Changes in Titin Isoform Expression in Pacing-Induced Cardiac Failure Give Rise to Increased Passive Muscle Stiffness

Wu, Yingliang; Bell, Stephen P.; Trombitás, K; Witt, Christian; Labeit, Siegfried; LeWinter, Martin M.; Granzier, Henk

doi:10.1161/01.cir.0000029804.61510.02

Cited by 162 publications

(135 citation statements)

References 41 publications

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“…Extracellular matrix function and myocyte adhesion capacity are decreased, and plasma catecholamines, endothelin, and renin activity are all increased. 16,17 Our paced NTG rabbits lacked any detectable ␣-MHC protein in the ventricles, a feature consistent with human DCM. 3,4 In the TG animals, the ␤-MHC promoter continued to express ␣-MHC.…”

Section: Discussionsupporting

confidence: 60%

“…Rapid ventricular pacing results in depressed myocardial function in many species with clinical and laboratory findings very similar to that seen in human DCM. 16,17 We applied TIC to the ␣-MHC TG rabbits and developed a protocol similar to that of Jeron et al 18 (Figure 2). The initial cohort consisted of 6 TG and 7 NTG 15-month line 45 rabbits of mixed gender (2 females and 4 males in the TG group, 2 females and 5 males in the NTG group).…”

Section: Resultsmentioning

confidence: 99%

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Forced Expression of α-Myosin Heavy Chain in the Rabbit Ventricle Results in Cardioprotection Under Cardiomyopathic Conditions

et al. 2005

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Background-The biochemical differences between the 2 mammalian cardiac myosin heavy chains (MHCs), ␣-MHC and ␤-MHC, are well described, but the physiological consequences of basal isoform expression and isoform shifts in response to altered cardiac load are not clearly understood. Mature human ventricle contains primarily the ␤-MHC isoform. However, the ␣-MHC isoform can be detected in healthy human ventricle and appears to be significantly downregulated in failing hearts. The unique biochemical properties of the ␣-MHC isoform might offer functional advantages in a failing heart that is expressing only the ␤-MHC isoform. This hypothesis cannot be tested in mice or rats because both species express ␣-MHC as the predominant isoform. Methods and Results-To test the effects of persistent ␣-MHC expression on the background of ␤-MHC, we made transgenic (TG) rabbits that expressed rabbit ␣-MHC cDNA in the ventricle so that the endogenous myosin was partially replaced by the transgenically encoded species. Molecular, histological, and functional analyses showed no significant baseline effects in the TG rabbits compared with nontransgenic (NTG) littermates. To determine whether ␣-MHC expression afforded any advantages to stressed myocardium, a cohort of TG and NTG rabbits was subjected to rapid ventricular pacing. Although both the TG and NTG rabbits developed dilated cardiomyopathy, the TG rabbits had a higher shortening fraction, less septal thinning, and more normal ϮdP/dt than paced NTG rabbits. Conclusions-Transgenic expression of ␣-MHC does not have any apparent detrimental effects under basal conditions and is cardioprotective in experimental tachycardia-induced cardiomyopathy.

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Section: Discussionsupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Forced Expression of α-Myosin Heavy Chain in the Rabbit Ventricle Results in Cardioprotection Under Cardiomyopathic Conditions

et al. 2005

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“…118 A reduced N2BA:N2B expression ratio was also seen in tachypaced dog hearts. 119,120 Taken together, eccentric remodeled hearts with systolic dysfunction (DCM/HFrEF/chronic ischemic cardiomyopathy) frequently seem to express higher N2BA proportions than healthy hearts ( Figure 5A), thereby reducing myofibrillar passive stiffness ( Figure 5B). An exception is the tachypaced dog HF model, which increases the proportion of stiff N2B titin.…”

