Ablation of the Cardiac-Specific Gene Leucine-Rich Repeat Containing 10 (Lrrc10) Results in Dilated Cardiomyopathy

Abstract

Leucine-rich repeat containing 10 (LRRC10) is a cardiac-specific protein exclusively expressed in embryonic and adult cardiomyocytes. However, the role of LRRC10 in mammalian cardiac physiology remains unknown. To determine if LRRC10 is critical for cardiac function, Lrrc10-null (Lrrc10−/−) mice were analyzed. Lrrc10− /− mice exhibit prenatal systolic dysfunction and dilated cardiomyopathy in postnatal life. Importantly, Lrrc10−/− mice have diminished cardiac performance in utero, prior to ventricular dilation observed in young adults. We demonstrate that LRRC10 endogenously interacts with α-actinin and α-actin in the heart and all actin isoforms in vitro. Gene expression profiling of embryonic Lrrc10−/− hearts identified pathways and transcripts involved in regulation of the actin cytoskeleton to be significantly upregulated, implicating dysregulation of the actin cytoskeleton as an early defective molecular signal in the absence of LRRC10. In contrast, microarray analyses of adult Lrrc10−/− hearts identified upregulation of oxidative phosphorylation and cardiac muscle contraction pathways during the progression of dilated cardiomyopathy. Analyses of hypertrophic signal transduction pathways indicate increased active forms of Akt and PKCε in adult Lrrc10−/− hearts. Taken together, our data demonstrate that LRRC10 is essential for proper mammalian cardiac function. We identify Lrrc10 as a novel dilated cardiomyopathy candidate gene and the Lrrc10−/− mouse model as a unique system to investigate pediatric cardiomyopathy.

LRRC10 is required to maintain cardiac function in response to pressure overload

“…Ϫ/Ϫ mice and littermate or age-matched WT control mice maintained on the same C57BL/6 genetic background (8,39). Mice were euthanized by cervical dislocation to harvest tissue for biochemical and histological analyses.…”

“…Transthoracic echocardiography was performed on mice under 1% isofluorane gas anesthesia using a Visual Sonics 770 ultrasonograph with a 30-MHz transducer (RMV 707B, Visual Sonics, Toronto, ON, Canada) as previously (8,22). Two-dimensional guided M-mode images of the left ventricle (LV) were acquired at the tips of the papillary muscles.…”

“…) mice exhibit perinatal defects in cardiac function and moderate dilated cardiomyopathy in adulthood (8). We have also recently reported that the cardiomyocyte-specific expression of Lrrc10 is regulated by Nkx2.5, GATA4, and serum response factor (7).…”

“…Lrrc10 is expressed exclusively in cardiomyocytes and is dramatically upregulated after birth, with robust expression maintained in the adult heart (7,28), implying important roles in the postnatal heart. LRRC10 interacts with actin and ␣-actinin in the heart (8) and localizes at the dyad region where the Z-disc comes into close juxtaposition to the T-tubule and sarcoplasmic reticulum (8,28). This places LRRC10 at a mechanosensitive signaling hub in cardiomyocytes (19).…”

“…In contrast, eccentric cardiac hypertrophy is caused by serial addition of sarcomeres, resulting in a disproportionate increase in the length relative to the width of cardiomyocytes that causes ventricular dilation (26,52). Eccentric cardiac hypertrophy occurs in conditions of volume overload, such as valvular regurgitation or after myocardial infarction, and in inherited cardiomyopathies associated with a wide range of genes, including many cytoskeletal and Z-disc genes (8,11,19,26,29,37,50,56). Therefore, the heart hypertrophies in response to a variety of pathological stimuli; however, the nature and resulting geometry of cardiac remodeling are stimulus dependent.…”