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Circulation Research. 2000;86:386-390

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(Circulation Research. 2000;86:386.)
© 2000 American Heart Association, Inc.


Clinical Research

Myosin Heavy Chain Isoform Expression in the Failing and Nonfailing Human Heart

Setsuya Miyata, Wayne Minobe, Michael R. Bristow, Leslie A. Leinwand

From the Department of Molecular, Cellular and Developmental Biology (S.M., L.A.L.), University of Colorado (Boulder); and Division of Cardiology (W.M., M.B.), University of Colorado Health Science Center (Denver).

Correspondence to Dr Leslie A. Leinwand, Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Campus Box 347, Boulder, CO 80309-0347. E-mail Leslie.Leinwand{at}colorado.edu


*    Abstract
up arrowTop
*Abstract
down arrowIntroduction
down arrowMaterials and Methods
down arrowResults and Discussion
down arrowReferences
 
Abstract—In the heart, the relative proportions of the 2 forms of the motor protein myosin heavy chain (MyHC) have been shown to be affected by a wide variety of pathological and physiological stimuli. Hearts that express the faster MyHC motor protein, {alpha}, produce more power than those expressing the slower MyHC motor protein, ß, leading to the hypothesis that MyHC isoforms play a major role in the determination of cardiac contractility. We showed previously that a significant amount of {alpha}MyHC mRNA is expressed in nonfailing human ventricular myocardium and that {alpha}MyHC mRNA expression is decreased 15-fold in end-stage failing left ventricles. In the present study, we determined the MyHC protein isoform content of human heart samples of known MyHC mRNA composition. We demonstrate that {alpha}MyHC protein was easily detectable in 12 nonfailing hearts. {alpha}MyHC protein represented 7.2±3.2% of total MyHC protein (compared with {approx}35% of the MyHC mRNA), suggesting that translational regulation may be operative; in contrast, there was effectively no detectable {alpha}MyHC protein in the left ventricles of 10 end-stage failing human hearts.


Key Words: myosin • heart failure • isoforms


*    Introduction
up arrowTop
up arrowAbstract
*Introduction
down arrowMaterials and Methods
down arrowResults and Discussion
down arrowReferences
 
In conjunction with 2 pairs of nonidentical light chains, 2 myosin heavy chain (MyHCs) constitute the functional myosin motor molecule. Two isoforms of MyHC ({alpha} and ß) are expressed in mammalian heart. Myosin consisting of {alpha}MyHC has a higher ATPase activity than myosin composed of ßMyHC,1 and in the rodent heart, contractile velocity correlates with the relative amount of each MyHC. Hearts expressing {alpha}MyHC have more rapid contractile velocity than hearts expressing ßMyHC, which allows greater economy in force generation because the tension-time integral for force per cross-bridge cycle is greater.2 3 The MyHC composition of the ventricular myocardium of rodents has been reported to be >90% {alpha}MyHC,4 5 6 whereas that of humans has been reported to be >95% ßMyHC.7 8 9 10 11 12 13 In the rodent heart, thyroid hormone elevation and exercise have been shown to increase {alpha}MyHC, whereas thyroid depletion, aging, cardiomyopathy, and pressure overload have been shown to increase ßMyHC (see Swynghedauw14 ). Because the normal human heart was previously thought to be entirely ßMyHC,7 8 9 10 11 12 13 stimuli that might induce isoform shifts toward ßMyHC in human heart disease were thought to be irrelevant.

The MyHC composition of human heart was originally investigated with immunohistochemistry, because of the difficulty in electrophoretic separation of the human {alpha}MyHC and ßMyHC,9 or by peptide mapping.7 10 Immunohistochemistry can show the spatial expression of each isoform, but it is not quantitative because 2 different antibodies cannot be directly compared.15 16 The results of immunohistochemical analysis were quite varied, with reports ranging from <5% to 88% of myocytes expressing {alpha}MyHC.8 11 12 We showed that {alpha}MyHC mRNA was expressed at considerable levels in the nonfailing human left ventricles (LVs) and was substantially decreased in end-stage failing human LVs.17 18 The proportion of total MyHC mRNA that is {alpha}MyHC mRNA was {approx}30% in nonfailing LVs and was reduced by 15-fold, to {approx}2%, in end-stage LVs.

Because of the potential functional significance of altered MyHC composition in contractility and to gain insight into the molecular mechanisms of changes in gene expression in heart failure, we quantified {alpha}MyHC and ßMyHC proteins in human nonfailing and failing LVs according to a recently reported gel electrophoretic method.19 We demonstrate that {alpha}MyHC protein is detectable in nonfailing LVs but is virtually undetectable in failing LVs.


