Lmod2 piggyBac mutant mice exhibit dilated cardiomyopathy.

Shuang Li,Zhen Zhang,Chen Chu,Tong-Ruei Li,Hong Tian,Ling V Sun,Tian Xu,Fang Liu,Sheng Ding,Shuna Sun,Kaiqi Mo,Lei Tian,Xiaohui Wu

doi:10.1186/s13578-016-0101-y

Abstract

BackgroundLeiomodin proteins, Lmod1, Lmod2 and Lmod3, are key regulators of the thin filament length in muscles. While Lmod1 is specifically expressed in smooth muscles, both Lmod2 and Lmod3 are expressed in striated muscles including both cardiac and skeletal muscles. We and others have previously shown that Lmod3 mainly function in skeletal muscles and the mutant mice display disorganized sarcomere. Lmod2 protein has been found to act as an actin filament nucleator in both cell-free assays and in cultured rat and chicken cardiomyocytes.ResultsTo better understand the function of Lmod2 in vivo, we have identified and characterized a piggyBac (PB) insertional mouse mutant. Our analysis revealed that the PB transposon inserts in the first exon of the Lmod2 gene and severely disrupts its expression. We found that Lmod2PB/PB mice exhibit typical dilated cardiomyopathy (DCM) with ventricular arrhythmias and postnatal lethality. Electron microscope reveals that the Lmod2PB/PB hearts carry disordered sarcomere, disarrayed thin filaments, and distorted intercalated discs (ICDs). Those ICDs display not only decreased convolutions, but also reduced electron-dense staining, indicating less ICDs component proteins in Lmod2PB/PB hearts. Consistent with the phenotype, the expression of the ICD component genes, β-catenin and Connexin43, are down-regulated.ConclusionsTaken together, our data reveal that Lmod2 is required in heart thin filaments for integrity of sarcomere and ICD and deficient mice exhibit DCM with ventricular arrhythmias and postnatal lethality. The Lmod2PB/PB mutant offers a valuable resource for interrogation of pathogenesis and development of therapeutics for DCM.

Highlights

Leiomodin proteins, Lmod1, Lmod2 and Lmod3, are key regulators of the thin filament length in muscles
While Lmod1 is expressed in smooth muscles, both Lmod2 and Lmod3 are expressed in striated muscles including both cardiac and skeletal muscles [4,5,6]
We analyzed the transcriptional level of Tmod1 by quantitative PCR and found that the mRNA level of Tmod1 remains the same in 25 days old Lmod2PB/PB hearts compared to controls (Fig. 2a)

Summary

Introduction

Lmod, Lmod and Lmod, are key regulators of the thin filament length in muscles. We and others have previously shown that Lmod mainly func‐ tion in skeletal muscles and the mutant mice display disorganized sarcomere. The Leiomodin proteins, Lmod, Lmod and Lmod, are a subgroup of the Tropomodulin (Tmod) protein family and are regulators of the thin filament length in muscles [1,2,3]. The mutant mice display disorganized sarcomere and the presence of nemaline bodies in skeletal muscles, a hallmark of the disease nemaline myopathy (NM), consistent with the finding that LMOD3 is mutated in the NM patients [7]. Overexpression of Lmod results in the elongated thin filaments and knockdown exhibited disrupted sarcomere assembly in cultured cardiomyocytes [2, 5]. Knockout mice of Tmod are embryonic lethal due to cardiac defects, and overexpression of Tmod in the heart causes myofibril disorganization

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