Section: Adjustment Of Titin Stiffness By Isoform Switching In Nonfaimentioning

confidence: 97%

Gigantic Business

Linke

Hamdani

2014

Circulation Research

292

232

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With every heartbeat, our cardiomyocytes are exposed to variable degrees of stress and strain of both internal and external origin. The unique mechanical properties of these myocytes are determined by the sarcomeric cytoskeleton. The actin (thin) and myosin (thick) filaments of the sarcomere are mainly relevant for active force generation, whereas the titin filaments determine sarcomeric viscoelasticity. The giant protein titin, which is the focus of this review, has various roles beyond viscoelastic force generation 1-3 : (1) it keeps the thick filaments centered in the sarcomere, allowing optimum active force development; (2) it is important for the assembly of the sarcomeres; (3) it participates in mechano-chemical signaling events via some of its binding partners; and (4) it may be crucial for the length-dependent activation of the contractile apparatus, which underlies the Frank-Starling law. During the past decade, we have learned that titin elasticity is highly variable in the developing and the adult healthy heart and that it can be pathologically altered in heart disease. These alterations greatly affect the extensibility and the diastolic passive stiffness of myocardium and presumably also the mechanosensitivity. Moreover, TTN, which encodes the titin protein, has been recognized as a major human disease gene. In this context, the properties and functions of cardiac titin have become of interest in the continuing search for the molecular origins of human heart disease and the identification of novel potential targets for therapeutic intervention. In our review, we begin with a short clinical perspective establishing the link between diastolic stiffness and titin and briefly compare the importance of titin versus collagen for myocardial passive stiffness. We then cover some details of titin protein structure and elasticity, before summarizing how titin-binding partners affect titin properties and broaden the range of titin functions, with a special focus on the standing of titin in pathways of protein quality control. We continue with a current overview of titin mutations in human skeletal muscle and heart disease. The remainder of the review deals with the contribution of titin to diastolic stiffness and how it is modulated in normal and failing hearts by mechanisms such as titin-isoform switching, titin phosphorylation (including heart failure [HF]-related alterations of it), and oxidative modifications. Clinical Context: Diastolic Function and Diastolic AbnormalitiesDiastolic function has moved into the focus of HF research, because an increasing number of patients with HF (≥50%) present with diastolic rather than systolic dysfunction. 4 Common abnormalities of diastolic function include impaired left ventricular (LV) relaxation, decreased LV distensibility, increased LV end-diastolic stiffness, and pericardial and right ventricular constraint. These abnormalities have been suggested to be contributing factors in diastolic HF or HF with a preserved ejection fraction (HFpEF).5 HFpEF is accompanied by ...

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“…The ratio of the N2BA to N2B isoforms affects passive tension in the heart with muscle containing higher N2BA proportions exhibiting lower tension at a given sarcomere length. The isoform ratio was shown to be altered by hypertension in the rat [16] and, artificially, by chronic pacing in the dog [17]. A genome-wide linkage scan found that exercise induced changes in cardiac stroke volume was linked to the titin gene chromosome region [18].…”

Section: Introductionmentioning

confidence: 99%

Mutation that dramatically alters rat titin isoform expression and cardiomyocyte passive tension

Greaser

Warren

Esbona

et al. 2008

Journal of Molecular and Cellular Cardiology

102

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Titin is a very large alternatively spliced protein that performs multiple functions in heart and skeletal muscle. A rat strain is described with an autosomal dominant mutation that alters the isoform expression of titin. While wild type animals go through a developmental program where the 3.0 MDalton N2B becomes the major isoform expressed by two to three weeks after birth (~85%), the appearance of the N2B is markedly delayed in heterozygotes and never reaches more than 50% of the titin in the adult. Homozygote mutants express a giant titin of the N2BA isoform type (3.9 MDalton) that persists as the primary titin species through ages of more than one and half years. The mutation does not affect the isoform switching of troponin T, a protein that also is alternatively spliced with developmental changes. The basis for the apparently greater size of the giant titin in homozygous mutants was not determined, but additional length was not due to inclusion of sequence from larger numbers of PEVK exons or the Novex III exon. Passive tension measurements using isolated cardiomyocytes from homozygous mutants showed that cells could be stretched to sarcomere lengths greater than 4 µm without breakage. This novel rat model should be useful for exploring the potential role of titin in the Frank-Starling relationship and mechano-sensing/signaling mechanisms.

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Changes in Titin Isoform Expression in Pacing-Induced Cardiac Failure Give Rise to Increased Passive Muscle Stiffness

Cited by 162 publications

References 41 publications

Forced Expression of α-Myosin Heavy Chain in the Rabbit Ventricle Results in Cardioprotection Under Cardiomyopathic Conditions

Forced Expression of α-Myosin Heavy Chain in the Rabbit Ventricle Results in Cardioprotection Under Cardiomyopathic Conditions

Gigantic Business

Mutation that dramatically alters rat titin isoform expression and cardiomyocyte passive tension

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