Ablation of palladin in adult heart causes dilated cardiomyopathy associated with intercalated disc abnormalities

Palladin (PALLD) is an actin-associated protein, which, together with myopalladin (MYPN) and myotilin (MYOT), belongs to a small protein family of immunoglobulin (Ig) domain-containing proteins in the Z-line associated with the actin cytoskeleton (reviewed in Otey et al., 2009). While MYPN and MYOT are specifically expressed in striated and skeletal muscle, respectively, PALLD is ubiquitously expressed in various tissues, including the heart, where it is expressed at high levels (Wang and Moser, 2008). Mutations in the MYPN gene have been associated with dilated (DCM), hypertrophic (HCM), and restrictive cardiomyopathy (Bagnall et al., 2010; Duboscq-Bidot et al., 2008; Meyer et al., 2013; Purevjav et al., 2012), while MYOT gene mutations can cause various skeletal muscle disorders (reviewed in Otey et al., 2009). Mutations in the PALLD gene have been linked to pancreatic cancer (Liotta et al., 2021; Pogue-Geile et al., 2006; Slater et al., 2007), and PALLD levels have been shown to correlate with increased invasiveness of cancer cells (Gilam et al., 2016; Goicoechea et al., 2009; von Nandelstadh et al., 2014). However, the role of PALLD in the heart has remained unknown. Whereas MYPN and MYOT are expressed as single isoforms, PALLD exists in many different isoforms due to the presence of four alternative promoters, alternative splicing, and early termination as illustrated in Figure 1—figure supplement 1 (Goicoechea et al., 2010; Wang and Moser, 2008). The longest 200 kDa isoform of PALLD is predominantly expressed in striated muscle and highly homologous in structure to MYPN, sharing five Ig domains and a central proline-rich region (Otey et al., 2009). Furthermore, PALLD contains an additional proline-rich region, not shared with MYPN. The 140 kDa and 90 kDa isoforms containing four and three Ig domains, respectively, are also expressed in the heart, but have a more ubiquitous expression pattern (Wang and Moser, 2008). Molecular weights and expression profiles of the other isoforms have not been determined in detail (Goicoechea et al., 2010; Wang and Moser, 2008). Within the cardiac Z-line, PALLD and MYPN share several interaction partners, including α-actinin (Bang et al., 2001; Rönty et al., 2004), nebulette (Bang et al., 2001), titin (Filomena et al., 2021), and members of the PDZ-LIM protein family (cypher/ZASP/LDB3, ALP/PDLIM3, CLP36/PDLIM1, RIL/PDLIM4) (von Nandelstadh et al., 2009) as illustrated in Figure 1A. Furthermore, PALLD and MYPN bind to myocardin-related transcription factors (MRTFs) (Filomena et al., 2020; Jin et al., 2010) as well as bind and bundle F-actin (Dixon et al., 2008; Filomena et al., 2020; Gurung et al., 2016), stabilizing the actin cytoskeleton and consequently promoting serum response factor (SRF) signaling. Additionally, PALLD binds to sorbin and SH3 domain-containing 2 (SORBS2) (Rönty et al., 2005), localized at the intercalated disc (ICD) and Z-line of the heart, as well as various proteins expressed in non-muscle cells, including actin-associated (Boukhelifa et al., 2006; Boukhelifa et al., 2004; Goicoechea et al., 2006; Jin et al., 2007; Mykkänen et al., 2001; Rachlin and Otey, 2006) and signaling/adaptor (Lai et al., 2006; Rönty et al., 2007) proteins.

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Confirmation of PALLD-CARP and PALLD-FHOD1 interactions in NanoBRET protein interaction assays.

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Consistent with the interaction of PALLD with F-actin and numerous actin binding proteins, PALLD is associated with various actin-based structures, including focal adhesions, stress fibers, cell-cell junctions, and Z-lines, and is important for the assembly, organization, and maintenance of the actin cytoskeleton (reviewed in Jin, 2011; Otey et al., 2009). PALLD is well-known for its involvement in cell motility and smooth muscle cell differentiation, implicating it in cancer (Jin, 2011), while its role in the heart has remained elusive, in part due to embryonic lethality of PALLD knockout mice (Luo et al., 2005). Thus, to provide insights into the specific role of PALLD in cardiac muscle, we generated conditional (cPKO) and inducible (cPKOi) cardiomyocyte (CMC)-specific knockout mice for the most common PALLD isoforms. While conditional knockout of PALLD in the heart did not cause any pathological cardiac phenotype, PALLD knockdown in adult heart resulted in left ventricular (LV) dilation and systolic dysfunction, associated with fibrosis and ICD abnormalities. Furthermore, we identified cardiac ankyrin repeat protein (CARP/Ankrd1) and formin homology 2 domain containing 1 (FHOD1) as novel interaction partners of the N-terminal region of PALLD. Quantitative real-time PCR (qRT-PCR) analyses on myocardial tissue from DCM and ischemic cardiomyopathy (ICM) patients showed increased transcript levels of MYPN and the PALLD long isoform in DCM patients, while total transcript levels of PALLD were reduced in both DCM and ICM patients. On the other hand, no changes in the protein levels of MYPN and PALLD were found.

