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© 2000 American Heart Association, Inc.
Clinical Research |
Myosin Heavy Chain Isoform Expression in the Failing and Nonfailing Human Heart
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
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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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,
, 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 MyHC mRNA is expressed in nonfailing human
ventricular myocardium and that 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 MyHC protein was easily detectable in 12 nonfailing
hearts. MyHC protein represented 7.2±3.2% of total
MyHC protein (compared with 
35% of the MyHC mRNA), suggesting that
translational regulation may be operative; in contrast, there was
effectively no detectable MyHC protein in the left ventricles of 10
end-stage failing human hearts.
Key Words: myosin • heart failure • isoforms
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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In conjunction with 2 pairs of nonidentical light chains, 2 myosin heavy chain (MyHCs) constitute the functional myosin motor molecule. Two isoforms of MyHC (
and ß) are expressed in mammalian
heart. Myosin consisting of 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 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% 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 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 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
MyHC.8 11 12 We showed that 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
MyHC mRNA was 30% in nonfailing LVs and was reduced by 15-fold,
to 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 MyHC and ßMyHC proteins in human nonfailing
and failing LVs according to a recently reported gel electrophoretic
method.19 We demonstrate that MyHC protein is
detectable in nonfailing LVs but is virtually undetectable in failing
LVs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Patients from whom hearts were provided through the Colorado Transplant Program are described in Tables 1
and 2.17 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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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 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).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The goals of the present study were to determine the amount of
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 MyHC mRNA content of the
patients analyzed in the present study are shown in Tables 1
and 2. The range of MyHC mRNA was 10.8% to 55% in
nonfailing LVs and 0% to 8.8% in failing LVs. To identify MyHC
protein, immunoblot analysis was carried out with a
monoclonal antibody specific to MyHC protein.15 To
quantify the proportion of MyHC protein, an electrophoretic
separation protocol was used, followed by silver staining and
densitometry. Figure 1 is an
immunoblot performed on a high-resolution gel that
separates MyHC and ßMyHC proteins. The gel was probed with
pansarcomeric MyHC antibody F5923 (top) and an
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
MyHC-specific antibody. 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 MyHC antibody. MyHC was easily
detectable in 2 nonfailing LVs (lanes 4 and 5). These results
demonstrate that human MyHC and ßMyHC can be resolved into 2 bands
and that the slower migrating species is MyHC. However, this
immunoblot analysis does not provide quantitative
information about MyHC levels. For that purpose, a high-resolution
gel was run, silver stained, and subjected to laser scanning
densitometry. Figure 2 is a
representative silver-stained gel of MyHC from
nonfailing and failing LVs. The results of the scan are
presented in Tables 1 and 2. The RA (right
atrial) sample contained 86% MyHC and 14% ßMyHC and served as a
positive control24 (Figure 2). 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 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
MyHC protein in a setting of LV dysfunction suggests that changes in
cardiac MyHC expression can precede the development of overt myocardial
failure. 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% MyHC mRNA (Figure 2). No MyHC protein was detected in the remaining 9 failing
LV samples.
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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 MyHC protein in the
myocardium, it was important to determine whether protein
was also present. 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 MyHC mRNA than protein (see Table 1).
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 MyHC, the ßMyHC band
may obscure a faint MyHC band. To complement the approach used here
and to be able to determine the absolute quantities of and ßMyHC,
we are in the process of developing ELISAs.
One question that arises from these observations is whether a
relatively small amount of 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 and ß isoforms, the decrease
in 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 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 and ß myosin show that
ß myosin can have a "slowing" effect on 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 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 MyHC and ßMyHC proteins
through electrophoresis and quantified the relative amounts of MyHC
and ßMyHC in nonfailing and failing LVs. MyHC is detectable in
nonfailing LVs but effectively undetectable in failing LVs. Future
experiments will be directed toward a determination of the mechanism of
MyHC mRNA decrease and the relevance of changes in MyHC gene
expression to human cardiac function.
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Acknowledgments |
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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.
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Footnotes |
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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.
