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(Circulation Research. 1996;78:504-509.)
© 1996 American Heart Association, Inc.

Articles

Transgenic Remodeling of the Contractile Apparatus in the Mammalian Heart

Joseph Palermo, James Gulick, Melissa Colbert, Jason Fewell, Jeffrey Robbins

From the Children's Hospital Research Foundation, Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati, Ohio.

Correspondence to Dr Jeffrey Robbins, Division of Molecular Cardiovascular Biology, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail teachdna@aol.com.

	Abstract

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Abstract The structure-function relationships of the sarcomeric proteins in the mammalian cardiac compartment remain ill-defined because of the lack of a suitable model in which they can be readily manipulated or exchanged in vivo. To establish the validity of the transgenic paradigm for remodeling the mammalian heart, the murine -cardiac myosin heavy chain gene promoter was used to express a ventricular myosin light chain-2 transgene (MLC2v) in both the atria and ventricles of the adult animal. Expression resulted in high levels of the transgene's transcript in both compartments. In the ventricle, the transgene was expressed against the background expression of the normal isoform. In the atrium, the transgene's expression would be ectopic, in that normally, MLC2v expression is restricted to the ventricle. Ectopic expression of the transgene in the atria resulted in a complete replacement of the atrial myosin light chain-2 protein isoform, although the endogenous isoform's steady state transcript levels were unchanged. In contrast, ventricular expression of the transgene had no effect at the protein level, despite an eightfold increase in MLC2v transcript levels. The data show that sarcomeric protein stoichiometry is maintained rigorously via posttranscriptional regulation and that protein replacement can be achieved through a single transgenic manipulation.

Key Words: transgenic • myosin light chain • gene • muscle

	Introduction

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The ability to modify the genetic apparatus in a defined manner underlies many of the approaches in molecular cardiovascular biology and biochemistry. Transgenesis has the potential to delineate the molecular, cellular, and functional consequences of protein replacement in the heart by creating animals in which modified genes or the cognate cDNAs are placed into the genome and the encoded proteins can be subsequently expressed in an organ-specific manner. The approach necessarily relies on the action of a strong cardiac-specific promoter that is able to drive high levels of cardiac-restricted expression. We have recently focused our attention on defining such promoters and have delineated the transcriptional elements in both -MyHC and ß-MyHC that are responsible for high levels of cardiac-specific gene expression.^{1 2 3} In the mouse, the animal that is most widely used for transgenic approaches, -MyHC is constitutively expressed before and after birth in the atria. ß-MyHC is expressed in the ventricle during gestation but is downregulated at birth as transcription is initiated from the -MyHC locus.^{4 5} Thus, the rigorous characterization of the -MyHC promoter^{1 2 6} provides a potentially useful reagent for the efficient overexpression of a target transgene in both cardiac compartments in the adult.

The -MyHC promoter has already been used successfully to drive high levels of expression of a ß-adrenergic receptor⁷ and ß-adrenergic receptor kinase.⁸ We wished to determine whether or not it was possible to achieve levels of transgene expression such that some of the most abundant components of the cardiomyocyte, the contractile proteins, could be effectively remodeled. Although the experiment appears straightforward, a number of possible outcomes could complicate the overall approach and subsequent interpretation of the data. For example, it is well documented in Drosophila that by merely altering contractile protein gene dosage, one significantly perturbs the overall stoichiometry of protein production with subsequent dramatic effects on function.^{9 10} Thus, if transgenesis were used in a structure-function or replacement study in the cardiac compartment, it is possible that an observed phenotype might be misleading. By merely overexpressing a normal form of the endogenous protein, the stoichiometry of the contractile apparatus could be perturbed significantly, with the resultant phenotype brought about by this change rather than by difference(s) in protein function due to a mutated polypeptide.