In this study, we show that in addition to its known localization in the sarcomeric Z-line, PALLD is located in the I-band, the ICD, and the nucleus of CMCs. The PALLD C-terminal region was previously found to target to the nucleus in podocytes (Endlich et al., 2009) and smooth muscle cells (SMCs) (Jin et al., 2010), while the N-terminal region was shown to be required for nuclear export (Endlich et al., 2009). Consistently, immunofluorescence stainings with antibodies towards all PALLD isoforms or the PALLD C-terminal region showed the localization of PALLD in the nucleus of CMCs. However, surprisingly, antibodies against the second proline-rich region present in the major isoforms did not stain the nucleus. This suggests that only isoforms without the second proline-rich region (indicated in Figure 1—figure supplement 1) are present in the nucleus, which is consistent with immunohistochemical stainings of human biopsies from pancreas (Goicoechea et al., 2010). Thus, PALLD isoforms may have different cellular functions depending on the presence or absence of the second proline-rich region. As shown in Figure 1A, many interaction partners of PALLD bind to its second proline-rich region, including SORBS2, which is present in the ICD and Z-line of the heart, so one possibility could be that the second proline-rich region tethers PALLD to the actin cytoskeleton, preventing it from going to the nucleus.

In a yeast two-hybrid screening, we identified CARP and FHOD1 as novel interaction partners of the PALLD N-terminal region for which no interaction partners have previously been identified. Since CARP is a well-known interaction partner of the MYPN N-terminal region (Bang et al., 2001), structurally homologous to the PALLD N-terminal region, it is not surprising that also PALLD binds to CARP. CARP and MYPN are known to form a complex in the I-band, where CARP is linked to the titin N2A region (Bang et al., 2001; Miller et al., 2003). Consistently, we found that also PALLD is located in the I-band but hypothesize that only the 200 kDa PALLD isoform containing the N-terminal CARP-binding region is targeted to the I-band. Titin is a largest known protein, stretching from the Z-line to the M-line and functioning as a molecular spring responsible for the passive stiffness of striated muscle, implicating it in force transmission and mechanosensing (Loescher et al., 2022). Thus, based on their link to titin and dual localization in the sarcomere and the nucleus, CARP and MYPN were previously proposed to form a complex involved in the transduction of stretch-induced signaling from the sarcomere to the nucleus (Laure et al., 2010; Miller et al., 2003). To determine whether CARP may be responsible for the targeting of PALLD to the nucleus, we performed immunofluorescence stainings of CMCs from CARP knockout mice. However, CARP ablation did not affect the localization of PALLD in the nucleus of CMCs, questioning the hypothesis of a role of PALLD and MYPN in mechanosensing. Consistent with targeting experiments in podocytes and SMCs, it is therefore likely that the PALLD C-terminal region is responsible for its targeting to the nucleus also in CMCs. In particular, based on the binding of the PALLD Ig3 domain to the transcriptional cofactor MRTF-A (Filomena et al., 2020; Jin et al., 2010), which cycles between the cytosol and nucleus to regulate SRF signaling, it is tempting to speculate that MRTF-A is responsible for the targeting of PALLD to the nucleus. Another possibility could be that PALLD contains a nuclear localization signal (NLS), as previously predicted by sequence analysis (Endlich et al., 2009). On the other hand, no NLSs were predicted in MYPN, which is also present in the nucleus. Based on the high homology between the two proteins, we therefore consider it most likely that PALLD and MYPN are transported to the nucleus through binding to proteins that translocate to the nucleus, such as MRTF-A.

