Cardiac myofilaments: from proteome to pathophysiology

Jin, Wenhai; Brown, Angela; Murphy, Anne M.

doi:10.1002/prca.200780075

Cited by 15 publications

(22 citation statements)

References 110 publications

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“…Myofilament protein PTMs have emerged as a key mechanism regulating cardiac contractility, and increasing evidence has shown that the alteration of myofilament protein PTMs, particularly phosphorylation, can contribute to contractile dysfunction and heart failure [9–12, 25, 26, 29, 30]. Additionally, studies in humans, as well as large and small animals, have shown that aging and pathological cardiac conditions induce transmural changes in contractile function that correlate with differences in the modification status of myofilament proteins [1, 2, 5].…”

Section: Discussionmentioning

confidence: 99%

“…Contractile heterogeneity, in particular, has taken on increased significance with the demonstration that transmural changes in myocardial contractility not only occur in the failing heart [1–3], but may also be predictive of adverse cardiac events [7, 8]. Myocardial contractility is governed by a number of factors, including the size and duration of Ca 2+ transients, as well as the intrinsic properties of the contractile apparatus, which depend primarily on the expression of myofilament protein isoforms and post-translational modifications (PTMs) [9–12]. …”

Section: Introductionmentioning

confidence: 99%

“…Myofilament protein PTMs have emerged as a key mechanism regulating cardiac contractility in health and disease [9–12]. Previous studies in humans, as well as large and small animals, have shown that aging and pathological cardiac conditions induce contractile heterogeneity across the free wall of the left ventricle (LV) that correlates with differences in the modification status of myofilament proteins [1, 2, 5].…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive assessment of chamber-specific and transmural heterogeneity in myofilament protein phosphorylation by top-down mass spectrometry

Gregorich

Peng

Lane

et al. 2015

Journal of Molecular and Cellular Cardiology

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The heart is characterized by a remarkable degree of heterogeneity, the basis of which is a subject of active investigation. Myofilament protein post-translational modifications (PTMs) represent a critical mechanism regulating cardiac contractility, and emerging evidence shows that pathological cardiac conditions induce contractile heterogeneity that correlates with transmural variations in the modification status of myofilament proteins. Nevertheless, whether there exists basal heterogeneity in myofilament protein PTMs in the heart remains unclear. Here we have systematically assessed chamber-specific and transmural variations in myofilament protein PTMs, specifically, the phosphorylation of cardiac troponin I (cTnI), cardiac troponin T (cTnT), tropomyosin (Tpm), and myosin light chain 2 (MLC2). We show that the phosphorylation of cTnI and αTm vary in the different chambers of the heart, whereas the phosphorylation of MLC2 and cTnT does not. In contrast, no significant transmural differences were observed in the phosphorylation of any of the myofilament proteins analyzed. These results highlight the importance of appropriate tissue sampling—particularly for studies aimed at elucidating disease mechanisms and biomarker discovery—in order to minimize potential variations arising from basal heterogeneity in myofilament PTMs in the heart.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comprehensive assessment of chamber-specific and transmural heterogeneity in myofilament protein phosphorylation by top-down mass spectrometry

Gregorich

Peng

Lane

et al. 2015

Journal of Molecular and Cellular Cardiology

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“…Myofilaments are the essential components of the contractile apparatus and the sliding of them generates contraction . Myofilaments consist of thin and thick filaments (Fig.…”