To begin to explore the usefulness of the transgenic paradigm in remodeling the cardiac compartment's contractile apparatus, we overexpressed MLC2v¹¹ in both cardiac compartments. The rationale was that expression of the transgene would be ectopic in the atrium but occur against the normal expression of the ventricular isoform in the ventricle. Such an experiment would allow examination of gene "cross talk" and perturbation of contractile protein stoichiometry to be considered against the backdrop of effective increases in gene dosage specifically in the cardiac compartment. Using the -MyHC promoter linked to a full-length MLC2v cDNA, high levels of transgene expression were achieved in both cardiac compartments. The data show that the contractile apparatus can be effectively remodeled using this methodology and that sarcomeric protein stoichiometry can be maintained despite changes in the steady state transcript levels.

	Materials and Methods

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Construction of Transgenic Mice and Analyses of Transgene Expression
LacZ-expressing transgenic mice were generated using a construct that contained the -MyHC promoter¹² driving the expression of a lacZ fusion gene.¹³ Embryos were removed at 9.5 and 10.5 dpc (noon on the day of the vaginal plug is taken as 0.5 day). Embryos or hearts were fixed and processed for ß-galactosidase staining as described previously.^{13 14} Older hearts were clipped at their apex to allow penetration of the substrate. For the transgene encoding MLC2v, a full-length murine cDNA isolated from a BALB/c adult mouse cardiac cDNA library (Clonetech), was sequenced, linked to the -MyHC promoter, and used to generate transgenic mice. A "tagged" MLC2v cDNA was also made (used to generate line 97; see Fig 2) by including, at the 3' end of the construct, a polyA tail and the exon sequences that make up the ß-MyHC 3'-UTR. This results in a transcript that is 200 to 250 bp longer than the endogenous MLC2v mRNA. The constructs were digested free of vector sequence with Not I and prepared for microinjection as described previously.¹⁵ The founder mice were identified using the polymerase chain reaction¹⁶ and confirmed by genomic Southern blots using DNA obtained from tail clips. Stable transgenic lines were generated by breeding the founder mice with nontransgenic littermates. Subsequent offspring were screened by the polymerase chain reaction. For the RNA analyses, Northern and dot blots were carried out as described previously.^{6 17} End-labeled oligonucleotides specific to MLC2v (5'-CACAGCCCTGGGATGGAGAGTGGGCTGTGGGTCACCTGAGGCTGTGGTTCAG-3'), GAPDH (5'-GGAACATGTAGACCATGTAGTTGAGGTCAATGAAG-3'), MLC2a (5'-GAGGTGACCTCAGCCTGTCTACTCCTCTTTCTCATCCCCG-3'), and -MyHC¹⁷ were used, and hybridization signals were quantified on a PhosphorImager (Molecular Dynamics).

View larger version (29K): [in this window] [in a new window]   Figure 2. Overexpression of MLC2v RNA in transgenic (tg) mice. A, MLC2v overexpression construct. The -MyHC promoter was spliced to the full-length MLC2v cDNA fragment containing the endogenous ATG, polyadenylation signal, and a 70-base polyA tract. The filled boxes in the proximal promoter correspond to the -MyHC exons encoding the 5'-UTR of the mRNA; the box at the 5' terminus corresponds to the last (3'-UTR–encoding) exon of the linked ß-MyHC gene. B, Expression of the tg message. A Northern blot of total RNA from atria (A) and ventricles (V) was hybridized with an MLC2v-specific probe: no differences in the overall patterns were observed if polyA+ RNA was used. Nontransgenic (ntg) tissues show that the probe is specific for the ventricular MLC2 isoform and identifies the expected 800-base fragment consistent with the full-length MLC2v message. In tg RNA, full-length MLC2v transcript is significantly overexpressed in both the atria and ventricles. In a separate tg line (line 97), the tg transcript was "tagged" at its 3'-UTR with additional sequence corresponding to the ß-MyHC terminal exon to discriminate endogenous from tg expression. Comparison of ventricular RNA from these tg animals (line 97) and their ntg littermates (V) indicates that overexpression does not alter the levels of endogenous MLC2v mRNA. C, Quantification of cardiac transcripts. RNA blot analyses were performed to determine RNA levels for -MyHC, MLC2a, and MLC2v. The tg atria and ventricles exhibited increases of eightfold and sevenfold, respectively, in MLC2v message relative to the ntg ventricle, whereas no changes were detected between ntg and tg tissues for MLC2a or -MyHC. GAPDH levels were used to control for loading variations.