The interaction of PALLD with FHOD1 is consistent with its location in the ICD, where it also binds to SORBS2 (Rönty et al., 2005). FHOD1 has been reported to be localized at the ICD and costamere of the heart (Al Haj et al., 2015; Dwyer et al., 2014) consistent with our findings. In contrast, Sanematsu et al., showed that FHOD1 is dispensable for normal cardiac development and function in mouse and failed to detect FHOD1 in the heart (Sanematsu et al., 2019). The reason for this discrepancy is unclear as several different FHOD1 antibodies were tested in each of the studies. Nevertheless, the low expression level of FHOD1 in the heart and absence of a pathological cardiac phenotype of FHOD1-deficient mice questions the relevance of the PALLD-FHOD1 interaction in CMCs. In contrast, FHOD1 is highly expressed in SMCs and other cell types, where also PALLD is present, so the interaction is likely to be important in other tissues. FHOD1 suppresses actin polymerization by inhibiting nucleation and elongation but stabilizes actin filaments by capping the actin barbed ends, protecting them from depolymerization, while simultaneously mediating F-actin bundling by connecting them to adjacent actin filaments (Schönichen et al., 2013). In line with this, FHOD1 silencing was shown to reduce migration and invasion of breast cancer cells by inhibiting the nuclear translocation of the SRF coactivator MRTF-A, which is sequestered in the cytoplasm by G-actin and regulated by changes in actin dynamics (Jurmeister et al., 2012). PALLD directly binds to MRTF-A (Filomena et al., 2020; Jin et al., 2010) and stabilizes the actin cytoskeleton by promoting actin polymerization and preventing actin depolymerization, consequently promoting MRTF-mediated activation of SRF signaling (Dixon et al., 2008; Filomena et al., 2020; Gurung et al., 2016). Thus, it is possible that PALLD and FHOD1 may cooperate in regulating actin dynamics and SRF signaling.

Global knockout of PALLD in mouse was reported to result in embryonic lethality before E15.5 due to multiple defects, including failure of body walls to close, resulting in exencephaly and herniation of abdominal organs (Luo et al., 2005). Furthermore, analysis of PALLD knockout embryos revealed a key role of PALLD in the induction of SMC differentiation in the developing vasculature (Jin et al., 2010) and fibroblasts derived from knockout embryos showed defects in stress fiber formation, cell adhesion, and motility (Luo et al., 2005). Based on its similarity to MYPN, associated with different forms of cardiomyopathy (Bagnall et al., 2010; Duboscq-Bidot et al., 2008; Meyer et al., 2013; Purevjav et al., 2012), as well as high expression levels of specific PALLD isoforms in cardiac muscle both during development and at adult stage, we hypothesized that PALLD plays an important role also in the heart (Wang and Moser, 2008).

To determine the role of PALLD in the heart in vivo, we floxed Palld exon 14 (see Figure 1—figure supplement 2), allowing us to generate conditional (cPKO) and inducible (cPKOi) CMC-specific knockout mice for all PALLD isoforms except for two predicted isoforms not containing exon 14. Due to extensive differential splicing of PALLD, it was not possible to target all isoforms. Unexpectedly, cPKO mice exhibited no pathological cardiac phenotype at basal levels and showed a normal hypertrophic response to TAC. In contrast, cPKOi mice induced at adult stage developed cardiac dilation and systolic dysfunction within 8 wk after TAM induction, associated with interstitial fibrosis and upregulation of cardiac stress markers. Consistently, reduced sarcomere shortening and Ca²⁺ transient amplitude were observed in CMCs, and decreased maximum Ca²⁺-activated isometric tension was found in cPKOi myofibrils, while the kinetics of contraction were unaffected. As biomechanical properties of myofibril preparations from the LV were measured at Ca²⁺ concentrations that cannot be reached under the physiological conditions of cardiac contraction, we cannot exclude that our observations might not fully recapitulate in vivo mechanisms. The heart weight to body weight ratio was unaltered, although CMC size was increased, mainly due to increased CMC width.

