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Reciprocal Regulation of MicroRNA-1 and Insulin-Like Growth Factor-1 Signal Transduction Cascade in Cardiac and Skeletal Muscle in Physiological and Pathological Conditions

2009; Lippincott Williams & Wilkins; Volume: 120; Issue: 23 Linguagem: Inglês

10.1161/circulationaha.109.879429

1524-4539

Leonardo Elia, Riccardo Contu, Manuela Quintavalle, Francesca Varrone, Cristina Chimenti, Matteo Antonio Russo, Vincenzo Cimino, Laura De Marinis, Andrea Frustaci, Daniele Catalucci, Gianluigi Condorelli,

FOXO transcription factor regulation

Background— MicroRNAs (miRNAs/miRs) are small conserved RNA molecules of 22 nucleotides that negatively modulate gene expression primarily through base paring to the 3′ untranslated region of target messenger RNAs. The muscle-specific miR-1 has been implicated in cardiac hypertrophy, heart development, cardiac stem cell differentiation, and arrhythmias through targeting of regulatory proteins. In this study, we investigated the molecular mechanisms through which miR-1 intervenes in regulation of muscle cell growth and differentiation. Methods and Results— On the basis of bioinformatics tools, biochemical assays, and in vivo models, we demonstrate that (1) insulin-like growth factor-1 (IGF-1) and IGF-1 receptor are targets of miR-1; (2) miR-1 and IGF-1 protein levels are correlated inversely in models of cardiac hypertrophy and failure as well as in the C2C12 skeletal muscle cell model of differentiation; (3) the activation state of the IGF-1 signal transduction cascade reciprocally regulates miR-1 expression through the Foxo3a transcription factor; and (4) miR-1 expression correlates inversely with cardiac mass and thickness in myocardial biopsies of acromegalic patients, in which IGF-1 is overproduced after aberrant synthesis of growth hormone. Conclusions— Our results reveal a critical role of miR-1 in mediating the effects of the IGF-1 pathway and demonstrate a feedback loop between miR-1 expression and the IGF-1 signal transduction cascade.