*    Materials and Methods
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up arrowAbstract
up arrowIntroduction
*Materials and Methods
down arrowResults and Discussion
down arrowReferences
 
Patients from whom hearts were provided through the Colorado Transplant Program are described in Tables 1Down and 2Down.17 LVs were obtained from 12 control organ donor candidates (5 men and 7 women, mean age 36.8±16.9 years) and 10 patients undergoing heart transplantation (8 men and 2 women, mean age 44.9±19.3 years).


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Table 1. Clinical Characteristics and {alpha}MyHC cDNA and Protein Ratios of 12 Organ Donors Without a Heart Failure History


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Table 2. Clinical Characteristics and {alpha}MyHC cDNA and Protein Ratios of 10 Patients With End-Stage Heart Failure

RNA was extracted and analyzed with quantitative polymerase chain reaction as previously described and reported.17 18

Samples for protein gel electrophoresis (15 to 200 mg) were prepared as described by Caforio et al20 from tissue that had no visible fat and no connective tissue. Briefly, samples were homogenized in low-salt buffer (20 mmol/L KCl, 2 mmol/L KH2PO4, 1 mmol/L EGTA, pH 6.8, 1 mmol/L PMSF, 100 µL N,N-dimethyl formamide). The samples were then centrifuged at 5000 rpm for 10 minutes at 4°C in a JA-17 rotor (Beckman Instruments). Pellets were suspended in high-salt buffer (40 mmol/L Na4P2O7, 1 mmol/L MgCl2, 1 mmol/L EGTA, pH 9.5) and then centrifuged at 15 000 rpm for 30 minutes at 4°C. Laemmli’s buffer was added to each sample, and then each sample was boiled.21 The preparation and composition of the gel were carried out as described by Reiser and Kline.19 Gel samples (0.25 to 1 µg) were loaded in a 3-µL volume onto 15-well gels. The stacking and separating gels (0.75 mm thick) consisted of 4% and 8% acrylamide, respectively; the stacking gels included 5% glycerol. The gels were run in a Hoeffer Scientific SE600 instrument at 5°C. The gels were run at a constant voltage of 200 V for 30 hours. The gels were fixed and silver stained as described in Blough et al.22 A gel documentation system (Bio-Rad) was used to scan the stained gels. The abundance of {alpha}MyHC and ßMyHC was determined with quantitative reverse transcription–polymerase chain reaction as previously described.17 18 Protein samples were subjected to electrophoresis as described earlier and transferred to 0.2-µm nitrocellulose. The blots were blocked in 10% nonfat dry milk in PBS for 2 hours at room temperature. Blots were incubated with a monoclonal antibody against sarcomeric MyHC (F59)23 or F88.12F8 (Alexis Biochemicals) at a dilution of 1:500 or 1:5000, respectively, in 5% BSA overnight at 4°C. After primary antibody incubations, 3 washes in PBS were followed by an incubation in the secondary antibody, peroxidase-conjugated goat anti-mouse IgG (Jackson Laboratories) diluted 1:5000 in 10% nonfat dry milk in PBS for 2 hours at room temperature. The blots were then washed 3 times in 0.05% NP-40/PBS. Immunoreactive bands were visualized by using the Renaissance Western Blot Chemiluminescence Reagent (NEN Life Sciences).


*    Results and Discussion
up arrowTop
up arrowAbstract
up arrowIntroduction
up arrowMaterials and Methods
*Results and Discussion
down arrowReferences
 
