Titin-Isoform Dependence of Titin-Actin Interaction and Its Regulation by S100A1/<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msup><mml:mtext>Ca</mml:mtext><mml:mrow><mml:mtext>2</mml:mtext><mml:mo>+</mml:mo></mml:mrow></mml:msup></mml:math>in Skinned Myocardium

Fukushima, Hideto; Chung, Charles S.; Granzier, Henk

doi:10.1155/2010/727239

Cited by 25 publications

(36 citation statements)

References 49 publications

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“…In-vitro motility assays (Yamasaki et al 2001; Linke et al 2002), single molecule studies (Bianco et al 2007), and myocyte mechanics (Yamasaki et al 2001) have established that the interaction between PEVK and actin retards filament sliding during systole and diastole. It has been shown that the PEVK-actin interaction is present in all cardiac isoforms and is a source of hysteresis (Fukushima et al 2010). Recently, studies using PEVK KO mice showed that the PEVK-actin interaction significantly contributes to viscosity in vivo (Chung et al 2011b).…”

Section: Viscoelasticitymentioning

confidence: 99%

Titin-based tension in the cardiac sarcomere: Molecular origin and physiological adaptations

Anderson

Granzier

2012

Progress in Biophysics and Molecular Biology

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The passive stiffness of cardiac muscle plays a critical role in ventricular filling during diastole and is determined by the extracellular matrix and the sarcomeric protein titin. Titin spans from the Z-disk to the M-band of the sarcomere and also contains a large extensible region that acts as a molecular spring and develops passive force during sarcomere stretch. This extensible segment is titin's I-band region, and its force-generating mechanical properties determine titin-based passive tension. The properties of titin's I-band region can be modulated by isoform splicing and post-translational modification and are intimately linked to diastolic function. This review discusses the physical origin of titin-based passive tension, the mechanisms that alter titin stiffness, and titin's role in stress-sensing signaling pathways.

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Section: Viscoelasticitymentioning

confidence: 99%

Titin-based tension in the cardiac sarcomere: Molecular origin and physiological adaptations

Anderson

Granzier

2012

Progress in Biophysics and Molecular Biology

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“…Periodically, it appears at the Z-and the M-line as well as within both the I-and A-band. [50][51][52] Within the I-band, S100A1 seems to interact with the PEVK domain of the giant protein titin in a Ca 2+ -dependent manner. 50 Titin is mainly responsible for the preservation of passive tension in CM and a single titin molecule spans half the length of a sarcomere.…”

Section: Exploring S100a1's Molecular and Cellular Biologymentioning

confidence: 99%

“…They furthermore proposed that this interaction frees the actin filaments from titin before active contraction, thereby reducing pre-contractile passive tension and facilitating initiation of contraction. 50,51 If S100A1 also interacts with titin at the A-band or with another sarcomeric protein remains to be established.…”

Section: Exploring S100a1's Molecular and Cellular Biologymentioning

confidence: 99%

“…[39][40][41]45 In addition, facilitated dissociation of Ca 2+ from the myofilaments and a decreased sarcomeric passive tension contributes to the diastolic improvements in CM. 50,51 In systole, S100A1-mediated increase in SR Ca 2+ load together with increased RyR2 opening and SR Ca 2+ release is responsible for increased cellular Ca 2+ transients, thereby supporting contractile performance. 40,[42][43][44] Regarding the increased energy demand that originates from increased SR and myofilament ATPase activity, S100A1 might be able to meet this demand by increasing ATP generation and cytoplasmic availability.…”

Section: Exploring S100a1's Molecular and Cellular Biologymentioning

confidence: 99%

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Targeting S100A1 in heart failure

Ritterhoff

Most

2012

Gene Ther

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Heart failure (HF) is the common endpoint of many cardiovascular diseases with a 1-year survival rate of about 50% in advanced stages. Despite increasing survival rates in the past years, current standard therapeutic strategies are far away from being optimal. For this reason, the concept of cardiac gene therapy for the treatment of HF holds great potential to improve disease progression, as it specifically targets key pathologies of diseased cardiomyocytes (CM). The small calcium (Ca 2+ )-binding protein S100A1 presents a promising target for cardiac gene therapy, as it has been identified as a central regulator of cardiac performance and the Ca 2+ -driven network within CM. S100A1 was shown to regulate sarcoplasmic reticulum, sarcomere and mitochondrial function by modulating target protein activity. Furthermore, deranged S100A1 expression has been linked to HF in human ischemic and dilated cardiomyopathies as well as in various HF animal models. Proof-of-concept studies in small and large animal models as wells as in human failing CM could demonstrate feasibility and efficacy of S100A1 genetically targeted therapy. This review summarizes the developmental steps of S100A1 gene therapy for the implementation into first human clinical trials.