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J. E. Stelzer, S. L. Brickson, M. R. Locher, and R. L. Moss Role of myosin heavy chain composition in the stretch activation response of rat myocardium J. Physiol., February 15, 2007; 579(1): 161 - 173. [Abstract] [Full Text] [PDF]
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M. L. Tschirgi, I. Rajapakse, and M. Chandra Functional consequence of mutation in rat cardiac troponin T is affected differently by myosin heavy chain isoforms J. Physiol., July 1, 2006; 574(1): 263 - 273. [Abstract] [Full Text] [PDF]
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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 Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H381 - H389. [Abstract] [Full Text] [PDF]
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C. A. Emter, S. A. McCune, G. C. Sparagna, M. J. Radin, and R. L. Moore Low-intensity exercise training delays onset of decompensated heart failure in spontaneously hypertensive heart failure rats Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2030 - H2038. [Abstract] [Full Text] [PDF]
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F. S. Korte, T. J. Herron, M. J. Rovetto, and K. S. McDonald Power output is linearly related to MyHC content in rat skinned myocytes and isolated working hearts Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H801 - H812. [Abstract] [Full Text] [PDF]
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E. Vellaichamy, M. L. Khurana, J. Fink, and K. N. Pandey Involvement of the NF-{kappa}B/Matrix Metalloproteinase Pathway in Cardiac Fibrosis of Mice Lacking Guanylyl Cyclase/Natriuretic Peptide Receptor A J. Biol. Chem., May 13, 2005; 280(19): 19230 - 19242. [Abstract] [Full Text] [PDF]
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F. J. Davis, J. B Pillai, M. Gupta, and M. P. Gupta Concurrent opposite effects of trichostatin A, an inhibitor of histone deacetylases, on expression of {alpha}-MHC and cardiac tubulins: implication for gain in cardiac muscle contractility Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1477 - H1490. [Abstract] [Full Text] [PDF]
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N.A. Narolska, R.B. van Loon, N.M. Boontje, R. Zaremba, S. E. Penas, J. Russell, S.R. Spiegelenberg, M.A.J.M. Huybregts, F.C. Visser, J.W. de Jong, et al. Myocardial contraction is 5-fold more economical in ventricular than in atrial human tissue Cardiovasc Res, January 1, 2005; 65(1): 221 - 229. [Abstract] [Full Text] [PDF]
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V. P.M van Empel and L. J De Windt Myocyte hypertrophy and apoptosis: a balancing act Cardiovasc Res, August 15, 2004; 63(3): 487 - 499. [Abstract] [Full Text] [PDF]
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T. Bupha-Intr and J. Wattanapermpool Cardioprotective effects of exercise training on myofilament calcium activation in ovariectomized rats J Appl Physiol, May 1, 2004; 96(5): 1755 - 1760. [Abstract] [Full Text] [PDF]
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Y. Huang, K.E. Walker, F. Hanley, J. Narula, S.R. Houser, and T.N. Tulenko Cardiac Systolic and Diastolic Dysfunction After a Cholesterol-Rich Diet Circulation, January 6, 2004; 109(1): 97 - 102. [Abstract] [Full Text] [PDF]
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H. Yamashita, S. Sugiura, H. Fujita, S.-i. Yasuda, R. Nagai, Y. Saeki, K. Sunagawa, and H. Sugi Myosin light chain isoforms modify force-generating ability of cardiac myosin by changing the kinetics of actin-myosin interaction Cardiovasc Res, December 1, 2003; 60(3): 580 - 588. [Abstract] [Full Text] [PDF]
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H. N. Sabbah, V. G. Sharov, R. C. Gupta, S. Mishra, S. Rastogi, A. I. Undrovinas, P. A. Chaudhry, A. Todor, T. Mishima, E. J. Tanhehco, et al. Reversal of Chronic Molecular and Cellular Abnormalities Due to Heart Failure by Passive Mechanical Ventricular Containment Circ. Res., November 28, 2003; 93(11): 1095 - 1101. [Abstract] [Full Text] [PDF]
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M. Gupta, V. Sueblinvong, J. Raman, V. Jeevanandam, and M. P. Gupta Single-stranded DNA-binding Proteins PUR{alpha} and PUR{beta} Bind to a Purine-rich Negative Regulatory Element of the {alpha}-Myosin Heavy Chain Gene and Control Transcriptional and Translational Regulation of the Gene Expression: IMPLICATIONS IN THE REPRESSION OF {alpha}-MYOSIN HEAVY CHAIN DURING HEART FAILURE J. Biol. Chem., November 7, 2003; 278(45): 44935 - 44948. [Abstract] [Full Text] [PDF]
