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Adult mice deficient in actinin–associated LIM-domain protein reveal a developmental pathway for right ventricular cardiomyopathy

Nature Medicine volume 7, pages 591–597 (2001)Cite this article

Abstract

Although cytoskeletal mutations are known causes of genetically based forms of dilated cardiomyopathy, the pathways that link these defects with cardiomyopathy are unclear. Here we report that the α-actinin–associated LIM protein (ALP; Alp in mice) has an essential role in the embryonic development of the right ventricular (RV) chamber during its exposure to high biomechanical workloads in utero. Disruption of the gene encoding Alp (Alp) is associated with RV chamber dilation and dysfunction, directly implicating α-actinin–associated proteins in the onset of cardiomyopathy. In vitro assays showed that Alp directly enhances the capacity of α-actinin to cross-link actin filaments, indicating that the loss of Alp function contributes to destabilization of actin anchorage sites in cardiac muscle. Alp also colocalizes at the intercalated disc with α-actinin and γ-catenin, the latter being a known disease gene for human RV dysplasia. Taken together, these studies point to a novel developmental pathway for RV dilated cardiomyopathy via instability of α-actinin complexes.

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Figure 1: Dynamic pattern of Alp expression in mouse heart.
Figure 2: Alp expression at various stages of mouse development.
Figure 3: Alp−/− embryos show predominant RV dilatation.
Figure 4: DCM in Alp−/− mice.
Figure 5: Alp alters cardiomyocyte cytoarchitecture and sarcomeric organization.
Figure 6: Localization of Alp in the adult mouse heart by immunostaining.
Figure 7: Alp enhances the ability of α-actinin to cross-link F-actin.

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Acknowledgements

We thank S. Evans and J. Chen for helpful comments; N. Dalton and Y. Gu for technical help with echocardiography and right/left heart catheterization; and E. King for contributing to electron microscopic analysis. This work was supported by grants from the Muscular Dystrophy Association (M.C.B.), the NIH (M.C.B. and K.R.C.) and the Jean Le Ducq Foundation (K.R.C.). M.C.B. is an Investigator of the Huntsman Cancer Institute. K.R.C. is supported by an Endowed Chair from the American Heart Association (California Affiliate).

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  1. Mohammad Pashmforoush and Pascal Pomiès: M.P. and P.P. contributed equally to this study.

Authors and Affiliations

  1. UCSD-Salk Program in Molecular Medicine and the UCSD Institute of Molecular Medicine, University of California at San Diego, La Jolla, California, USA

    Mohammad Pashmforoush, Kirk L. Peterson, John Ross Jr & Kenneth R. Chien

  2. Huntsman Cancer Institute and Department of Biology, University of Utah, Salt Lake City, Utah, USA

    Pascal Pomiès & Mary C. Beckerle

  3. Biozentrum, University of Basel, Basel, Switzerland

    Andreas Hefti & Ueli Aebi

  4. Department of Cell Biology, Medical University of South Carolina, Charleston, South Carolina, USA

    Steve Kubalak

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Correspondence to Kenneth R. Chien.

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Pashmforoush, M., Pomiès, P., Peterson, K. et al. Adult mice deficient in actinin–associated LIM-domain protein reveal a developmental pathway for right ventricular cardiomyopathy. Nat Med 7, 591–597 (2001). https://doi.org/10.1038/87920

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