Sarcomeric Protein Analyses
The atrial flaps and ventricular apex were excised from adult transgenic and nontransgenic littermates. Myofilament protein was extracted,^{18 19} and all washes were collected to obtain the entire complement of cardiac proteins. Myofilament protein (20 µg) and the corresponding wash fractions were electrophoresed on a 15% polyacrylamide gel in the presence of 0.1% SDS and stained with Coomassie brilliant blue R250.

MLC Immunofluorescence
Hearts were excised from adult (>8-week-old) transgenic and nontransgenic littermates, drop-fixed in 4% paraformaldehyde, and embedded in either paraffin for immunoperoxidase analyses or O.C.T. compound (Miles) for immunofluorescence. Sections (5 or 10 µm) were incubated with rabbit polyclonal antisera against either MLC2a or MLC2v.²⁰ Immunoperoxidase staining was accomplished by use of an avidin-biotin ABC kit (Vector Laboratories, Inc) to increase the sensitivity of the primary antibodies. Immunofluorescence was performed without amplification using a goat anti-rabbit (IgG) secondary antibody conjugated to L-rhodamine (Boehringer-Mannheim).

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Compartment-Specific Expression of the -MyHC Promoter–Driven Transgene During Development
To ensure that the -MyHC promoter fragment does, in fact, drive transgene expression in a compartment-restricted fashion during early development and that ectopic expression is absent, the 5.5-kb fragment that lies between ß- and -MyHC and contains the active -MyHC promoter^{1 6} was linked to lacZ. Transgene expression was determined by staining for ß-galactosidase activity. The data show that expression of lacZ recapitulates exactly the pattern of -MyHC gene expression in the heart (Fig 1). As is the case for endogenous -MyHC expression,^{4 5} reporter gene activity is limited to the atrial compartments during gestation and is rapidly activated in the postnatal ventricles.

View larger version (63K): [in this window] [in a new window]   Figure 1. . Cardiac chamber–specific expression of an -MyHC promoter–driven transgene. Whole-mount preparations of embryos (A and B) and postnatal hearts (C and D) are shown. A, Embryo at 9.5 dpc shows lacZ expression in the primitive atrium (a) as it emerges from the sinus venosus (sv). B, By 10.5 dpc, lacZ staining is strong in the common atrium. C, Anterior (left) and posterior (right) views of the newborn animal's heart are shown. At birth, transgene expression is limited to the atria, the right superior vena cava (vc) as it enters the right atrium, and the pulmonary veins (out of the plane of focus). No expression is seen in the ventricles (v). D, Anterior view of lacZ expression in hearts from transgenic (left) and nontransgenic (right) littermates at 2 weeks of age is shown. In the transgenic hearts, both atria and ventricles are intensely stained, as are the right and left superior VC and the pulmonary veins (not shown). ao indicates aorta; b, bulbus cordis; and pa, pulmonary artery.

Expression of a Transgene Encoding an Ectopic and Endogenous Contractile Protein Isoform
To assess the potential of the -MyHC promoter to effect a remodeling of the heart's contractile apparatus, we tested the effects of transgenic overexpression under conditions in which the transgene's product is endogenously produced and in which transgene expression might lead to ectopic expression of the protein product. The ventricular and atrial isoforms of MLC2 are encoded by two members of a multigene family of Ca²⁺ binding proteins whose cardiac expression is chamber specific throughout development.^{11 21} Each MLC2 is a small phosphoprotein that is intimately associated at stoichiometric levels with the globular head region of the MyHC^{22 23} and may modulate striated muscle contractility by increasing the sensitivity of the sarcomere to Ca²⁺.^{24 25 26} We isolated a full-length MLC2v cDNA (see "Materials and Methods") and sequenced it completely to confirm the open reading frame.²⁷

