期刊
JOURNAL OF GENERAL PHYSIOLOGY
卷 143, 期 6, 页码 782-796出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1085/jgp.201311125
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资金
- EU (STREP project BIG HEART, seventh European Framework Program) [241577]
- Telethon [GGP13162]
- Heart and Stroke Foundations of Alberta, the North West Territories and Nunavut
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.
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