Cardiac differentiation of mouse embryonic stem cells is influenced by a PPAR γ/PGC-1α-FNDC5 pathway during the stage of cardiac precursor cell formation

Peroxisome proliferator-activated receptor (PPAR) gamma co-activator Its (PGC-1 alpha) up-regulation induces FNDC5 expression in muscle and consequently causes browning of white adipose tissue (WAT). In addition to skeletal muscle, FNDC5 is mainly expressed in heart and brain tissues. Here, we demonstrate that FNDC5 expression increased during the process of cardiac differentiation of mouse embryonic stem cells (mESCs) similar to PGC-1 alpha and PPAR alpha. To testify the correlation between PGC-1 alpha and FNDC5 in cardiac cell differentiation of mESCs, we utilized specific PPAR gamma agonist and antagonist in two stages of cardiac differentiation, during and post-cardiac precursor cells (CPCs) formation. Our results indicated that a reduction in PGC-1 alpha expression, via treatment with GW9662 during CPCs formation stage, down-regulated FNDC5 transcript levels as well as mitochondrial markers which negatively influenced on the whole process of cardiac differentiation efficiency. On the other hand, increase PGC-1 alpha expression during CPCs formation stage via rosiglitazone treatment increase FNDC5 and mitochondrial markers transcript levels which enhanced cardiac differentiation efficiency. Importantly, such alteration in PGC-1a expression at post-CPCs formation stage did not affect overall cardiac differentiation rate as expression of FNDC5 and mitochondrial markers were not significantly changed. We concluded that PPAR gamma agonist and antagonist induced up and down-regulation of PGC-1 alpha and subsequently modulated the process of CPCs formation through an alteration in FNDC5 and mitochondrial markers expression. (C) 2015 Elsevier GmbH. All rights reserved.