Investigation of changes in skeletal muscle α-actin expression in normal and pathological human and mouse hearts

Copeland, O'Neal; Nowak, Kristen J.; Laing, Nigel G.; Ravenscroft, Gianina; Messer, Andrew E.; Bayliss, Christopher R.; Marston, Steven B.

doi:10.1007/s10974-010-9224-7

Cited by 26 publications

(42 citation statements)

References 27 publications

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“…In the obstructive variant of HCM (HOCM) the hypertrophied interventricular septum causes LVOTO (left ventricular outflow tract obstruction) and pressure overload. Several abnormalities in the contractile proteins in septal tissue from HOCM patients have been observed including; low phosphorylation levels of TnI and MyBP-C (Messer et al, 2009; Copeland et al, 2010b), differences in actin isoform expression (Copeland et al, 2010a) and loss of function in myosin (Jacques et al, 2008). Most of these abnormalities are shared with end-stage failing heart, but the Ca 2+ -sensitivity of Tn from HOCM samples, studied by IVMA, was not as expected from its low TnI phosphorylation level and this was found to be due to uncoupling of the relationship between Ca 2+ -sensitivity and TnI phosphorylation (Gallon et al, 2007; Jacques et al, 2008; Bayliss et al, 2012b).…”

Section: Uncoupling Is a Common Feature Of Cardiomyopathiesmentioning

confidence: 99%

Investigating the role of uncoupling of troponin I phosphorylation from changes in myofibrillar Ca2+-sensitivity in the pathogenesis of cardiomyopathy

Messer

Marston

2014

Front. Physiol.

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Contraction in the mammalian heart is controlled by the intracellular Ca2+ concentration as it is in all striated muscle, but the heart has an additional signaling system that comes into play to increase heart rate and cardiac output during exercise or stress. β-adrenergic stimulation of heart muscle cells leads to release of cyclic-AMP and the activation of protein kinase A which phosphorylates key proteins in the sarcolemma, sarcoplasmic reticulum and contractile apparatus. Troponin I (TnI) and Myosin Binding Protein C (MyBP-C) are the prime targets in the myofilaments. TnI phosphorylation lowers myofibrillar Ca2+-sensitivity and increases the speed of Ca2+-dissociation and relaxation (lusitropic effect). Recent studies have shown that this relationship between Ca2+-sensitivity and TnI phosphorylation may be unstable. In familial cardiomyopathies, both dilated and hypertrophic (DCM and HCM), a mutation in one of the proteins of the thin filament often results in the loss of the relationship (uncoupling) and blunting of the lusitropic response. For familial dilated cardiomyopathy in thin filament proteins it has been proposed that this uncoupling is causative of the phenotype. Uncoupling has also been found in human heart tissue from patients with hypertrophic obstructive cardiomyopathy as a secondary effect. Recently, it has been found that Ca2+-sensitizing drugs can promote uncoupling, whilst one Ca2+-desensitizing drug Epigallocatechin 3-Gallate (EGCG) can reverse uncoupling. We will discuss recent findings about the role of uncoupling in the development of cardiomyopathies and the molecular mechanism of the process.

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Section: Uncoupling Is a Common Feature Of Cardiomyopathiesmentioning

confidence: 99%

Investigating the role of uncoupling of troponin I phosphorylation from changes in myofibrillar Ca2+-sensitivity in the pathogenesis of cardiomyopathy

Messer

Marston

2014

Front. Physiol.

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“…Uniquely among the contractile proteins, both skeletal and cardiac actin have identical amino acid sequences in humans and mice and an identical isoform distribution in heart (25% ACTA1 and 75% ACTC) (25,26). In vivo there are no posttranslational modifications of actin that regulate activity.…”

Section: Hypertrophic Cardiomyopathy (Hcm)mentioning

confidence: 99%

Molecular Mechanism of the E99K Mutation in Cardiac Actin (ACTC Gene) That Causes Apical Hypertrophy in Man and Mouse

