Leiomodin 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. To 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 Lmod2 PB/PB mice exhibit typical dilated cardiomyopathy (DCM) with ventricular arrhythmias and postnatal lethality. Electron microscope reveals that the Lmod2 PB/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 Lmod2 PB/PB hearts. Consistent with the phenotype, the expression of the ICD component genes, β-catenin and Connexin43, are down-regulated. Taken 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 Lmod2 PB/PB mutant offers a valuable resource for interrogation of pathogenesis and development of therapeutics for DCM.

Transcriptome-wide analysis is powerful in studying systemic RNA changes following environmental exposures. However, impacts of ozone inhalation on circulating transcriptome have not yet been examined. To explore the impact of acute ozone exposure on circulating transcriptome using RNA sequencing (RNA-seq). We recruited 32 healthy young adults in a randomized, crossover, controlled exposure trial. Each participant completed two 2-h exposure sessions of ozone (200 ppb) and clean air, respectively. Blood samples were collected at the end of each session and were used for RNA-seq. The differentially expressed genes associated with ozone exposure were assessed using Bayesian adjusted statistics from linear models in the limma R package. A total of 29 participants finished this trial and donated their blood samples for transcriptome analysis. The average concentration of ozone was 7.8 ± 2.6 ppb under clean air and 201.1 ± 1.7 ppb under ozone exposure session. A total of 1899 genes were significantly changed (1067 up-regulated and 832 down-regulated) by ozone exposure at a false discovery rate < 0.05, in which 403 genes had a fold change of > 1.2 or < 0.8. The top 10 terms of biological processes showed that most of the differentially expressed genes were related to various functions, such as neutrophil degranulation, immune response, and neutrophil activation. Pathway enrichment analysis showed dozens of pathways were dysregulated after ozone exposure, including mitochondrial dysfunction, and glucocorticoid receptor signaling. For the first time this trial characterized the genome-wide changes of mRNA in response to ozone exposure. We identified a range of differentially expressed genes that were involved in dozens of biological processes and pathways, providing novel biological insights into the systemic health effects of ozone.