At the ultrastructural level, ICDs in cPKOi mice were disorganized and more convoluted compared to those of control mice. The ICD is a highly complex structure joining together adjacent CMCs in the heart and is made up of three major complexes: adherens junctions, where actin filaments are anchored and connect the sarcomere to the cell membrane; desmosomes, which tether the cell membrane to the intermediate filament network; and gap junctions, which permit the passage of ions and small molecules between neighboring CMCs, allowing for electrical and metabolic coupling between cells (reviewed in Vermij et al., 2017). In contrast to previous belief, rather than functioning independently, the three junctions cooperate via crosstalk between their components in mixed-type junctions termed ‘area composita’ (Borrmann et al., 2006; Franke et al., 2006). Thus, the ICD can be considered as a single functional unit important for mechanical coupling and transmission of contractile force and electrical signals between adjacent CMCs. PALLD plays a well-known role in the organization of the actin cytoskeleton (Jin, 2011; Otey et al., 2009) and binds directly to F-actin (Dixon et al., 2008), ALP (von Nandelstadh et al., 2009), and SORBS2 (Rönty et al., 2005), which are associated with the adherens junction (Ding et al., 2020; Pashmforoush et al., 2001). Thus, destabilization of the adherens junction in cPKOi mice may be responsible for the structural alterations at the ICD, also affecting nearby sarcomeres, as evident by Z-line abnormalities and sarcomere disruption in the vicinity of the adherens junction in high-amplitude ICDs. PALLD also interacts with several components of the transitional junction, where the contractile apparatus is connected the ICD to allow force transmission between adjacent CMCs (Bennett, 2012). In particular, titin (Filomena et al., 2021), α-actinin (Bang et al., 2001; Rönty et al., 2004), and cypher (von Nandelstadh et al., 2009), all interaction partners of PALLD, are associated with the transitional junction, suggesting a possible effect of PALLD on the attachment of the myofilament to the ICD and the stability of the junction. Immunofluorescence stainings and western blot analyses did not show any changes in the localization of ICD proteins, including the PALLD interaction partners FHOD1 and SORBS2. However, the protein level of SORBS2 was ~1.6-fold upregulated in cPKOi heart. SORBS2, also known as Arg kinase-binding protein 2 (ArgBP2), is a scaffold protein localized at the adherens junction of the ICD as well as the Z-line at lower levels (Ding et al., 2020). SORBS2 overexpression in mouse heart was reported to lead to upregulation of β-tubulin, a direct interaction partner of SORBS2, and consequent microtubule densification, resulting in junctophilin 2 translocation, T-tubule disorganization, defective excitation-contraction coupling, and systolic dysfunction (Li et al., 2020). Furthermore, SORBS was found to be upregulated in patients with left ventricular non-compaction (LVNC), but not HCM and arrhythmogenic cardiomyopathy, and may play a role in the progression of heart failure in LVNC patients (Li et al., 2020). Thus, increased SORBS2 expression in cPKOi mice may contribute to ICD instability and cardiac dysfunction. ICD alterations, such as altered expression of ICD proteins and increased, more variable ICD amplitude, are commonly associated with DCM both in human and mouse (Wilson et al., 2014). In addition, mutations in several genes (VCL,DSP,DSG2, DES) encoding ICD proteins have been associated with DCM and several knockout mouse models of adherens junction and desmosomal proteins develop DCM (Bang et al., 2022; Hirschy et al., 2010; Kostetskii et al., 2005; Li et al., 2012; Norgett et al., 2000; Sheikh et al., 2006; Zemljic-Harpf et al., 2007). Thus, it is plausible to suggest that structural alteration of the ICD in the absence of PALLD is the primary event leading to DCM and systolic dysfunction in cPKOi mice. Our data has shown that, in addition to the ICD, PALLD localizes to other cellular compartments, including the nucleus. Therefore, we cannot rule out the possibility that ultrastructural changes observed in cPKOi cardiomyocytes might be a consequence of LV dilation rather than the primary cause of the observed phenotype. Interestingly, MKO mice, which developed a mild form of DCM under basal conditions, also showed an increase in ICD fold amplitude, although only by ~27% and without other obvious ICD abnormalities (Filomena et al., 2021), suggesting that PALLD plays a more important structural role in the ICD than MYPN.

The absence of a pathological cardiac phenotype in cPKO mice is surprising based on the rather severe cardiac phenotype of cPKOi mice induced at adult stage. Due to the structural homology of PALLD to MYPN, we hypothesized that MYPN can compensate for the absence of PALLD. However, the phenotype of cPKO/MKO dKO mice was indistinguishable from that of MKO mice, strongly suggesting that MYPN does not compensate for the loss of PALLD in cPKO mice. Another possibility is that the small PALLD isoforms not targeted by our knockout approach can compensate for the absence of the other PALLD isoforms when absent during development. However, these isoforms were not upregulated in cPKO mice and do not contain binding sites for most of the PALLD interaction partners, so we consider this rather unlikely. We hypothesize that when PALLD is knocked out during embryonic development, the mice are able to adapt through activation of compensatory mechanisms, whereas this is not anymore possible when PALLD is knocked out in adult mice. This phenomenon has also been observed in other genetic models (reviewed in El-Brolosy and Stainier, 2017).

