Reciprocal regulation of microRNA-1 and insulin-like growth factor-1 signal transduction cascade in cardiac and skeletal muscle in physiological and pathological conditions.
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.


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.
Elia
Leonardo
L
Department of Medicine, University of California-San Diego, La Jolla, CA, USA.
Contu
Riccardo
R
Quintavalle
Manuela
M
Varrone
Francesca
F
Chimenti
Cristina
C
Russo
Matteo Antonio
MA
Cimino
Vincenzo
V
De Marinis
Laura
L
Frustaci
Andrea
A
Catalucci
Daniele
D
Condorelli
Gianluigi
G
D000328:Adult; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D008875:Middle Aged; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology* / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000473:pathology* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; D007334:Insulin-Like Growth Factor I