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(Circulation Research. 2005;97:1152.)
© 2005 American Heart Association, Inc.

Cellular Biology

Nuclear RNA Foci in the Heart in Myotonic Dystrophy

Ami Mankodi, Xiaoyan Lin, Burns C. Blaxall, Maurice S. Swanson, Charles A. Thornton

From the Departments of Neurology (A.M., C.A.T.), Neuroscience (X.L.), and Cardiovascular Research Institute (B.C.B.), University of Rochester Medical Center, New York; and the Department of Molecular Genetics and Microbiology (M.S.S.), University of Florida, Gainesville.

Correspondence to Charles A. Thornton, MD, Department of Neurology, Box 673, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642. E-mail Charles_Thornton{at}URMC.Rochester.Edu

	Abstract

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The disease mechanism underlying myotonic dystrophy type 1 (DM1) pathogenesis in skeletal muscle may involve sequestration of RNA binding proteins in nuclear foci of expanded poly(CUG) RNA. Here we report evidence for a parallel mechanism in the heart. Accumulation of expanded poly(CUG) RNA in nuclear foci is associated with sequestration of muscleblind proteins and abnormal regulation of alternative splicing in DM1 cardiac muscle. A toxic effect of RNA with an expanded repeat may contribute to cardiac disease in DM1.

Key Words: myotonic dystrophy • CUG repeats • RNA foci • muscleblind • alternative splicing

	Introduction

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Cardiac disease in myotonic dystrophy type 1 (DM1) is characterized by interstitial fibrosis and fatty infiltration with preferential involvement of the specialized conduction tissue.^1,2 This degenerative process results in progressive failure of the conduction system, atrial and ventricular tachyarrhythmia, and mild diastolic dysfunction.³ Sudden cardiac death ranks second after respiratory failure as a cause of death among patients with DM1.⁴ The genetic basis for this multisystem, dominantly inherited disorder is an unstable expansion of CTG repeats in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene.⁵ Variability of the DM1 phenotype is explained partly, but not entirely, by variation in length of the expanded repeat.^6,7 The tract of expanded triplet repeats is highly unstable in somatic cells and may reach massive lengths (>10 kb) in skeletal and cardiac muscle.⁸

DM1 is the most common cause of muscular dystrophy in adults. Recent evidence indicates that the skeletal myopathy of DM1 results from a novel RNA-mediated disease mechanism.⁹ The mutant DMPK mRNA, which contains an expanded CUG repeat, is retained in nuclear foci.¹⁰ Accumulation of this mutant RNA in the nucleus interferes with the alternative splicing of other pre-mRNAs.¹¹ Only a subset of alternatively spliced pre-mRNAs is susceptible to this trans-dominant effect. For example, misregulated splicing of the CLCN1 chloride ion channel leads to reduced chloride conductance and repetitive action potentials (myotonia) in skeletal muscle.¹² Although this effect on alternative splicing is thought to reflect an interaction of the expanded poly(CUG) RNA with specific splicing factors, the exact mechanism is unknown.

DMPK mRNA is expressed most highly in the heart,⁵ raising the possibility that a similar RNA-mediated disease process may occur in cardiac muscle. Indeed, the initial observation of misregulated alternative splicing was made in cardiac tissue. Phillips et al observed that alternative splicing of cardiac troponin T (TNNT2) was abnormal in DM1 heart, and they postulated that altered activity of CUG binding protein 1 (CUGBP1) was the cause.¹¹ Among other functions, CUGBP1 is a splicing factor that binds to short (CUG)₈ oligonucleotides in vitro.¹³ In skeletal muscle, attempts to show interaction of CUGPB1 with expanded poly(CUG) in vivo, by colocalizing the protein with nuclear RNA foci, have not met with success.^14,15 In contrast, in DM1 cardiac muscle, CUGBP1 was reported to fractionate with expanded poly(CUG) in cytoplasmic extracts, suggesting that mutant DMPK mRNA is not retained in the nucleus of cardiomyocytes.¹⁶ However, the distribution of expanded poly(CUG) has not been investigated in DM1 cardiac muscle in situ.

