UCSF

microRNA-1 (miR-1) is an evolutionarily conserved, striated muscle enriched miRNA. Most mammalian genomes contain two copies of miR-1, both of which are transcribed with another myogenic miRNA, miR-133a. Compound miR-1 knockout mice died uniformly before weaning due to severe cardiac dysfunction. miR-1-null cardiomyocytes had abnormal sarcomere organization and decreased phosphorylation of the regulatory myosin light chain-2 (MLC2), a critical cytoskeletal regulator. The smooth muscle-restricted inhibitor of MLC2 phosphorylation, Telokin, was ectopically expressed in the myocardium, along with other smooth-muscle genes. miR-1 repressed Telokin expression through direct targeting and by repressing its transcriptional regulator, Myocardin. Our results reveal that miR-1 is required for postnatal cardiac function and reinforces the striated muscle phenotype by regulating both transcriptional and effector nodes of the smooth-muscle gene-expression network.

miR-133a also represses the smooth muscle gene program in postnatal hearts and thus cooperates with miR-1 in this context. Interestingly, during cardiac precursor differentiation, these miRNAs have opposing regulatory functions suggesting that the relative expression of these miRNAs may be functionally important. The RNA binding protein, LIN28, regulates miR-1 but not miR-133a post-transcriptionally and may provide a mechanism for their differential accumulation in the heart. However, we find LIN28A loss in vivo is insufficient to alter the expression of either miR-1 or miR-133a in embryonic mouse hearts, suggesting that another mechanism may regulate these miRNAs in this context.

Among its many functions, miR-1 generally inhibits cell proliferation and promotes differentiation. In postnatal mouse hearts, miR-1 expression is inversely correlated with cardiomyocyte proliferative and regenerative potential. We find that reduced miR-1 in vivo is sufficient to inhibit the process of neonatal cardiomyocyte binucleation, a process closely linked with cardiomyocyte maturation and the loss of proliferative potential. However, we find that animals with reduced miR-1 display decreased regenerative potential, an increase in scar size and a greater impairment of cardiac function following myocardial infarction. Our results suggest that normal levels of miR-1 may be required for limiting tissue damage and promoting healing in injured hearts. Collectively, our data reveal that miR-1 is an essential cardiac gene that plays a variety of roles in the mammalian heart.