skinned muscle fiber
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2016 ◽  
Vol 113 (50) ◽  
pp. 14426-14431 ◽  
Author(s):  
Dennis M. Abraham ◽  
Robert T. Davis ◽  
Chad M. Warren ◽  
Lan Mao ◽  
Beata M. Wolska ◽  
...  

The Frank–Starling law of the heart is a physiological phenomenon that describes an intrinsic property of heart muscle in which increased cardiac filling leads to enhanced cardiac contractility. Identified more than a century ago, the Frank–Starling relationship is currently known to involve length-dependent enhancement of cardiac myofilament Ca2+ sensitivity. However, the upstream molecular events that link cellular stretch to the length-dependent myofilament Ca2+ sensitivity are poorly understood. Because the angiotensin II type 1 receptor (AT1R) and the multifunctional transducer protein β-arrestin have been shown to mediate mechanosensitive cellular signaling, we tested the hypothesis that these two proteins are involved in the Frank–Starling mechanism of the heart. Using invasive hemodynamics, we found that mice lacking β-arrestin 1, β-arrestin 2, or AT1R were unable to generate a Frank–Starling force in response to changes in cardiac volume. Although wild-type mice pretreated with the conventional AT1R blocker losartan were unable to enhance cardiac contractility with volume loading, treatment with a β-arrestin–biased AT1R ligand to selectively activate β-arrestin signaling preserved the Frank–Starling relationship. Importantly, in skinned muscle fiber preparations, we found markedly impaired length-dependent myofilament Ca2+ sensitivity in β-arrestin 1, β-arrestin 2, and AT1R knockout mice. Our data reveal β-arrestin 1, β-arrestin 2, and AT1R as key regulatory molecules in the Frank–Starling mechanism, which potentially can be targeted therapeutically with β-arrestin–biased AT1R ligands.


1995 ◽  
Vol 73 (10) ◽  
pp. 1451-1457 ◽  
Author(s):  
G. Suarez-Kurtz ◽  
C. G. Ponte ◽  
M.-P. Catinot ◽  
Y. Mounier ◽  
R. Vianna-Jorge

Chemically skinned muscle fibers from rat extensor digitorum longus muscle were used to study the effects of uridine triphosphate (UTP) on Ca2+ uptake and release by the sarcoplasmic reticulum (SR) and on Ca2+-activated tensions. Total replacement (2.5 mM) of adenosine triphosphate (ATP) with UTP (i) increased submaximal Ca2+-induced tension (pCa 6.2–5.8) but diminished Po, the maximum tension elicited by pCa 4.2, by ca. 15%; (ii) markedly reduced Ca2+ uptake by the SR (evaluated by caffeine-elicited tension); and (iii) induced tension in Ca2+-loaded fibers. The UTP-induced tension averaged 55% of Po and its rates of development and decay were considerably slower than those of caffeine-evoked tension. The UTP-induced tension (i) depended on the Ca2+-loading conditions; (ii) was reversibiy blocked by brief (15 s) exposures of Ca2+-loaded fibers to 5 mM EGTA or by pretreatment with caffeine; (iii) was abolished by functional disruption of the SR with the nonionic detergent Brij-58; and (iv) persisted after blockade of the SR Ca2+ release channels with ruthenium red. Exposure of Ca2+-loaded fibers to UTP depressed the tension elicited subsequently by caffeine, and enhanced the rate of depletion of caffeine-sensitive Ca2+ stores during soaking in relaxing solutions containing 5 mM EGTA. The UTP-induced tension is attributed to increased release of Ca2+ from the SR, via a ruthenium red insensitive pathway(s), combined with reduced Ca2+ uptake by the SR and increased Ca2+ affinity of the contractile proteins.Key words: skinned muscle fiber, UTP-induced tension, tension–pCa relationship, sarcoplasmic reticulum, calcium transport.


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