ArticleHuman molecular genetics2012
Congenital myopathy-causing tropomyosin mutations induce thin filament dysfunction via distinct physiological mechanisms.
Article in Human molecular genetics, 2012. 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, 51 citations in OpenAlex.
- Alterations of actin in aging.Journal of cell science · 2026Review
- Troponin and a Myopathy-Linked Mutation inInternational journal of molecular sciences · 2023Article
- Tropomyosin 3 (TPM3) function in skeletal muscle and in myopathy.Skeletal muscle · 2023Review
- Small molecule drugs to improve sarcomere function in those with acquired and inherited myopathies.American journal of physiology. Cell physiology · 2023Review
- Molecular Mechanisms of Deregulation of Muscle Contractility Caused by the R168H Mutation in TPM3 and Its Attenuation by Therapeutic Agents.International journal of molecular sciences · 2023Article
- NEB mutations disrupt the super-relaxed state of myosin and remodel the muscle metabolic proteome in nemaline myopathy.Acta neuropathologica communications · 2022Article
- Thin filament dysfunctions caused by mutations in tropomyosin Tpm3.12 and Tpm1.1.Journal of muscle research and cell motility · 2020Review
- Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb.Acta neuropathologica communications · 2020Article
- A Stochastic Multiscale Model of Cardiac Thin Filament Activation Using Brownian-Langevin Dynamics.Biophysical journal · 2019Article
- Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy.Acta neuropathologica · 2019Article
- Congenital myopathy-related mutations in tropomyosin disrupt regulatory function through altered actin affinity and tropomodulin binding.The FEBS journal · 2019Article
- Prelamin A causes aberrant myonuclear arrangement and results in muscle fiber weakness.JCI insight · 2018Article
- Dysfunctional sarcomere contractility contributes to muscle weakness in ACTA1-related nemaline myopathy (NEM3).Annals of neurology · 2018Article
- Stabilization of F-actin by tropomyosin isoforms regulates the morphology and mechanical behavior of red blood cells.Molecular biology of the cell · 2017Article
- Software-based measurement of thin filament lengths: an open-source GUI for Distributed Deconvolution analysis of fluorescence images.Journal of microscopy · 2017Article
- Novel myosin-based therapies for congenital cardiac and skeletal myopathies.Journal of medical genetics · 2016Review
- Why Is there a Limit to the Changes in Myofilament CaFrontiers in physiology · 2016Review
- Tropomodulin 1 directly controls thin filament length in both wild-type and tropomodulin 4-deficient skeletal muscle.Development (Cambridge, England) · 2015Article
- TPM3 deletions cause a hypercontractile congenital muscle stiffness phenotype.Annals of neurology · 2015Article
- Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres.Human molecular genetics · 2015Article
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Authors and funding
8 authors at 5 institutions in 3 countries.
Funding
Abstract
In humans, congenital myopathy-linked tropomyosin mutations lead to skeletal muscle dysfunction, but the cellular and molecular mechanisms underlying such dysfunction remain obscure. Recent studies have suggested a unifying mechanism by which tropomyosin mutations partially inhibit thin filament activation and prevent proper formation and cycling of myosin cross-bridges, inducing force deficits at the fiber and whole-muscle levels. Here, we aimed to verify this mechanism using single membrane-permeabilized fibers from patients with three tropomyosin mutations (TPM2-null, TPM3-R167H and TPM2-E181K) and measuring a broad range of parameters. Interestingly, we identified two divergent, mutation-specific pathophysiological mechanisms. (i) The TPM2-null and TPM3-R167H mutations both decreased cooperative thin filament activation in combination with reductions in the myosin cross-bridge number and force production. The TPM3-R167H mutation also induced a concomitant reduction in thin filament length. (ii) In contrast, the TPM2-E181K mutation increased thin filament activation, cross-bridge binding and force generation. In the former mechanism, modulating thin filament activation by administering troponin activators (CK-1909178 and EMD 57033) to single membrane-permeabilized fibers carrying tropomyosin mutations rescued the thin filament activation defect associated with the pathophysiology. Therefore, administration of troponin activators may constitute a promising therapeutic approach in the future.
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