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“…Although detailed proof of the molecular mechanism of S100A1's actions is not reported, Brinks et al speculate that they result from direct interaction of S100A1 with SR and mitochondrial proteins (i.e., RyR, SERCA, and F 1 -ATPase). Recent studies also indicate that S100A1 may enhance contractility and relaxation dynamics by regulating the interaction between the sarcomeric proteins titin and cardiac actin (13).…”

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confidence: 99%

S100A1: Another Step Toward Therapeutic Development for Heart Failure

Belmonte¹,

Margulies²,

Blaxall³

2011

Journal of the American College of Cardiology

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It has been nearly 130 years since Sydney Ringer's astute observations on the indispensability of extracellular Ca 2ϩ to heart muscle contraction (1). At the cellular level, we now know that fluctuations of cytosolic Ca 2ϩ are coordinated by several myocyte proteins in order to functionally couple the cardiac action potential to sarcomeric shortening and mitochondrial energy production. This elegant myocardial Ca 2ϩ cycling demands precise regulation of intracellular Ca 2ϩ , as evidenced by the numerous examples of cardiac dysfunction arising from altered expression or activity of Ca 2ϩ handling proteins (2-5). One such protein, S100A1, has attracted the interest of cardiac scientists because of its myocardial enrichment, known interactions with several other Ca 2ϩ See page 966 handling proteins, including ryanodine receptors (RyR) and sarcoplasmic reticulum (SR) Ca 2ϩ ATPase (SERCA), and the observation that its expression is progressively downregulated in failing myocardium (6). Furthermore, cardiacspecific S100A1 deletion accelerated the progression to heart failure (HF) after myocardial infarction in mice (7), whereas restoration of S100A1 expression via intracoronary adenoviral gene delivery to failing rat hearts normalized contractile performance (8).In this issue of the Journal, Brinks et al. (9) provide the first evidence that S100A1 gene delivery can functionally improve human failing cardiomyocytes. Using ventricular tissue from ischemic HF patients, cardiomyocytes were isolated and infected with adenovirus encoding S100A1 (Ad-S100A1). The authors show that restoring S100A1 expression improved failing cardiomyocyte fractional shortening, relaxation rates, and Ca 2ϩ transients compared with control cells. Moreover, Ad-S100A1 improved both ratedependent and ␤-adrenergic-mediated contractile reserve, while ameliorating markers of abnormal energy metabolism in isolated cardiomyocytes and mitochondria from failing hearts. Despite increases in SR Ca 2ϩ load, elevated S100A1 expression reduced diastolic SR Ca 2ϩ leak and the propensity for aberrant depolarizations.From a mechanistic standpoint, Brinks et al. (9) propose that S100A1 enhances failing cardiomyocyte contraction through improved cytosolic Ca 2ϩ handling. In this regard, it is particularly interesting that the ability of S100A1 to improve Ca 2ϩ transients and pathological shorteningfrequency responses occurred without altering either pathological decreases in SERCA abundance or increases in sarcolemmal Na ϩ /Ca 2ϩ exchanger that have been previously identified as major determinants of these defects in human myocardium (10 -12). Although detailed proof of the molecular mechanism of S100A1's actions is not reported, Brinks et al. speculate that they result from direct interaction of S100A1 with SR and mitochondrial proteins (i.e., RyR, SERCA, and F 1 -ATPase). Recent studies also indicate that S100A1 may enhance contractility and relaxation dynamics by regulating the interaction between the sarcomeric proteins titin and cardiac actin (13).These findin...

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Titin-Isoform Dependence of Titin-Actin Interaction and Its Regulation by S100A1/Ca2+in Skinned Myocardium

Cited by 25 publications

References 49 publications

Titin-based tension in the cardiac sarcomere: Molecular origin and physiological adaptations

Titin-based tension in the cardiac sarcomere: Molecular origin and physiological adaptations

Targeting S100A1 in heart failure

S100A1: Another Step Toward Therapeutic Development for Heart Failure

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