The goals of the present study were to determine the amount of {alpha}MyHC protein in the nonfailing and failing human hearts and to determine the relationship between MyHC mRNA and protein levels. The clinical characteristics and the {alpha}MyHC mRNA content of the patients analyzed in the present study are shown in Tables 1Up and 2Up. The range of {alpha}MyHC mRNA was 10.8% to 55% in nonfailing LVs and 0% to 8.8% in failing LVs. To identify {alpha}MyHC protein, immunoblot analysis was carried out with a monoclonal antibody specific to {alpha}MyHC protein.15 To quantify the proportion of {alpha}MyHC protein, an electrophoretic separation protocol was used, followed by silver staining and densitometry. Figure 1Down is an immunoblot performed on a high-resolution gel that separates {alpha}MyHC and ßMyHC proteins. The gel was probed with pansarcomeric MyHC antibody F5923 (top) and an {alpha}MyHC-specific antibody (bottom).15 Lane 1 represents rabbit skeletal MyHC, used as a control. It was recognized by the pansarcomeric MyHC antibody but not by the {alpha}MyHC-specific antibody. {alpha}MyHC was prominently expressed in a right atrial sample (lane 2), as expected.24 As an additional control, the right atrial sample was mixed 1:1 with an LV sample (lane 3). Two bands were recognized by the pansarcomeric antibody, but only the top band was recognized by the {alpha}MyHC antibody. {alpha}MyHC was easily detectable in 2 nonfailing LVs (lanes 4 and 5). These results demonstrate that human {alpha}MyHC and ßMyHC can be resolved into 2 bands and that the slower migrating species is {alpha}MyHC. However, this immunoblot analysis does not provide quantitative information about {alpha}MyHC levels. For that purpose, a high-resolution gel was run, silver stained, and subjected to laser scanning densitometry. Figure 2Down is a representative silver-stained gel of MyHC from nonfailing and failing LVs. The results of the scan are presented in Tables 1Up and 2Up. The RA (right atrial) sample contained 86% {alpha}MyHC and 14% ßMyHC and served as a positive control24 (Figure 2Down). {alpha}MyHC protein was detected in all 12 nonfailing LVs and corresponded to 7.2±3.2% of total MyHC ([mean±SD] range 1.2% to 13%). One patient’s heart that was originally included in the nonfailing group had no {alpha}MyHC protein. However, when the clinical characteristics were examined in greater detail, it was found that this patient had a history of myocardial infarction and exhibited an anterior wall motion abnormality; data on this patient’s tissue were subsequently eliminated from the analysis. However, the finding of no {alpha}MyHC protein in a setting of LV dysfunction suggests that changes in cardiac MyHC expression can precede the development of overt myocardial failure. {alpha}MyHC protein was barely detectable (0.75%) in 1 of 10 failing LVs, from an 18-year-old patient with idiopathic dilated cardiomyopathy and with 8.8% {alpha}MyHC mRNA (Figure 2Down). No {alpha}MyHC protein was detected in the remaining 9 failing LV samples.



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Figure 1. Immunodetection of {alpha}MyHC and ßMyHC after high-resolution gel electrophoresis. Top, Probed with F59, which recognizes all sarcomeric MyHCs.23 Bottom, Probed with F88.12.F8, which is specific to {alpha}MyHC.15 Lane 1 indicates rabbit skeletal MyHC; lane 2, human right atrial sample; lane 3, a 1:1 mixture of right atrium and LV; lane 4, NFH-1; and lane 5, NFH-3.



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Figure 2. Separation of human {alpha}MyHC and ßMyHC proteins. Protein samples of human left ventricles were resolved on an SDS–8% polyacrylamide gel. The gel was fixed and silver stained as described previously.19 The relative amounts of {alpha}MyHC and ßMyHC protein in nonfailing and failing heart LVs were determined with scanning densitometry and are presented in Tables 1Up and 2Up.

Investigation into the molecular and cellular mechanisms of heart failure has provided some insight into changes in gene expression that could contribute to contractile dysfunction. Given the potential functional significance of {alpha}MyHC protein in the myocardium, it was important to determine whether protein was also present. {alpha}MyHC protein was detected all 12 nonfailing LVs but was undetectable in 9 of 10 failing LVs and barely detectable in the remaining failing LV. Interestingly, in all nonfailing LVs, there was more {alpha}MyHC mRNA than protein (see Table 1Up). Discordance between MyHC mRNA and protein has been demonstrated in several reports and systems.25 For example, electrical stimulation of adult cardiac myocyte contraction accelerates MyHC synthesis by increasing the rate of translation initiation. This occurs in the absence of an increase in mRNA abundance.26 After 7 days of ascending aortic constriction, ßMyHC protein increases from 5% to 31% of total MyHC in the absence of changes in mRNA abundance.27 Finally, contractile arrest of cardiac myocytes has been shown to inhibit MyHC synthesis and to decelerate MyHC degradation.28 Protein synthesis in the heart is regulated by changes in efficiency and capacity and has been shown to vary widely depending on the stimulus.29 30 31 Before drawing firm conclusions about the degree of discordance between mRNA and protein, 1 limitation of the silver-staining approach should be noted: in samples with very low amounts of {alpha}MyHC, the ßMyHC band may obscure a faint {alpha}MyHC band. To complement the approach used here and to be able to determine the absolute quantities of {alpha} and ßMyHC, we are in the process of developing ELISAs.