More recently, sequestration of splicing factor muscleblind-like 1 (MBNL1) has been implicated in the pathogenesis of DM1. MBNL1 binds avidly to expanded poly(CUG) in vitro, and it colocalizes with nuclear foci in DM1 skeletal muscle cells.^17,18 Disruption of the murine Mbnl1 gene reproduces the splicing defects for CLCN1 in skeletal muscle and TNNT2 in heart.¹⁹ Indeed, the interaction of expanded poly(CUG) with MBNL1 may be required for development of RNA foci.²⁰ However, the distribution of MBNL1 has not been investigated in DM1 cardiac muscle.

	Materials and Methods

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Tissue samples for fluorescence in situ hybridization (FISH) and immunofluorescence (IF) were obtained at autopsy from DM1 patients (n=6; age at death 50 to 61 years; mean postmortem interval 5.8 hours; range 2.6 to 12 hours) and controls without heart disease (n=4; mean postmortem interval 8 hours; range 4 to 13 hours) and snap-frozen in liquid nitrogen. All patients with DM1 had advanced disease with grade 4 weakness on the DM1 muscle impairment rating scale.²¹ DM1 patients died of respiratory failure (n=5; precipitated by aspiration pneumonia in two cases) or pulmonary embolus (n=1). Information regarding cardiac histology was available for 5 patients and showed increased interstitial fibrosis in the left ventricle (n=5), fatty infiltration (n=3), and increased variability of cardiomyoctye size (n=3). Dense fibrosis of the atrioventricular (AV) node and right bundle was reported in one patient. FISH was performed on frozen sections (6 µm) using a (CAG)₇-Texas Red–labeled RNA probe (complementary to CUG repeats) as described previously.¹⁵ FISH was also combined with IF as described previously.¹⁸ We examined one to three regions of left ventricle from every DM1 patient, and sections of interventricular septum containing the conduction system were also examined from two of the patients. IF was performed using rabbit polyclonal antibodies directed against myosin binding protein H²² (MyBP-H; D. Fischman; New York, NY), MBNL1 (X. Lin, A. Mankodi, and C. Thornton, unpublished data, 2005), and ETR3²³ (T. Cooper; Houston, Tex; or monoclonal antibodies against MBNL1 [3A4¹⁵], MBNL2 [2D9²⁴], and CUGBP1 [3B1¹³]). Antibodies to MyBP-H were previously shown to identify Purkinje fibers.²² Secondary antibodies were labeled with Alexa 488 (Molecular Probes). Splicing assays were performed as described previously.¹² In brief, RNA was isolated (TriReagent; Molecular Research Center) from DM1 autopsy samples (n=4; postmortem interval 3 to 12 hours) or cardiac explants from failing (n=2 ischemic cardiomyopathy; n=2 dilated cardiomyopathy) or nonfailing (n=4) hearts. cDNA was synthesized using SuperScript II reverse transcriptase (Invitrogen) with oligodT_(12–18). Splicing was analyzed by RT-PCR using primers flanking the alternatively spliced exons (supplemental Tables I and II, available online at http://circres.ahajournals.org). RT-PCR products were resolved on agarose gels, stained with SybrGreenII (Molecular Probes), and analyzed on a laser fluorimager. In the case of cardiac sodium channel SCN5A, the entire coding region (28 splice junctions) was screened for splicing abnormalities by RT-PCR (supplemental Methods, available online). For genetic confirmation of DM1, a Southern blot was performed on at least one postmortem tissue sample from every DM1 patient using methods we described previously.⁸

	Results

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Nuclear foci of expanded poly(CUG) mRNA were detected by FISH in each of 6 DM1 patients (Figure 1A) but not in controls without heart disease (n=4). Nuclear RNA foci were present in the left ventricular free wall (Figure 1A) and also in MyBP-H–positive cells of the conduction system in the interventricular septum (Figure 1B). RNA foci were not observed in the cytoplasm in any patients. The fraction of cardiomyoctyes containing nuclear RNA foci could not be quantified because we could not reliably distinguish nuclei of interstitial cells from cardiomyocytes on FISH preparations and because many nuclei were transected by the plane of sectioning. However, nuclear foci were highly abundant in every DM1 section that we examined.

