Control of myosin heavy chain expression in cardiac hypertrophy

Umeda, Patrick K.; Darling, Douglas S.; Kennedy, John M.; Jakovcic, Smilja; Zak, Radovan

doi:10.1016/0002-9149(87)90176-7

Cited by 38 publications

(13 citation statements)

References 23 publications

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“…However, consistent with other adult models of hypertrophy, we have recently demonstrated that continuous electrical stimulation of adult feline cardiocytes increased protein content and cell size over 7 days without any significant changes in morphology and myofibrillar architecture (7). It is well established in several models of hypertrophy that transcription has a role in regulating the synthesis of contractile proteins, particularly qualitative changes in the expression of contractile protein isoforms in rodent species (11,30). However, in the ventricles of larger animals, including humans, these changes in isoform expression occur only to a very limited extent for actin and do not occur for myosin (11,24,30).…”

Section: Discussionsupporting

confidence: 80%

“…It is well established in several models of hypertrophy that transcription has a role in regulating the synthesis of contractile proteins, particularly qualitative changes in the expression of contractile protein isoforms in rodent species (11,30). However, in the ventricles of larger animals, including humans, these changes in isoform expression occur only to a very limited extent for actin and do not occur for myosin (11,24,30). In a quantitative context, changes in contractile protein synthesis rates in response to load do not necessarily correspond to mRNA levels in adult myocardium (18,31).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Contraction Accelerates Myosin Heavy Chain Synthesis Rates in Adult Cardiocytes by an Increase in the Rate of Translational Initiation

Ivester

Tuxworth

Cooper

et al. 1995

Journal of Biological Chemistry

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The purpose of this study was to determine the mechanism by which contraction acutely accelerates the synthesis rate of the contractile protein myosin heavy chain (MHC). Laminin-adherent adult feline cardiocytes were maintained in a serum-free medium and induced to contract at 1 Hz via electrical field stimulation. Electrical stimulation of contraction accelerated rates of MHC synthesis 28%, p < 0.05 by 4 h as determined by incorporation of [ 3 H]phenylalanine into MHC. MHC mRNA expression as measured by RNase protection was unchanged after 4 h of electrical stimulation. MHC mRNA levels in messenger ribonucleoprotein complexes and translating polysomes were examined by sucrose gradient fractionation. The relative percentage of polysomebound MHC mRNA was equal at 47% in both electrically stimulated and control cardiocytes. However, electrical stimulation of contraction resulted in a reproducible shift of MHC mRNA from smaller polysomes into larger polysomes, indicating an increased rate of initiation. This shift resulted in significant increases in MHC mRNA levels in the fractions containing the larger polysomes of electrically stimulated cardiocytes as compared with nonstimulated controls. These data indicate that the rate of MHC synthesis is accelerated in contracting cardiocytes via an increase in translational efficiency.Hypertrophic growth occurs in terminally differentiated adult cardiocytes by an increase in cellular mass via a relatively coordinate increase in the proteins comprising each of the cellular components (1). This accumulation of cardiocyte proteins occurs by an increase in rates of protein synthesis relative to rates of protein degradation (2). The anabolic changes that occur during hypertrophy of the adult myocardium are generally considered to be a compensatory response to an increase in hemodynamic load (3). As demonstrated in studies employing isolated papillary muscle preparations, both the active tension and passive strain components of load have been identified as mechanical stimuli for accelerating protein synthesis rates in adult myocardium (4, 5). These findings have been extended to isolated adult cardiocytes in culture. Rates of protein synthesis were accelerated in response to electrically stimulated cardiocyte contraction (6, 7), in response to a basal load as defined by adherence of the cardiocytes to the culture dish and establishment of a resting length (8) and in response to passive stretch of cardiocytes adherent to a deformable membrane (9). Thus, the integrity of adult cardiocytes in primary culture is maintained with respect to the ability to transduce changes in mechanical load into an anabolic response such as accelerated protein synthesis rate.The specific mechanisms by which cardiocyte protein synthesis is regulated probably occur at many levels, including transcriptional, post-transcriptional, and translational processes (10). It is well established, for example, that transcriptional and post-transcriptional mechanisms regulate steady state mRNA levels and are respon...

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Contraction Accelerates Myosin Heavy Chain Synthesis Rates in Adult Cardiocytes by an Increase in the Rate of Translational Initiation

Ivester

Tuxworth

Cooper

et al. 1995

Journal of Biological Chemistry

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“…Researchers have taken advantage of this finding to suppress the switch from β-cardiac myosin to α-cardiac myosin during development by manipulating thyroid function, such that adult rodent models express increasing levels of β-MyHC [34, 35]. However, the sliding velocity for mouse and rat α- and β-cardiac myosin are higher than their counterparts in rabbit, pig, and human, suggesting that both the isoform distribution and function is species specific [28].…”

Section: Single Molecule Techniquesmentioning

confidence: 99%

Insights into Human β-Cardiac Myosin Function from Single Molecule and Single Cell Studies

Sivaramakrishnan

Ashley

Leinwand

et al. 2009

J. of Cardiovasc. Trans. Res.

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β-Cardiac myosin is a mechanoenzyme that converts the energy from ATP hydrolysis into a mechanical force that drives contractility in muscle. Thirty percent of the point mutations that result in hypertrophic cardiomyopathy are localized to MYH7, the gene encoding human β-cardiac myosin heavy chain (β-MyHC). Force generation by myosins requires a tight and highly conserved allosteric coupling between its different protein domains. Hence, the effects of single point mutations on the force generation and kinetics of β-cardiac myosin molecules cannot be predicted directly from their location within the protein structure. Great insight would be gained from understanding the link between the functional defect in the myosin protein and the clinical phenotypes of patients expressing them. Over the last decade, several single molecule techniques have been developed to understand in detail the chemomechanical cycle of different myosins. In this review, we highlight the single molecule techniques that can be used to assess the effect of point mutations on β-cardiac myosin function. Recent bioengineering advances have enabled the micromanipulation of single cardiomyocyte cells to characterize their force–length dynamics. Here, we briefly review single cell micromanipulation as an approach to determine the effect of β-MyHC mutations on cardiomyocyte function. Finally, we examine the technical challenges specific to studying β-cardiac myosin function both using single molecule and single cell approaches.

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“…In particular, the hypertrophy induced by thyroxine appears to be quite different from that induced by pressure overload. 62 - 63 Triiodothyronine does not activate protooncogenes 1 ; instead, the hormone permeates the cell membrane and interacts directly with a nuclear protein (which, interestingly, is itself the homologue of the proto-oncogene c-erb-A 64 ) to modulate transcription. 59 The end result differs in that the isozyme composition of the contractile protein (a-myosin heavy chain) is quite distinct from that induced by pressure overload or by a,-adrenergic stimulation O-myosin heavy chain, a-skeletal actin).…”

Section: Unanswered Questionsmentioning

confidence: 99%