We anticipated that the -MyHC promoter would drive ectopic expression of MLC2v in the atrium while expression in the ventricle would occur against the endogenous gene's activity. Hemizygous transgenic mice overexpressing MLC2v message in the atria and ventricles were generated by using the -MyHC gene promoter to drive transcription of the full-length mouse MLC2v cDNA (Fig 2A). The integrity of the transgenic transcript was confirmed by Northern analysis (Fig 2B), and the data show that the amount of full-length MLC2v mRNA is significantly increased in both the atria and ventricles of the transgenic animals. Analysis of a transgenic construct (line 97), which carries an MLC2v transgene "tagged" at its 3'-UTR with an additional sequence to distinguish it from its endogenous counterpart, shows that MLC2v overexpression does not significantly alter endogenous MLC2v mRNA levels in the transgenic ventricles (Fig 2B). To quantify possible changes in other cardiac transcript levels that might arise as a result of MLC2v overexpression, RNA blots were prepared from atrial and ventricular tissue and hybridized with transcript-specific probes (Fig 2C). Comparison of nontransgenic and transgenic tissues show that MLC2v mRNA in the transgenic atria and ventricles was eightfold and sevenfold higher, respectively, than in nontransgenic ventricles. Despite the high levels of MLC2v mRNA in the atria, MLC2a transcript levels were identical in the nontransgenic and transgenic hearts, suggesting that accumulation of the ectopic transcript does not affect endogenous gene expression. The data also show that the -MyHC–driven transgene did not titrate out transcription factors essential for the endogenous gene promoter's activity, since -MyHC transcript levels were identical in the transgenic and nontransgenic hearts.

Ectopic Replacement of a Sarcomeric Protein
Sarcomeric and total protein pools in the transgenic hearts were analyzed by electrophoresis to examine the effects of transgene expression on component protein accumulation. Contractile protein isoform levels are controlled mainly at the transcriptional level²⁸ or, in some cases, by alternative splicing of the primary transcript.²⁹ Thus, under normal circumstances the amount of protein correlates with the level of its cognate mRNA. Transgenic overexpression clearly perturbs this relationship, as evidenced by a complete MLC2 isoform switch (MLC2aMLC2v) in the atria (Fig 3A) despite the persistence of normal MLC2a transcript levels. Even more surprising is the fact that no increase in MLC2v protein levels occurs in the transgenic ventricles (Fig 3A) despite a sevenfold excess in the transcript level (Fig 2B and 2C). Nor do there appear to be pools of nonsarcomeric-associated MLC2 proteins in the transgenic hearts (Fig 3B, lanes b, d, f, and h). Moreover, the myofilament preparations and washes show that there are no overt changes in the other sarcomeric proteins due to MLC2v overexpression in either cardiac compartment.

View larger version (68K): [in this window] [in a new window]   Figure 3. Changes in myocardial proteins due to MLC2v overexpression. A, Myofilament proteins were extracted18 from tissues of adult (>8-week-old) nontransgenic (ntg) and transgenic (tg) mice, subjected to SDS-PAGE, and stained with Coomassie blue. Thick- and thin-filament proteins are indicated. Overexpression of MLC2v in the atria resulted in the complete replacement of MLC2a with the MLC2v isoform in the myofilaments without altering the levels of the other sarcomeric proteins. Expression patterns were identical for line 97 (data not shown). In the ventricles, no overexpression of MLC2v protein could be detected, nor was there any overt effect on the myofilament stoichiometry of the other contractile proteins. TM indicates tropomyosin; TNI, troponin I. B, Nonmyofilament proteins are shown. To detect any cytoplasmic protein pools of myosin light chain, the washes from the myofilament extractions were saved and electrophoresed along with ntg myofilament proteins (mf). Lanes a, b, e, and f contain nonmyofilament cytosolic proteins, and lanes c, d, g, and h correspond to the remaining membrane-bound (Triton X–washed)18 proteins.