View larger version (28K): [in this window] [in a new window]   Figure 1. FISH and IF on frozen sections of postmortem cardiac tissue. A, B, C, D, and G, FISH with a Texas Red-labeled oligonucleotide probe shows foci of expanded poly(CUG) RNA (left panels). IF shows location of indicated protein (center panels, green). Merged images show location of nuclei (right panels, blue). A and B, Nuclear foci of CUG expansion RNA are present in the DM1 left ventricle (A) and also in the interventricular septum in cells of the conduction system (B; identified by IF for MyBP-H). C, MBNL1 protein (monoclonal antibody 3A4, green) colocalizes with nuclear foci of poly(CUG) RNA. D, MBNL2 protein (monoclonal antibody 2D9, green) also colocalizes with nuclear RNA foci. E and F, IF using polyclonal anti-MBNL1 antibody shows that MBNL1 is widely distributed in the nucleoplasm in normal heart (E), whereas in DM1 heart, it is recruited into nuclear foci and depleted in the nucleoplasm (F). Images in E and F were processed on the same slide, imaged under the same exposure settings, and displayed with identical threshold settings. G, CUGBP1 (monoclonal antibody 3B1, green) does not localize to nuclear foci of poly(CUG) RNA in DM1 cardiac cells. Bar=5 µm. Bar in G applies to all panels except E and F. NL indicates normal.

To determine whether MBNL proteins are expressed in adult human heart and recruited into nuclear RNA foci, IF with monoclonal antibodies directed against MBNL1 and MBNL2 was combined with FISH. MBNL1 and MBNL2 colocalized with the nuclear foci of poly(CUG) RNA (Figure 1C and 1D). IF with a polyclonal antibody showed that MBNL1 protein normally was present in the nucleus in controls (Figure 1E), but in DM1 heart, it was sequestered in nuclear foci (Figure 1F). In contrast, splicing factors in the CELF (CUGBP1 and ETR3-like factors) family, including CUGBP1 (Figure 1G) and ETR3 (data not shown), showed a similar nuclear distribution in patients with DM1 and controls and did not colocalize with nuclear RNA foci in DM1 heart.

To investigate the effects of expanded poly(CUG) on RNA processing in the heart, we used RT-PCR to examine splicing in left ventricular myocardium from DM1 patients (n=4) and controls with failing (n=4) or nonfailing (n=4) hearts. We first confirmed that each of the DM1 samples showed increased inclusion of TNNT2 exon 5 (Figure 2), as reported previously by Philips et al.¹¹ Next, we examined 30 additional exons known to undergo alternative splicing in cardiac muscle (supplemental Table II). For this analysis, we selected genes (n=19) that have one or more alternatively spliced exon cassettes. We used RT-PCR to determine the ratio of inclusion and exclusion products for each alternatively spliced exon. Among 30 exons examined, 4 showed abnormal splicing regulation in DM1 compared with controls (Figure 2). KCNAB1 encodes an auxiliary ß-subunit (Kvß) that binds to and regulates the (pore-forming) -subunits of voltage-gated potassium channels. Compared with controls, DM1 hearts showed increased expression of Kvß1.3 relative to Kvß1.2 isoforms²⁵ indicating misregulated alternative splicing of exon 2 (Figure 2). DM1 hearts also showed increased inclusion for exon 5 in the M-line region of titin, a sarcomeric protein, and increased utilization of exon 5b in place of exon 5a for the -actinin–associated LIM protein (ALP), a component of the Z disc (Figure 2). ZASP, a gene encoding another protein of the Z disc, also showed increased inclusion of exon 11 in DM1, but two other alternatively spliced exons (exons 4 and 6) in this transcript were normally regulated (data not shown). We screened for abnormal splicing of SCN5A because previous work has shown that mutations that alter the function of this sodium ion channel are associated with familial cardiac conduction defects.²⁶ Because SCN5A is not known to undergo alternative splicing, we screened all of its 28 splice junctions and found no difference in splicing between DM1 and control hearts. However, a limitation of our screening procedure is that splice alternations having only a slight effect on size of the SCN5A cDNA may have been overlooked.

View larger version (94K): [in this window] [in a new window]   Figure 2. Misregulated alternative splicing of TNNT2, KCNAB1, Titin, and ALP in adult DM1 cardiac cells. RT-PCR splicing assays were performed with RNA extracted from DM1 patients (n=4) and controls with failing (n=4) or nonfailing (n=4) hearts. The alternatively spliced exon (gray) is diagrammed for each pre-mRNA.

