Impact of detubulation on force and kinetics of cardiac muscle contraction
Authors: Ferrantini C., Coppini R., Sacconi L., Tosi B., Zhang M.L., Wang G.L., de Vries E., Hoppenbrouwers E., Pavone F.S., Cerbai E., Tesi C., Poggesi C., Ter Keurs H.E.
Autors Affiliation: Center of Molecular Medicine, Department of Experimental and Clinical Medicine, Division of Physiology, Department of NeuroFarBa, Division of Pharmacology, LENS, European Laboratory for Non-Linear Spectroscopy, and Department of Physics, University of Florence, 50121 Florence, Italy; National Institute of Optics, National Research Council, 50019 Sesto Fiorentino, Italy; Department of Cardiac Sciences of the Libin Institute at the Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 1N4, Canada
Abstract: Action potential-driven Ca2+ currents from the transverse tubules (t-tubules) trigger synchronous Ca2+ release from the sarcoplasmic reticulum of cardiomyocytes. Loss of t-tubules has been reported in cardiac diseases, including heart failure, but the effect of uncoupling t-tubules from the sarcolemma on cardiac muscle mechanics remains largely unknown. We dissected intact rat right ventricular trabeculae and compared force, sarcomere length, and intracellular Ca2+ in control trabeculae with trabeculae in which the t-tubules were uncoupled from the plasma membrane by formamide-induced osmotic shock (detubulation). We verified disconnection of a consistent fraction of t-tubules from the sarcolemma by two-photon fluorescence imaging of FM4-64-labeled membranes and by the absence of tubular action potential, which was recorded by random access multiphoton microscopy in combination with a voltage-sensitive dye (Di-4-AN(F)EPPTEA). Detubulation reduced the amplitude and prolonged the duration of Ca2+ transients, leading to slower kinetics of force generation and relaxation and reduced twitch tension (1 Hz, 30 degrees C, 1.5 mM [Ca2+](o)). No mechanical changes were observed in rat left atrial trabeculae after formamide shock, consistent with the lack of t-tubules in rodent atrial myocytes. Detubulation diminished the rate-dependent increase of Ca2+-transient amplitude and twitch force. However, maximal twitch tension at high [Ca2+](o) or in post-rest potentiated beats was unaffected, although contraction kinetics were slower. The ryanodine receptor (RyR)2 Ca-sensitizing agent caffeine (200 mu M), which increases the velocity of transverse Ca2+ release propagation in detubulated cardiomyocytes, rescued the depressed contractile force and the slower twitch kinetics of detubulated trabeculae, with negligible effects in controls. We conclude that partial loss of t-tubules leads to myocardial contractile abnormalities that can be rescued by enhancing and accelerating the propagation of Ca2+-induced Ca2+ release to orphan RyR2 clusters.
Journal/Review: JOURNAL OF GENERAL PHYSIOLOGY
Volume: 143 (6) Pages from: 783 to: 797
More Information: This work was supported by the EU (STREP project 241577 \”BIG HEART,\” seventh European Framework Program, to C. Poggesi), the Telethon (grant GGP13162), and the Heart and Stroke Foundations of Alberta, the North West Territories and Nunavut.DOI: 10.1085/jgp.201311125Citations: 23data from “WEB OF SCIENCE” (of Thomson Reuters) are update at: 2019-10-13References taken from IsiWeb of Knowledge: (subscribers only)Connecting to view paper tab on IsiWeb: Click hereConnecting to view citations from IsiWeb: Click here