ArticleThe Journal of clinical investigation2024
A Laing distal myopathy-associated proline substitution in the β-myosin rod perturbs myosin cross-bridging activity.
Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
7 citing papers in PubMed, 1 synthesis or guideline pooled it, 9 citations in OpenAlex.
- ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation.Circulation. Genomic and precision medicine · 2025Pooled it
- Review
- Longevity of cardiac and skeletal muscle proteins is dependent on tissue and subcellular compartmentation patterns.Cell reports · 2026Article
- Cardiac Myosin Activators in Heart Failure: Experimental Advances Amid Clinical Uncertainty.Drug design, development and therapy · 2026Review
- Article
- Reassessing the unifying hypothesis for hypercontractility caused by myosin mutations in hypertrophic cardiomyopathy.The EMBO journal · 2024Review
- A therapeutic leap: how myosin inhibitors moved from cardiac interventions to skeletal muscle myopathy solutions.The Journal of clinical investigation · 2024Article
Corrections and comments
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Authors and funding
13 authors at 8 institutions in 7 countries.
Funding
Abstract
Proline substitutions within the coiled-coil rod region of the β-myosin gene (MYH7) are the predominant mutations causing Laing distal myopathy (MPD1), an autosomal dominant disorder characterized by progressive weakness of distal/proximal muscles. We report that the MDP1 mutation R1500P, studied in what we believe to be the first mouse model for the disease, adversely affected myosin motor activity despite being in the structural rod domain that directs thick filament assembly. Contractility experiments carried out on isolated mutant muscles, myofibrils, and myofibers identified muscle fatigue and weakness phenotypes, an increased rate of actin-myosin detachment, and a conformational shift of the myosin heads toward the more reactive disordered relaxed (DRX) state, causing hypercontractility and greater ATP consumption. Similarly, molecular analysis of muscle biopsies from patients with MPD1 revealed a significant increase in sarcomeric DRX content, as observed in a subset of myosin motor domain mutations causing hypertrophic cardiomyopathy. Finally, oral administration of MYK-581, a small molecule that decreases the population of heads in the DRX configuration, significantly improved the limited running capacity of the R1500P-transgenic mice and corrected the increased DRX state of the myofibrils from patients. These studies provide evidence of the molecular pathogenesis of proline rod mutations and lay the groundwork for the therapeutic advancement of myosin modulators.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.