	Discussion

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Previous studies of molecular pathogenesis in DM1 cardiac muscle focused on silencing effects of the expanded CTG repeat on genes at the DM1 locus. For example, nuclear retention of mutant DMPK mRNA may reduce the synthesis of DMPK protein, or effects of the repeat expansion on chromatin structure may reduce the transcription of SIX5, a flanking gene that encodes a transcription factor.²⁷ The SIX5 promoter region lies within 1 kb of the expanded CTG. Although targeted disruption of murine Dmpk or Six5 is associated with PR or QRS prolongation,^28,29 respectively, there is uncertainty about the actual extent of DMPK or SIX5 protein loss in DM1 heart. Furthermore, neither Dmpk nor Six5 heterozygous knockout mice have been shown to reproduce the progressive fibrosis of the conduction system and eventually conduction block that are characteristic of DM1.³⁰ Accordingly, it remains possible that major aspects of DM1-related cardiac disease are not explained by partial DMPK or SIX5 deficiency.

Our results indicate that circumstances in DM1 cardiac muscle are conducive for an RNA-mediated pathogenic cascade similar to that recently elucidated in skeletal muscle. Despite previous evidence that the expanded poly(CUG) RNA resides in a cytoplasmic complex,¹⁶ based on biochemical fractionation of DM1 postmortem heart tissue from a single subject, we have not found evidence for expanded poly(CUG) outside of the nucleus in cardiac cells. However, the limits of detection sensitivity for our FISH methods have not been determined, and the possibility that a fraction of mutant DMPK mRNA, or its degradation intermediates, are exported to the cytoplasm has not been eliminated. Notably, in our postmortem samples of DM1 cardiac muscle, the intranuclear sequestration of MBNL1 is more complete than what we observe in biopsy samples of skeletal muscle, although the latter were obtained at an earlier stage of disease progression (X. Lin, A. Mankodi, C. Thornton, unpublished observations, 2005). Thus, exons for which alternative splicing depends on this splicing factor, such as exon 5 of TNNT2,¹⁹ are clearly at risk for aberrant regulation in DM1. Finally, we confirmed the initial observation of misregulated splicing for TNNT2,¹¹ and identified other pre-mRNAs subject to misregulated splicing in DM1 heart. However, the functional consequences of misregulated alternative splicing for Kvß, titin, ALP, and ZASP are uncertain. An important question not addressed in the present study is whether the individual or cumulative effects of this splicing defect, which involves a subset of pre-mRNAs and generally leads to inappropriate expression of fetal splice isoforms in mature striated muscle, can induce progressive degeneration of the conduction system. Recent studies of mice having conditional ablation of splicing factor ASF/SF2 in the heart established that persistent expression of fetal splice isoforms in adult cardiac muscle can induce progressive cardiomyopathy.³¹ Our results suggest that accumulation of expanded poly(CUG) in nuclear foci may arrive at a similar, tissue-specific knockdown of activity for MBNL1 and perhaps other MBNL proteins in cardiomyocytes. These results point to a need for models that directly examine the effects of poly(CUG) expression or MBNL loss in cardiac muscle.

	Acknowledgments

 
This work comes from the University of Rochester Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center (NIH/NS48843), with support from NIH/NIAMS AR49077, AR48143 (C.T.), the Muscular Dystrophy Association, and the Saunders Family Neuromuscular Research Fund. The authors thank Matt Krym and Don Henderson for excellent technical assistance. The authors thank Drs Thomas Cooper and Donald Fischman for gifts of antibodies.

	Footnotes

 
Original received June 14, 2005; revision received September 15, 2005; accepted October 18, 2005.

	References

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This Article Abstract Full Text (PDF) Data Supplement All Versions of this Article: 97/11/1152    most recent 01.RES.0000193598.89753.e3v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mankodi, A. Articles by Thornton, C. A. Search for Related Content PubMed PubMed Citation Articles by Mankodi, A. Articles by Thornton, C. A. Related Collections Genetics of cardiovascular disease Cell biology/structural biology Gene expression