MicroRNAs are noncoding RNAs of approximately 22-24 nucleotides which are capable of interacting with the 3' untranslated region of coding RNAs (mRNAs), leading to mRNA degradation and/or protein translation blockage. In recent years, differential microRNA expression in distinct cardiac development and disease contexts has been widely reported, yet the role of individual microRNAs in these settings remains largely unknown. We provide herein evidence of the role of miR-27 and miR-125 regulating distinct muscle-enriched transcription factors. Overexpression of miR-27 leads to impair expression of Mstn and Myocd in HL1 atrial cardiomyocytes but not in Sol8 skeletal muscle myoblasts, while overexpression of miR-125 resulted in selective upregulation of Mef2d in HL1 atrial cardiomyocytes and downregulation in Sol8 cells. Taken together our data demonstrate that a single microRNA, that is, miR-27 or miR-125, can selectively upregulate and downregulate discrete number of target mRNAs in a cell-type specific manner.