.
methodsContractile protein function was determined in permeabilised muscle cells isolated from frozen patient biopsies. The effect of 5 μM CK-2066260 on force production was assessed.
resultsNebulin protein concentrations were severely reduced in muscle cells from these patients compared to controls, while myofibrillar ultrastructure was largely preserved. Both maximal active tension and the calcium-sensitivity of force generation were lower in patients compared to controls. Importantly, CK-2066260 greatly increased the calcium-sensitivity of force generation-without affecting the cooperativity of activation-in patients to levels that exceed those observed in untreated control muscle.
conclusionsFast skeletal troponin activation is a therapeutic mechanism to augment contractile protein function in nemaline myopathy patients with nebulin mutations and with other neuromuscular diseases.
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