The transcriptome of mouse

Cumulative research demonstrated that heart muscles in the dilated cardiomyopathy (DCM) patients are marked by down-regulated expression of a-myosin heavy chain (a-MHC) coding by MYH6 while it remains unknown whether this reduction contributes to DCM. In our work, we proved that the expression level of a-MHC was decreased in the heart of DCM patients compared to that of non-failure donors. We established two Myh6 down-expressed Syrian Hamster models: one with a-MHC deficiency across all systems, the other with a-MHC knockdown specifically in the heart by using adeno-associatedvirus (AAV). Besides the animal models, we also programmed MYH6 knockout human-induced pluripotent stem cells (hiPSCs) which differentiated later into cardiomyocytes (hiPS-CMs) in vitro. We found a-MHC deficiency in vivo or in vitro both resulted in DCM phenotypes, meanwhile we demonstrated a-MHC deficiency is a causative factor of DCM. We also proved that the DCM-associated a-MHC deficiency was mediated by the autophagy flux. At the same time, the DCM phenotypes were attenuated by rapamycin, an autophagy activator, and exacerbated by inhibiting autophagic activities. Transcriptomic and proteomics results revealed that cardiomyocytes with a-MHC deficiency apparently exhibited actin cytoskeleton dysfunction. Our data demonstrated that a-MHC deficiency influenced the actin cytoskeleton network to regulate the autophagy activity suggesting that overexpress a-MHC or regulating autophagy would be a promising therapeutic candidate for DCM. Overall design: WT male mice at 12W were sacrificed,and the hearts were performed for RNAseq analysis.