Knockout of Lmod2 Results in Shorter Thin Filaments Followed by Dilated Cardiomyopathy and Juvenile Lethality

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2015 Oct 22

PMID 26487682

Citations 56

Authors

Christopher T Pappas

Rachel M Mayfield

Christine Henderson

Nima Jamilpour

Cathleen Cover

Zachary Hernandez

Kirk R Hutchinson

Miensheng Chu

Ki-Hwan Nam

Jose M Valdez

Pak Kin Wong

Henk L Granzier

Carol C Gregorio

Affiliations

Soon will be listed here.

Abstract

Leiomodin 2 (Lmod2) is an actin-binding protein that has been implicated in the regulation of striated muscle thin filament assembly; its physiological function has yet to be studied. We found that knockout of Lmod2 in mice results in abnormally short thin filaments in the heart. We also discovered that Lmod2 functions to elongate thin filaments by promoting actin assembly and dynamics at thin filament pointed ends. Lmod2-KO mice die as juveniles with hearts displaying contractile dysfunction and ventricular chamber enlargement consistent with dilated cardiomyopathy. Lmod2-null cardiomyocytes produce less contractile force than wild type when plated on micropillar arrays. Introduction of GFP-Lmod2 via adeno-associated viral transduction elongates thin filaments and rescues structural and functional defects observed in Lmod2-KO mice, extending their lifespan to adulthood. Thus, to our knowledge, Lmod2 is the first identified mammalian protein that functions to elongate actin filaments in the heart; it is essential for cardiac thin filaments to reach a mature length and is required for efficient contractile force and proper heart function during development.

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References

Nam K, Jamilpour N, Mfoumou E, Wang F, Zhang D, Wong P . Probing mechanoregulation of neuronal differentiation by plasma lithography patterned elastomeric substrates. Sci Rep. 2014; 4:6965. PMC: 4223667. DOI: 10.1038/srep06965. View

Ehler E, Fowler V, Perriard J . Myofibrillogenesis in the developing chicken heart: role of actin isoforms and of the pointed end actin capping protein tropomodulin during thin filament assembly. Dev Dyn. 2004; 229(4):745-55. DOI: 10.1002/dvdy.10482. View

Gates B, Xu Q, Stewart M, Ryan D, Willson C, Whitesides G . New approaches to nanofabrication: molding, printing, and other techniques. Chem Rev. 2005; 105(4):1171-96. DOI: 10.1021/cr030076o. View

Gregorio C, Fowler V . Mechanisms of thin filament assembly in embryonic chick cardiac myocytes: tropomodulin requires tropomyosin for assembly. J Cell Biol. 1995; 129(3):683-95. PMC: 2120443. DOI: 10.1083/jcb.129.3.683. View

Medeiros D . Assessing mitochondria biogenesis. Methods. 2008; 46(4):288-94. DOI: 10.1016/j.ymeth.2008.09.026. View

Sniadecki N, Chen C . Microfabricated silicone elastomeric post arrays for measuring traction forces of adherent cells. Methods Cell Biol. 2007; 83:313-28. DOI: 10.1016/S0091-679X(07)83013-5. View

Cenik B, Garg A, McAnally J, Shelton J, Richardson J, Bassel-Duby R . Severe myopathy in mice lacking the MEF2/SRF-dependent gene leiomodin-3. J Clin Invest. 2015; 125(4):1569-78. PMC: 4396495. DOI: 10.1172/JCI80115. View

Sussman M, Welch S, Gude N, Khoury P, Daniels S, Kirkpatrick D . Pathogenesis of dilated cardiomyopathy: molecular, structural, and population analyses in tropomodulin-overexpressing transgenic mice. Am J Pathol. 1999; 155(6):2101-13. PMC: 1866919. DOI: 10.1016/S0002-9440(10)65528-9. View

Nworu C, Kraft R, Schnurr D, Gregorio C, Krieg P . Leiomodin 3 and tropomodulin 4 have overlapping functions during skeletal myofibrillogenesis. J Cell Sci. 2014; 128(2):239-50. PMC: 4294772. DOI: 10.1242/jcs.152702. View

10.

Gramlich M, Michely B, Krohne C, Heuser A, Erdmann B, Klaassen S . Stress-induced dilated cardiomyopathy in a knock-in mouse model mimicking human titin-based disease. J Mol Cell Cardiol. 2009; 47(3):352-8. PMC: 2764556. DOI: 10.1016/j.yjmcc.2009.04.014. View

11.

Chereau D, Boczkowska M, Skwarek-Maruszewska A, Fujiwara I, Hayes D, Rebowski G . Leiomodin is an actin filament nucleator in muscle cells. Science. 2008; 320(5873):239-43. PMC: 2845909. DOI: 10.1126/science.1155313. View

12.

Arber S, Hunter J, ROSS Jr J, Hongo M, Sansig G, Borg J . MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell. 1997; 88(3):393-403. DOI: 10.1016/s0092-8674(00)81878-4. View

13.

Tan J, Tien J, Pirone D, Gray D, Bhadriraju K, Chen C . Cells lying on a bed of microneedles: an approach to isolate mechanical force. Proc Natl Acad Sci U S A. 2003; 100(4):1484-9. PMC: 149857. DOI: 10.1073/pnas.0235407100. View

14.

Fowler V, Sussmann M, Miller P, Flucher B, Daniels M . Tropomodulin is associated with the free (pointed) ends of the thin filaments in rat skeletal muscle. J Cell Biol. 1993; 120(2):411-20. PMC: 2119515. DOI: 10.1083/jcb.120.2.411. View

15.

Littlefield R, Fowler V . Actin dynamics at pointed ends regulates thin filament length in striated muscle. Nat Cell Biol. 2001; 3(6):544-51. DOI: 10.1038/35078517. View

16.

Zheng M, Cheng H, Li X, Zhang J, Cui L, Ouyang K . Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death. Hum Mol Genet. 2008; 18(4):701-13. PMC: 2722217. DOI: 10.1093/hmg/ddn400. View

17.

Gregorio C, Weber A, Bondad M, Pennise C, Fowler V . Requirement of pointed-end capping by tropomodulin to maintain actin filament length in embryonic chick cardiac myocytes. Nature. 1995; 377(6544):83-6. DOI: 10.1038/377083a0. View

18.

Yuen M, Sandaradura S, Dowling J, Kostyukova A, Moroz N, Quinlan K . Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy. J Clin Invest. 2014; 124(11):4693-708. PMC: 4347224. DOI: 10.1172/JCI75199. View

19.

Purevjav E, Varela J, Morgado M, Kearney D, Li H, Taylor M . Nebulette mutations are associated with dilated cardiomyopathy and endocardial fibroelastosis. J Am Coll Cardiol. 2010; 56(18):1493-502. PMC: 2957670. DOI: 10.1016/j.jacc.2010.05.045. View

20.

Gokhin D, Fowler V . Tropomodulin capping of actin filaments in striated muscle development and physiology. J Biomed Biotechnol. 2011; 2011:103069. PMC: 3196151. DOI: 10.1155/2011/103069. View