One question that arises from these observations is whether a relatively small amount of {alpha}MyHC is capable of changing the contractile properties of the heart. Thus far, the cases in which shifts in myosin composition have been studied have generally been at end points where the shift has been quite large. The impact of small shifts such as those described here have not yet been reported. However, with the assumption of a 3-fold difference in the velocity of shortening in muscles expressing the {alpha} and ß isoforms, the decrease in {alpha}MyHC from 7.5% to <0.1% could theoretically reduce systolic function by 12.5%, although the direct relationship to velocity of contraction would have to be tested directly. In support of this hypothesis, we recently used transgenesis to express ßMyHC in the adult mouse heart, which normally expresses exclusively {alpha}MyHC. When only 12% of the total MyHC is ßMyHC, there is a significant decrease in systolic function and Ca+2-activated myofibrillar ATPase activity.32 However, in vitro biochemical mixing experiments with varying proportions of {alpha} and ß myosin show that ß myosin can have a "slowing" effect on {alpha} myosin, suggesting that the impact of myosin changes in the intact heart may not reflect the behavior of purified molecules in solution.33 The sensitivity of the cardiac sarcomere to alterations in MyHC has been emphasized by the discovery of >50 alleles of the ßMyHC gene found in patients with hypertrophic cardiomyopathy (see Bonne et al34 ). Most of these alleles have mutations in the motor domain, and in vitro biochemical studies have shown that the motor activity is impaired in at least 3 different alleles.35 36 37 Somewhat surprisingly, the functional differences in the mutant alleles are less than the difference between wild-type {alpha}MyHC and ßMyHC.37 Further investigation is required to understand the relationship of decreased myosin motor activity and the pathogenesis of hypertrophic cardiomyopathy and heart failure.

In summary, we separated human {alpha}MyHC and ßMyHC proteins through electrophoresis and quantified the relative amounts of {alpha}MyHC and ßMyHC in nonfailing and failing LVs. {alpha}MyHC is detectable in nonfailing LVs but effectively undetectable in failing LVs. Future experiments will be directed toward a determination of the mechanism of {alpha}MyHC mRNA decrease and the relevance of changes in MyHC gene expression to human cardiac function.


*    Acknowledgments
 
This work was supported by NIH grant HL-50560 (to Dr Leinwand) and an American Heart Association, Colorado-Wyoming Affiliate, fellowship award (to Dr Miyata. The authors would like to thank Jill Jones for manuscript preparation and Kurt Haubold for figure preparation.


*    Footnotes
 
This manuscript was sent to Harry A. Fozzard, Consulting Editor, for review by expert referees, editorial decision, and final disposition.

Received March 18, 1999; accepted July 7, 1999.


*    References
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up arrowAbstract
up arrowIntroduction
up arrowMaterials and Methods
up arrowResults and Discussion
*References
 

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B. Schoffstall, N. M. Brunet, S. Williams, V. F. Miller, A. T. Barnes, F. Wang, L. A. Compton, L. A. McFadden, D. W. Taylor, M. Seavy, et al.
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M. L. Tschirgi, I. Rajapakse, and M. Chandra
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CirculationHome page
Y. Kong, P. Tannous, G. Lu, K. Berenji, B. A. Rothermel, E. N. Olson, and J. A. Hill
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Toxicol SciHome page
K. W. Chaudhary, N. X. Barrezueta, M. B. Bauchmann, A. J. Milici, G. Beckius, D. B. Stedman, J. E. Hambor, W. L. Blake, J. D. McNeish, A. Bahinski, et al.
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A. Kenessey, E. A. Sullivan, and K. Ojamaa
Nuclear localization of protein kinase C-{alpha} induces thyroid hormone receptor-{alpha}1 expression in the cardiomyocyte
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C. A. Emter, S. A. McCune, G. C. Sparagna, M. J. Radin, and R. L. Moore
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J. A. Kuzman, T. A. Thomas, K. A. Vogelsang, S. Said, B. E. Anderson, and A. M. Gerdes
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F. S. Korte, T. J. Herron, M. J. Rovetto, and K. S. McDonald
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CirculationHome page
E. Carniel, M. R.G. Taylor, G. Sinagra, A. Di Lenarda, L. Ku, P. R. Fain, M. M. Boucek, J. Cavanaugh, S. Miocic, D. Slavov, et al.
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Cardiovasc ResHome page
D. Fraccarollo, P. Galuppo, I. Schmidt, G. Ertl, and J. Bauersachs
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X.-M. Gao, H. Kiriazis, X.-L. Moore, X.-H. Feng, K. Sheppard, A. Dart, and X.-J. Du
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E. Vellaichamy, M. L. Khurana, J. Fink, and K. N. Pandey
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A.J. Marian
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J. James, L. Martin, M. Krenz, C. Quatman, F. Jones, R. Klevitsky, J. Gulick, and J. Robbins
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