Decorin promotes cardiac organoid maturation by activating AMPK-PGC1A pathway to enhance cardiac metabolism and mitophagy

Abstract

RationaleCardiac organoids (COs) are advanced models for investigating heart development and disease, while require maturation to resemble the structural and functional characteristics of the human heart. ObjectiveThis study reveals the role of Decorin (DCN) contributes to the mature and vascularized COs and assesses the biological mechanism responsible for CO maturation. Methods and ResultsDCN-treated COs exhibit structural maturation involving aligned sarcomere, mitochondria, and t-tubule structures, and vessel formations, as well as functional maturation involving synchronized contraction-relaxation, Ca2+ transient, and increases ion channel expressions. DCN-treated COs also show metabolic maturation, including enhanced fatty acid oxidation and increased mitophagy. Transcriptional profiling results indicate that DCN-treated COs have increased levels of AMPK signaling and mitophagy. In DCN-treated COs, AMPK knockdown affects mitochondrial biogenesis, cardiac metabolism, ion channels, and mitophagy. ConclusionsThese findings indicate that DCN is crucial for development of mature, vascularized COs and that CO maturation is primarily regulated through AMPK signaling, which is triggered by DCN. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=175 SRC="FIGDIR/small/599970v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1333cfaorg.highwire.dtl.DTLVardef@e842baorg.highwire.dtl.DTLVardef@74ce1corg.highwire.dtl.DTLVardef@87ad38_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHIC ABSTRACTC_FLOATNO A graphic abstract is available for this article. DCN enhances metabolic maturation in COs by AMPK-triggered regulation of the glycolysis, fatty acid oxidation, and mitophagy. C_FIG