Downregulation of Scd1 promotes cardiac reprogramming by enhancing mitochondrial metabolism through PGC1a

Direct cardiac reprogramming of fibroblasts into induced cardiac-like myocytes (iCMs) has emerged as a promising therapeutic strategy to remuscularize injured myocardium. However, the intrinsic metabolic demands that drive the iCM program and maturity remain unclear. Here, we induce efficient iCM production and maturation through metabolic pathway modulations. We show that the knockdown of Stearoyl-CoA desaturase 1 (Scd1) facilitates cardiac reprogramming and functional maturation of iCM. Through Bulk-RNAseq analysis, we found that compared with control group, fibrosis and inflammatory response pathway were significantly down-regulated, while cardiac related features and fatty acid metabolism related genes were up-regulated in shscd1 group. We further observed the expression level of PGC1a which serves as a master regulator of mitochondrial biogenesis and function was significantly increased in shScd1 group from RNA-seq. Mechanistically, we proved that Scd1 knockdown activates PGC1a/PPARß transcription signal, which further promotes cardiac reprogramming, and induced cardiomyocytes demonstrated more frequent beating, calcium oscillation, and higher energy metabolism as evidenced by increased mitochondrial respiration and gene expression associated with FAO, which provides a new strategy and theoretical basis for cardiac regeneration and repair Overall design: To determine the molecular basis by which knockdown Scd1 enhances iCM reprogramming, we conducted RNA-seq using shScd1-iCMs and shNT-iCMs collected at reprogramming day 7.