To ensure that these changes (or the lack thereof) in the MLC2 isoforms, identified by SDS-PAGE, were uniform throughout the atria and ventricles, immunohistochemical studies were carried out with antibodies directed against either MLC2a or MLC2v (Fig 4). The normal patterns of isoform expression seen in the nontransgenic hearts (Fig 4A and 4E) are clearly modified in the transgenic animals. The ectopic replacement of MLC2a with MLC2v in the transgenic atria is confirmed by a total loss of staining with the anti-MLC2a antibody (Fig 4B and 4C) and by the high levels of immunoreactivity with anti-MLC2v in this compartment (Fig 4F and 4G). At higher magnification (Fig 4G), it is apparent that the transgenic atria are homogeneously transformed, and the isoform switch results in a level of MLC2v expression comparable to that observed in the transgenic ventricle. Immunofluorescent analysis confirmed that anti-MLC2v staining of the transgenic atrial cardiomyocytes (Fig 4H) decorated the sarcomeres, producing striations identical to anti-MLC2a staining in the control atria (Fig 4D).

View larger version (78K): [in this window] [in a new window]   Figure 4. Distribution of MLC2 isoforms in nontransgenic and transgenic hearts. The top panels show staining with anti-MLC2a; the bottom panels, with anti-MLC2v. A and E, The presence of MLC2a (A) or MLC2v (E) is indicated in the nontransgenic atria or ventricles by the brown peroxidase precipitate. B, C, F and G, Transgenic hearts were stained as described above. C and G are higher magnifications of sections of B and F, respectively. Immunohistochemical detection of MLC2 isoforms in transgenic hearts verified that MLC2v was homogeneously expressed throughout the atrial myocardium and replaced the endogenous MLC2a isoform. D and H, Indirect immunofluorescence localization of anti-MLC2a in control atria (D) and anti-MLC2v in transgenic atria (H). Regularly spaced striations (arrows) are apparent in both the control and transgenic atria. The striations apparent with anti-MLC2v in the transgenic atria demonstrate that ectopic MLC2v was incorporated into the sarcomeres of the cardiomyocytes. Original magnifications x20 (A, B, E, and F), x70 (C and G), and x100 (D and H) (oil).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
These data indicate that it is possible to remodel the protein complement of the contractile apparatus with directed transgenic overexpression. A total of six lines carrying the MLC2v transgene were generated. Of these, three generated high levels of the transgenic transcript and were selected for further study and subsequently shown to produce high levels of the cognate protein that resulted in either a partial or complete MLC2aMLC2v switch in the atria.²⁷ Similar results have been obtained in parallel experiments in which the -MyHC promoter was used to overexpress the isoform present in the fast fibers of skeletal muscle (MLC2f) in both cardiac compartments. Line-to-line variation was again observed, but in 30% of the lines, an essentially complete switch (MLC2aMLC2f) was observed in the atria. In all cases, the overall stoichiometry of the MLC2 isoform was maintained (J. Gulick and J. Robbins, unpublished data, 1996).

To date, expression of the transgenes, although they vary from line to line, have remained stable within a line. Our working hypothesis is that the line-to-line variation is due to the differences in copy number and/or position effects, and this can be formally tested as multiple lines are accumulated and analyzed for a variety of transgenes. The variation in expression can be used to one's experimental advantage, as the different degrees of replacement observed between multiple lines generated from the identical transgene can be used to carry out a dose-response curve for the phenotypic consequences of the altered protein complement.

Structure-function relationships can thus be explored directly, both within a protein and between the different contractile isoforms directly using a one-step transgenic procedure. Indeed, we have noted that ectopic replacement of MLC2a with MLC2v leads to significant changes in heart function as assessed by a working heart preparation (authors' unpublished data, 1995). Transgenic overexpression can offer an alternative to the more laborious two-step gene targeting/replacement approach,^{30 31} and its efficacy for exploring the functional aspects of the contractile apparatus is increased by the rigorous posttranscriptional controls.

