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• W1992125306 abstract "The mechanisms underlying the Frank-Starling Law, i.e. the relationship between the strength of cardiac contraction and its end-diastolic volume, at the resting heart rate and at increased and decreased rates have remained an enigma for over a century. Recent evidence, however, related the mechanisms to the force–length relationship in cardiac fibres and to the properties of the fibre's sarcomeres (Sela & Landesberg, 2009). Following phase 0 of the action potential, influx of Ca2+ via L-type Ca2+ channel induces Ca2+ release from the sarcoplasmic reticulum, the majority of which binds to troponin. Binding of Ca2+ to troponin C induces a cascade of structural changes within the troponin complex: conformation movement of tropomyosin, exposing the myosin binding sites on the actin molecules, and cross-bridge attachment. Among other mechanisms, the effects of posttranslational modifications on multiple myofibrillar substrates and on Ca2+ cycling proteins have been suggested to control the force–length relationship. Calcium affinity is generally reduced (shifted to a greater calcium concentration at half-maximal force generation) during phosphorylation, but there is a significant increase in the Hill coefficient which is often interpreted as a result of cooperative strong cross-bridge binding. The different modification sites and target proteins in the sarcomere can take part in controlling the force–length relationship, specifically with an increase in the heart beating rate. Several kinases have been suggested to dominate the regulation of sarcomere function: protein kinase A (PKA), protein kinase C, Ca2+–calmodulin-dependent protein kinase II, etc. (Streng et al. 2013). However, much of the recent work on sarcomere protein phosphorylation has focused on PKA.An increase in PKA-mediated phosphorylation in response to β-adrenergic stimulation decreases troponin affinity for Ca2+ and enhances cross-bridge cycling kinetics. These positive lusitropic effects enable the heart to relax more rapidly when the heart rate increases (Streng et al. 2013). However, the exact PKA phosphorylation targets in the myofibrils that affect cardiac contractility are still controversial. A recent article published in The Journal of Physiology addresses this knowledge gap by reporting that cardiac troponin I (cTnI) phosphorylation sites at serine 23/24 control force–length relationships over the entire working sarcomere length range of rat cardiac muscle (Hanft et al. 2013). Their data demonstrate that phosphorylation increases the steepness of the force–length relationship, which suggests altered responsiveness of thin filament activation by sarcomere strain. Interestingly, similar targets have been identified in human cardiac tissue (Wijnker et al. 2013). The latter report has documented that human PKA phosphorylation at serine 23/24 of cardiac cTnI decreases troponin affinity for Ca2+, without an effect on cross-bridge cycling kinetics. Similar results have been documented in mouse trabeculae (Colson et al. 2012). Note, however, that different phosphorylation sites on the myosin binding protein-C modulate the kinetics of force development as well as the troponin affinity for Ca2+ (Colson et al. 2012).Literature reports are contradictory on whether the sarcomere properties, the major basis for the Frank-Starling mechanism, are altered by β-adrenergic activation via PKA (review in Streng et al. 2013). In a prior report Hanft et al. suggest an explanation for this controversy: cardiac myocytes exhibit two populations of length–tension relationships, one steep, like fast-twitch fibres, and the other shallow, like slow-twitch fibres, that can be shifted to a steep one by PKA-mediated phosphorylation of myofilament proteins (Hanft & McDonald, 2010). The fast-twitch skeletal muscle fibre length–tension relationship, however, shows little or no response to PKA-mediated phosphorylation of troponin.Slow twitch skeletal muscle has a relatively shallow length–tension relationship that is universally unresponsive to PKA (Hanft & McDonald, 2010). Hanft et al. (2013) also investigated whether switching TnI from the skeletal to the cardiac isoform can induce a force–length relationship that is PKA dependent. They found that when the majority of skeletal TnI is replaced by cTnI, phosphorylation of cTnI by PKA can then modulate the force–length relationship in a rat slow-twitch skeletal muscle fibre. Therefore they concluded that phosphorylation of cTnI at serine 23/24 can modulate the force–length mechanics of any striated muscle.Because the sarcomeres are the major ATP consumers and the mitochondria are the major ATP supplier in the heart, the same mechanism, PKA signalling, may be a common pathway to match ATP supply to demand. Specifically, the mitochondria around the myofilament may directly sense the local PKA gradient and adapt the ATP production rate accordingly to maintain a steep length–force relationship. Evidence has recently emerged of the existence of cAMP–PKA signalling around and inside the mitochondria (for review see Valsecchi et al. 2013). PKA was proposed to phosphorylate different enzymes in the mitochondria taking part in ATP production, and therefore changes in its local concentration can serve as a second messenger for matching ATP supply to demand. Specifically, recent evidence in sinoatrial node, i.e. the heart's primary pacemaker, illustrates that both an increase in mitochondrial Ca2+ and an increase in Ca2+-activated cAMP–PKA signalling regulates the increase in ATP supply to meet ATP demand above the basal level (no β-adrenergic activation; Yaniv et al. 2013).Finally, the paper of Hanft et al. has direct clinical interest because mutations in cTnI have been associated with cardiomyopathies. Specifically, mutant mice with knock-in cTnI genes that limit its phosphorylation exhibit a limited lusitropic effect in response to β-adrenergic stimulation which may induce a hypertrophic response (Wang et al. 2012). The paper of Hanft et al. (2013) therefore inspires future research to understand how a change in specific cTnI phosphorylation sites affects cardiac contractility in different pathological states." @default.
• W1992125306 created "2016-06-24" @default.
• W1992125306 creator A5049573849 @default.
• W1992125306 date "2013-12-15" @default.
• W1992125306 modified "2023-09-23" @default.
• W1992125306 title "Cardiac troponin I phosphorylation and the force-length relationship" @default.
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• W1992125306 doi "https://doi.org/10.1113/jphysiol.2013.265090" @default.
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