Section: Introductionmentioning

confidence: 99%

Top‐down mass spectrometry of cardiac myofilament proteins in health and disease

Peng

Ayaz-Güner

et al. 2014

Proteomics Clinical Apps

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Myofilaments are composed of thin and thick filaments which coordinate with each other to regulate muscle contraction and relaxation. Posttranslational modifications (PTMs) together with genetic variations and alternative splicing of the myofilament proteins play essential roles in regulating cardiac contractility in health and disease. Therefore, a comprehensive characterization of the myofilament proteins in physiological and pathological conditions is essential for better understanding the molecular basis of cardiac function and dysfunction. Due to the vast complexity and dynamic nature of proteins, it is challenging to obtain a holistic view of myofilament protein modifications. In recent years, top-down mass spectrometry (MS) has emerged as a powerful approach to study isoform composition and PTMs of proteins owing to its advantage of complete sequence coverage and its ability to identify PTMs and sequence variants without a priori knowledge. In this review, we will discuss the application of top-down MS to study cardiac myofilaments and highlight the insights it provides into the understanding of molecular mechanisms in contractile dysfunction of heart failure. Particularly, recent results of cardiac troponin and tropomyosin modifications will be elaborated. The limitations and perspectives on the use of top-down MS for myofilament protein characterization will also be briefly discussed.

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“…Our first goal was to assess sarcomeric contractile properties by measuring direct isometric forces on skinned isolated cell preparations. Second, since the cardiac sarcomeric proteins myosin binding protein C (MyBPC), troponin T (TnT), troponin I (TnI), tropomyosin (Tm), and regulatory myosin light chain (MLC-2) are known to effect contractility, 13 we assessed whether post-translational modifications and/or other alterations in these proteins were affected with LVAD support.…”

mentioning

confidence: 99%

Incomplete Recovery of Myocyte Contractile Function Despite Improvement of Myocardial Architecture With Left Ventricular Assist Device Support

Ambardekar

Walker

et al. 2011

Circ: Heart Failure

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Background Unloading a failing heart with a left ventricular assist device (LVAD) can improve ejection fraction (EF) and left ventricular (LV) size; however, recovery with LVAD explantation is rare. We hypothesized that evaluation of myocyte contractility and biochemistry at the sarcomere level before and after LVAD may explain organ level changes. Methods and Results Paired LV tissue samples were frozen from 8 patients with nonischemic cardiomyopathy at LVAD implantation (Before LVAD) and prior to transplant (After LVAD). These were compared to 8 nonfailing hearts. Isolated skinned myocytes were purified, attached to a force transducer, and dimensions, maximal calcium saturated force (Fmax), calcium sensitivity, and myofilament cooperativity were assessed. Relative isoform abundance and phosphorylation levels of sarcomeric contractile proteins were measured. With LVAD support, the unloaded EF improved (10.0±1.0 to 25.6±11.0%, p=0.007), LV size decreased (LVIDd 7.6±1.2 to 4.9±1.4cm, p<0.001), and myocyte dimensions decreased (cross-sectional area 1247±346 to 638±254μm2, p=0.001). Fmax improved after LVAD (3.6±0.9 to 7.3±1.8mN/mm2, p<0.001), but was still lower than nonfailing (7.3±1.8 vs. 17.6±1.8mN/mm2, p<0.001). An increase in troponin I (TnI) phosphorylation after LVAD was noted, but protein kinase C phosphorylation of TnI decreased. Biochemical changes of other sarcomeric proteins were not observed after LVAD. Conclusions There is significant improvement in LV and myocyte size with LVAD, but there is only partial recovery of EF and myocyte contractility. LVAD support was only associated with biochemical changes in TnI. This suggests that alternate mechanisms might contribute to contractile changes after LVAD and that additional interventions may be needed to alter biochemical remodeling of the sarcomere to further enhance myofilament and organ level recovery.

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Cardiac myofilaments: from proteome to pathophysiology

Cited by 15 publications

References 110 publications

Comprehensive assessment of chamber-specific and transmural heterogeneity in myofilament protein phosphorylation by top-down mass spectrometry

Comprehensive assessment of chamber-specific and transmural heterogeneity in myofilament protein phosphorylation by top-down mass spectrometry

Top‐down mass spectrometry of cardiac myofilament proteins in health and disease

Incomplete Recovery of Myocyte Contractile Function Despite Improvement of Myocardial Architecture With Left Ventricular Assist Device Support

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