The data are significant in light of the stoichiometric concerns outlined above when a transgenic approach to remodeling the heart is being considered. Data obtained from experiments carried out in Drosophila, in which the gene dosage of the myosin heavy chain was methodically varied, showed that as few as four functional copies of the gene resulted in elevated accumulation of the protein and a flightless phenotype. Further increases in copy number were lethal.³² Particularly intriguing in light of those data is the observation that the transgenic mice used in the present study are characterized by low (2 to 10 copies per diploid genome) transgene copy number.²⁷ Other viable lines we have generated carrying transgenes encoding contractile proteins also have copy numbers in this range (authors' unpublished data, 1996). This contrasts with the wide variability seen in copy number when reporter transgenes, such as cat, were used with the MyHC promoters.^{1 6 33} We have not yet generated a sufficient number of lines expressing a transgene encoding a sarcomeric protein to allow us to establish a statistically significant link between copy number and expression levels or lethality. Nevertheless, in our experience, the narrow range of transgene copy number is striking.

The mechanism by which normal MLC2v protein levels in the ventricle are maintained in the presence of significantly higher steady state transcript levels in this cardiac compartment is presently unknown. The transcripts present are polyadenylated and intact (Fig 2B) and presumably are accessible to the translational apparatus. Our working hypothesis is that increased protein turnover may account for the maintenance of the stoichiometry in the presence of increased de novo protein synthesis. Alternatively, it is possible that the translational efficiency of these transcripts is somehow modified. It will be necessary to measure the rate of MLC2v protein synthesis in the transgenic animals and calculate the flux through the protein pool in the intact hearts to rigorously demonstrate the validity of this idea. If MLC2 turnover is not increased, the translational efficiency of the transgenic transcripts will need to be assessed by comparing the fraction of the transcripts in polysomes derived from the transgenic and nontransgenic hearts. The relative abilities of RNA derived from these fractions could also be tested in in vitro translation assays.

If high copy numbers of the transgene do prove to be lethal, it may well be that this control point (or others, as yet undetermined) can be eventually overwhelmed with a resultant change in the contractile protein stoichiometry, leading to cardiac insufficiency during the latter half of gestation. The transgenic system will certainly be a useful tool for exploring in detail these questions of gene dosage and the resultant contractile protein stoichiometries in the whole-animal context.

These considerations, should they prove germane, do not, however, negate the general usefulness of transgenesis for remodeling the contractile apparatus in the heart. We have demonstrated that the -MyHC promoter can drive very high levels of contractile protein expression and can be used to effectively replace an atrial isoform with the corresponding ventricular protein. Furthermore, despite high levels of "wild-type" transgenic transcript (ie, MLC2v), an increase in the cognate protein level, with the attendant possibilities for modifying function via changes in contractile protein levels, does not occur. This should allow a straightforward assessment of the functional correlates with isoform replacements/mutations that can be made, free of the confounding variable of changes in the relative levels of the sarcomere's components.

	Selected Abbreviations and Acronyms

 

-MyHC, ß-MyHC = - and ß-MyHC dpc = days post coitum MLC1, MLC2 = myosin light chain-1 and -2 MLC1a, MLC1v = atrial- and ventricular-specific isoforms of regulatory MLC1 MLC2a, MLC2v, MLC2f = atrial-, ventricular-, and fast skeletal muscle–specific isoforms of regulatory MLC2 MyHC = myosin heavy chain UTR = untranslated region

	Acknowledgments

 
This study was supported by National Institutes of Health grants HL-22619, HL-41496, HL-52318, and HL-46826 (to Dr Robbins); by the Marion Merrell-Dow Foundation (to Dr Palermo); and by National Institutes of Health training grant HL-07752 (to Dr Fewell). We thank K. Chien and S. Kubalak for the MLC2a and MLC2v antibodies.

Received November 6, 1995; accepted December 26, 1995.

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