MicroRNAs (miRNAs) are a class of small noncoding RNAs that have gained status as important regulators of gene expression. Here, we investigated the function and molecular mechanisms of the miR-208 family of miRNAs in adult mouse heart physiology. We found that miR-208a, which is encoded within an intron of α-cardiac muscle myosin heavy chain gene (Myh6), was actually a member of a miRNA family that also included miR-208b, which was determined to be encoded within an intron of β-cardiac muscle myosin heavy chain gene (Myh7). These miRNAs were differentially expressed in the mouse heart, paralleling the expression of their host genes. Transgenic overexpression of miR-208a in the heart was sufficient to induce hypertrophic growth in mice, which resulted in pronounced repression of the miR-208 regulatory targets thyroid hormone-associated protein 1 and myostatin, 2 negative regulators of muscle growth and hypertrophy. Studies of the miR-208a Tg mice indicated that miR-208a expression was sufficient to induce arrhythmias. Furthermore, analysis of mice lacking miR-208a indicated that miR-208a was required for proper cardiac conduction and expression of the cardiac transcription factors homeodomain-only protein and GATA4 and the gap junction protein connexin 40. Together, our studies uncover what we believe are novel miRNA-dependent mechanisms that modulate cardiac hypertrophy and electrical conduction.
Cardiovascular disease is the leading cause of human morbidity and mortality. Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy associated with heart failure. Here, we report that cardiac-specific knockout of Dicer, a gene encoding a RNase III endonuclease essential for microRNA (miRNA) processing, leads to rapidly progressive DCM, heart failure, and postnatal lethality. Dicer mutant mice show misexpression of cardiac contractile proteins and profound sarcomere disarray. Functional analyses indicate significantly reduced heart rates and decreased fractional shortening of Dicer mutant hearts. Consistent with the role of Dicer in animal hearts, Dicer expression was decreased in end-stage human DCM and failing hearts and, most importantly, a significant increase of Dicer expression was observed in those hearts after left ventricle assist devices were inserted to improve cardiac function. Together, our studies demonstrate essential roles for Dicer in cardiac contraction and indicate that miRNAs play critical roles in normal cardiac function and under pathological conditions. cardiac function ͉ microRNA T he heart is the first organ to form and to function during vertebrate embryogenesis (1). Perturbations in normal cardiac development and function result in a variety of cardiovascular diseases, the overall leading cause of death in developed countries (2, 3). Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy, in which the heart becomes weakened and affects the ability of the cardiovascular system to meet the metabolic demands of the body. DCM, characterized by cardiac chamber dilation and systolic impairment, has been associated with mutation of specific contractile proteins and components of stress sensor machinery (2, 4). However, the regulatory events required for appropriate coordination of contractile function are still elusive.MicroRNAs (miRNAs) are a class of recently discovered Ϸ22-nt regulatory RNAs that posttranscriptionally regulate gene expression (5). Despite the large number of miRNAs identified thus far, the biological roles of most miRNAs and the molecular mechanisms underlying their function remain largely unknown. Emerging evidence suggests that miRNAs play important roles in a variety of biological processes, including cancer and stem cell biology (6, 7). Recent studies uncovered the involvement of several musclespecific miRNAs, miR-1, -133, and -208 in particular, in the regulation of cardiac and skeletal muscle gene expression and muscle proliferation and differentiation (8-11). Specifically, gene targeting studies demonstrate that miR-1 and -208 are required for proper cardiac development and/or function (9,10).In this study, we took a global approach to study cardiac miRNAs by deleting Dicer, an endonuclease required for the processing of all miRNAs, in the heart. Here we report that loss of Dicer results in a dramatic decrease in the level of mature miRNAs. All Dicer mutant mice die postnatally due to severe DCM and heart failure.Furthermore, we have ...
Pax7 is a target of two miRNAs that are induced during muscle satellite cell differentiation and repressed in response to muscle injury.
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