ArticleProceedings of the National Academy of Sciences of the United States of America2016
Titin strain contributes to the Frank-Starling law of the heart by structural rearrangements of both thin- and thick-filament proteins.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 131 papers, 1 of them a synthesis that pooled it.
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131 citing papers in PubMed, 1 synthesis or guideline pooled it, 185 citations in OpenAlex.
- Implications of S-glutathionylation of sarcomere proteins in cardiac disorders, therapies, and diagnosis.Frontiers in cardiovascular medicine · 2022Pooled it
- Diastolic contributors in cardiomyocytes of a cardiometabolic HFpEF-like mouse model.The Journal of general physiology · 2026Article
- Cross-bridge model for predicting muscle short-range stiffness during movement.PLoS computational biology · 2026Article
- Effects of chemical myosin II cross-bridge inhibitors on eccentric force production in skinned muscle fibres.Experimental physiology · 2026Article
- The CabioRxiv : the preprint server for biology · 2026Article
- A primer on the methods of skeletal and cardiac muscle mechanics using permeabilized preparations.The Journal of general physiology · 2026Review
- Human atrial skinned muscle fibers exhibit reduced length-dependent activation but show faster force development kinetics than ventricular muscle.Journal of molecular and cellular cardiology · 2026Article
- Mending the Achilles heels of titin in cardiac and musculoskeletal disease.Biophysical reviews · 2026Review
- Cardiac myosin-binding protein-C acts as a tunable load sensor to regulate afterload dependence of ventricular function.American journal of physiology. Heart and circulatory physiology · 2025Article
- Mavacamten facilitates myosin head ON-to-OFF transitions and shortens thin filament length in relaxed mouse skeletal muscle.Physiological reports · 2025Article
- CaJournal of molecular and cellular cardiology · 2025Article
- Myosin-actin crossbridge independent sarcomere length induced CaJournal of molecular and cellular cardiology · 2025Article
- Thick-Filament-Based Regulation and the Determinants of Force Generation.Biomedicines · 2025Article
- The role of mechanosignaling in the control of myocardial mass.American journal of physiology. Heart and circulatory physiology · 2025Review
- The Heart Is a Smart Pump: Mechanotransduction Mechanisms of the Frank-Starling Law and the Anrep Effect.Annual review of physiology · 2025Review
- Functional control of myosin motors in the cardiac cycle.Nature reviews. Cardiology · 2025Review
- The distinctive mechanical and structural signatures of residual force enhancement in myofibers.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Load-dependence of the activation of myosin filaments in heart muscle.The Journal of physiology · 2024Article
- Calcium has a direct effect on thick filament activation in porcine myocardium.The Journal of general physiology · 2024Article
- Cardiac length-dependent activation driven by force-dependent thick-filament dynamics.Biophysical journal · 2024Article
71 more citing papers are in PubMed but not listed here.
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7 authors at 3 institutions in 1 country.
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Abstract
The Frank-Starling mechanism of the heart is due, in part, to modulation of myofilament Ca(2+) sensitivity by sarcomere length (SL) [length-dependent activation (LDA)]. The molecular mechanism(s) that underlie LDA are unknown. Recent evidence has implicated the giant protein titin in this cellular process, possibly by positioning the myosin head closer to actin. To clarify the role of titin strain in LDA, we isolated myocardium from either WT or homozygous mutant (HM) rats that express a giant splice isoform of titin, and subjected the muscles to stretch from 2.0 to 2.4 μm of SL. Upon stretch, HM compared with WT muscles displayed reduced passive force, twitch force, and myofilament LDA. Time-resolved small-angle X-ray diffraction measurements of WT twitching muscles during diastole revealed stretch-induced increases in the intensity of myosin (M2 and M6) and troponin (Tn3) reflections, as well as a reduction in cross-bridge radial spacing. Independent fluorescent probe analyses in relaxed permeabilized myocytes corroborated these findings. X-ray electron density reconstruction revealed increased mass/ordering in both thick and thin filaments. The SL-dependent changes in structure observed in WT myocardium were absent in HM myocardium. Overall, our results reveal a correlation between titin strain and the Frank-Starling mechanism. The molecular basis underlying this phenomenon appears not to involve interfilament spacing or movement of myosin toward actin but, rather, sarcomere stretch-induced simultaneous structural rearrangements within both thin and thick filaments that correlate with titin strain and myofilament LDA.
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