Song

Dyer

Stuckey

et al. 2011

Journal of Biological Chemistry

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We generated a transgenic mouse model expressing the apical hypertrophic cardiomyopathy-causing mutation ACTC E99K at 50% of total heart actin and compared it with actin from patients carrying the same mutation. The actin mutation caused a higher Ca 2؉ sensitivity in reconstituted thin filaments measured by in vitro motility assay (2.3-fold for mice and 1.3-fold for humans) and in skinned papillary muscle. The mutation also abolished the change in Ca 2؉ sensitivity normally linked to troponin I phosphorylation. MyBP-C and troponin I phosphorylation levels were the same as controls in transgenic mice and human carrier heart samples. ACTC E99K mice exhibited a high death rate between 28 and 45 days (48% females and 22% males). At 21 weeks, the hearts of the male survivors had enlarged atria, increased interstitial fibrosis, and sarcomere disarray. MRI showed hypertrophy, predominantly at the apex of the heart. End-diastolic volume and end-diastolic pressure were increased, and relaxation rates were reduced compared with nontransgenic littermates. End-systolic pressures and volumes were unaltered. ECG abnormalities were present, and the contractile response to ␤-adrenergic stimulation was much reduced. Older mice (29-week-old females and 38-week-old males) developed dilated cardiomyopathy with increased end-systolic volume and continuing increased end-diastolic pressure and slower contraction and relaxation rates. ECG showed atrial flutter and frequent atrial ectopic beats at rest in some ACTC E99K mice. We propose that the ACTC E99K mutation causes higher myofibrillar Ca 2؉ sensitivity that is responsible for the sudden cardiac death, apical hypertrophy, and subsequent development of heart failure in humans and mice.

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“…1,6 α-cardiac actin (αCAA) and α-skeletal actin (αSKA), which are encoded by two different genes: ACTC and ACTA, respectively, are the major actin isoforms expressed in striated muscles. 1,5-7 αCAA is the major isoform expressed in cardiac muscle, whereas αSKA is the predominant isoform expressed in skeletal muscle. 4,8 Although both αCAA and αSKA are expressed in cardiac muscle, the relative expression levels of αSKA and αCAA have been shown to vary between species, during development, and under pathological conditions.…”

Section: Introductionmentioning

confidence: 99%

“…1,4-13 In particular, an increase in the expression of αSKA has been observed in diseased hearts using experimental animal models and human clinical samples. 5,7,10-12 Thus, augmented αSKA expression is believed to be a programmed response of a diseased heart and it is essential to determine the αSKA/αCAA isoform ratio for its potential as a cardiac disease marker. 5,8 …”

Section: Introductionmentioning

confidence: 99%

Effective Top-Down LC/MS+ Method for Assessing Actin Isoforms as a Potential Cardiac Disease Marker

Chen¹,

Ayaz-Güner²,

Peng³

et al. 2015

Anal. Chem.

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Actin is the major component of the cytoskeleton playing an essential role in the structure and motility of both muscle and non-muscle cells. It is highly conserved and encoded by a multigene family. α-cardiac actin (αCAA) and α-skeletal actin (αSKA), encoded by two different genes, are the primary actin isoforms expressed in striated muscles. The relative expression levels of αSKA and αCAA have been shown to vary between species and under pathological conditions. In particular, an increased αSKA expression is believed to be a programmed response of a diseased heart. Therefore, it is essential to quantify the relative expression of αSKA and αCAA, which remains challenging due to the high degree of sequence similarity between these isoforms (98.9%). Herein, we developed a top-down liquid chromatography mass spectrometry-based (“LC/MS+”) method for the rapid purification and comprehensive analysis of α-actin extracted from muscle tissues. We thoroughly investigated all of the actin isoforms in healthy human cardiac and skeletal muscles. We found that αSKA is the only isoform expressed in skeletal muscle, whereas αCAA and αSKA are co-expressed in cardiac muscle. We then applied our method to quantify the α-actin isoforms in human healthy hearts and failing hearts with dilated cardiomyopathy (DCM). We found that αSKA is augmented in DCM compared with healthy controls, 43.1 ± 0.9% versus 23.6 ± 1.7%, respectively. As demonstrated, top-down LC/MS+ provides an effective and comprehensive method for the purification, quantification, and characterization of α-actin isoforms, enabling assessment of their clinical potential as cardiac disease markers.

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Investigation of changes in skeletal muscle α-actin expression in normal and pathological human and mouse hearts

Cited by 26 publications

References 27 publications

Investigating the role of uncoupling of troponin I phosphorylation from changes in myofibrillar Ca2+-sensitivity in the pathogenesis of cardiomyopathy

Investigating the role of uncoupling of troponin I phosphorylation from changes in myofibrillar Ca2+-sensitivity in the pathogenesis of cardiomyopathy

Molecular Mechanism of the E99K Mutation in Cardiac Actin (ACTC Gene) That Causes Apical Hypertrophy in Man and Mouse

Effective Top-Down LC/MS+ Method for Assessing Actin Isoforms as a Potential Cardiac Disease Marker

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