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F. Haddad, P. W. Bodell, A. X. Qin, J. M. Giger, and K. M. Baldwin Role of Antisense RNA in Coordinating Cardiac Myosin Heavy Chain Gene Switching J. Biol. Chem., September 26, 2003; 278(39): 37132 - 37138. [Abstract] [Full Text] [PDF]
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L. W. Stevenson Clinical Use of Inotropic Therapy for Heart Failure: Looking Backward or Forward?: Part II: Chronic Inotropic Therapy Circulation, July 29, 2003; 108(4): 492 - 497. [Full Text] [PDF]
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W. H. Barry and E. M. Gilbert How Do {beta}-Blockers Improve Ventricular Function in Patients With Congestive Heart Failure? Circulation, May 20, 2003; 107(19): 2395 - 2397. [Full Text] [PDF]
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M. Krenz, A. Sanbe, F. Bouyer-Dalloz, J. Gulick, R. Klevitsky, T. E. Hewett, H. E. Osinska, J. N. Lorenz, C. Brosseau, A. Federico, et al. Analysis of Myosin Heavy Chain Functionality in the Heart J. Biol. Chem., May 2, 2003; 278(19): 17466 - 17474. [Abstract] [Full Text] [PDF]
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S. R. Houser and K. B. Margulies Is Depressed Myocyte Contractility Centrally Involved in Heart Failure? Circ. Res., March 7, 2003; 92(4): 350 - 358. [Abstract] [Full Text] [PDF]
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J van der Velden, Z Papp, R Zaremba, N.M Boontje, J.W de Jong, V.J Owen, P.B.J Burton, P Goldmann, K Jaquet, and G.J.M Stienen Increased Ca2+-sensitivity of the contractile apparatus in end-stage human heart failure results from altered phosphorylation of contractile proteins Cardiovasc Res, January 1, 2003; 57(1): 37 - 47. [Abstract] [Full Text] [PDF]
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T. J. Herron and K. S. McDonald Small Amounts of {alpha}-Myosin Heavy Chain Isoform Expression Significantly Increase Power Output of Rat Cardiac Myocyte Fragments Circ. Res., June 14, 2002; 90(11): 1150 - 1152. [Abstract] [Full Text] [PDF]
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V. L.J.L Thijssen, H. M.W van der Velden, E. P van Ankeren, J. Ausma, M. A Allessie, M. Borgers, G. J.J.M van Eys, and H. J Jongsma Analysis of altered gene expression during sustained atrial fibrillation in the goat Cardiovasc Res, May 1, 2002; 54(2): 427 - 437. [Abstract] [Full Text] [PDF]
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D. Fraccarollo, J. Bauersachs, M. Kellner, P. Galuppo, and G. Ertl Cardioprotection by long-term ETA receptor blockade and ACE inhibition in rats with congestive heart failure: mono- versus combination therapy Cardiovasc Res, April 1, 2002; 54(1): 85 - 94. [Abstract] [Full Text] [PDF]
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T. J. Herron, F. S. Korte, and K. S. McDonald Loaded shortening and power output in cardiac myocytes are dependent on myosin heavy chain isoform expression Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H1217 - H1222. [Abstract] [Full Text] [PDF]
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K. Kinugawa, W. A. Minobe, W. M. Wood, E. C. Ridgway, J. D. Baxter, R. C. J. Ribeiro, M. F. Tawadrous, B. A. Lowes, C. S. Long, and M. R. Bristow Signaling Pathways Responsible for Fetal Gene Induction in the Failing Human Heart : Evidence for Altered Thyroid Hormone Receptor Gene Expression Circulation, February 27, 2001; 103(8): 1089 - 1094. [Abstract] [Full Text] [PDF]
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K. M. Baldwin and F. Haddad Plasticity in Skeletal, Cardiac, and Smooth Muscle: Invited Review: Effects of different activity and inactivity paradigms on myosin heavy chain gene expression in striated muscle J Appl Physiol, January 1, 2001; 90(1): 345 - 357. [Abstract] [Full Text] [PDF]
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R. J. Henning, J. Silva, V. Reddy, S. Kamat, M. B. Morgan, Yong Xiang Li, and S. Chiou Cocaine Increases {beta}-Myosin Heavy-Chain Protein Expression in Cardiac Myocytes Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(4): 313 - 322. [Abstract] [PDF]
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