Analysis of MYPN and PALLD mRNA levels in LV biopsies from human ICM and DCM patients showed an ~2.9-fold upregulation of MYPN and an ~1.9-fold upregulation of the structurally similar 200 kDa PALLD isoform in DCM hearts, whereas the overall transcript level of all PALLD isoforms except for potential truncated N-terminal transcript(s) was ~2.8- and ~3.0-fold reduced in DCM and ICM patients, respectively. Similarly, in two RNA-Seq studies, PALLD was reported to be downregulated in both DCM/non-ischemic cardiomyopathy (NICM) (~1.7- to ~2.0-fold) and ICM (~1.6- to ~2.1-fold) patients, while MYPN was upregulated in both DCM/NICM (~1.5- to ~1.6-fold) and ICM (~1.6- to ~1.7-fold) patients (Sweet et al., 2018; Yang et al., 2014). The absent modulation of MYPN in ICM patients in this study may be due to different patient cohorts and detection methods used. The 90 kDa PALLD isoform is the predominant isoform in the heart, while the 200 kDa PALLD isoform is expressed at much lower levels, explaining the upregulation of the 200 kDa PALLD isoform despite the overall reduced transcript level of PALLD. Notwithstanding the transcriptional modulation of both MYPN and PALLD in DCM and ICM patients, no changes in protein expression were found, so the altered transcript levels are unlikely to have any functional effects. As previously reported, CARP/Ankrd1 protein levels were significantly increased in DCM patients (Kempton et al., 2018; Nagueh et al., 2004; Zolk et al., 2002).

Altogether, our data demonstrate an important role of PALLD for normal heart function, suggesting PALLD as a possible candidate gene for cardiomyopathy. Based on the absence of a phenotype in cPKO mice, loss-of-function mutations are unlikely to affect cardiac function and would likely lead to embryonic lethality due to the essential role of PALLD in other tissues and cell types. However, as for MYPN, whose ablation does not severely affect cardiac function, it is possible that mutations with dominant negative effects may be linked to cardiac disease. The reason why a putative link between PALLD mutations and cardiac disease has not been established could be due to lack of focus on the PALLD gene.

All data generated and analysed during this study are included in the manuscript and figure supplements. Source data files have been provided for all figures.

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Author details

1. Giuseppina Mastrototaro

   1. University of Milan-Bicocca, Milan, Italy
   2. IRCCS Humanitas Research Hospital, Milan, Italy

   Present address

   AGC Biologics, Milan, Italy

   Contribution

   Formal analysis, Investigation, Writing – original draft

   Competing interests

   No competing interests declared

2. Pierluigi Carullo

   1. IRCCS Humanitas Research Hospital, Milan, Italy
   2. Institute of Genetic and Biomedical Research, National Research Council, Milan unit, Milan, Italy

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

3. Jianlin Zhang

   University of California, San Diego, La Jolla, United States

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

4. Beatrice Scellini

   Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

5. Nicoletta Piroddi

   Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

6. Simona Nemska

   IRCCS Humanitas Research Hospital, Milan, Italy

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

7. Maria Carmela Filomena

   1. IRCCS Humanitas Research Hospital, Milan, Italy
   2. Institute of Genetic and Biomedical Research, National Research Council, Milan unit, Milan, Italy

   Contribution

   Investigation

   Competing interests

   No competing interests declared

8. Simone Serio

   IRCCS Humanitas Research Hospital, Milan, Italy

   Contribution

   Formal analysis

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7294-2094

9. Carol A Otey

   Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, United States

   Contribution

   Conceptualization, Resources

   Competing interests

   No competing interests declared

10. Chiara Tesi

    Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

    Contribution

    Formal analysis, Investigation

    Competing interests

    No competing interests declared

11. Fabian Emrich

    Department of Cardiac Surgery, Goethe University, Frankfurt, Germany

    Contribution

    Resources, Provided patient biopsies

    Competing interests

    No competing interests declared

12. Wolfgang A Linke

    Institute of Physiology II, University of Münster, Münster, Germany

    Contribution

    Resources, Supervision

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-0801-3773

13. Corrado Poggesi

    Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

    Contribution

    Resources, Supervision, Funding acquisition, Writing – original draft

    Competing interests

    No competing interests declared

14. Simona Boncompagni

    Department of Neuroscience, Imaging and Clinical Sciences and Center for Advanced Studies and Technology, University G. d'Annunzio, Chieti, Italy

    Contribution

    Formal analysis, Investigation, Writing – original draft, Writing - review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-5308-5069

15. Marie-Louise Bang

    1. IRCCS Humanitas Research Hospital, Milan, Italy
    2. Institute of Genetic and Biomedical Research, National Research Council, Milan unit, Milan, Italy

    Contribution

    Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing – original draft, Project administration, Writing - review and editing

    For correspondence

    marie-louise.bang@cnr.it

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-8859-5034

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