developmental enhancement of adenylate kinase-ampk metabolic signaling axis supports stem cell cardiac differentiation腺苷酸的发展增强kinase-ampk代谢信号轴支持干细胞心脏分化.pdfVIP

Developmental Enhancement of Adenylate Kinase-AMPK Metabolic Signaling Axis Supports Stem Cell Cardiac Differentiation Petras P. Dzeja*., Susan Chung., Randolph S. Faustino, Atta Behfar, Andre Terzic* Marriott Heart Disease Research Program, Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, and Medical Genetics, Mayo Clinic, Rochester, Minnesota, United States of America Abstract Background: Energetic and metabolic circuits that orchestrate cell differentiation are largely unknown. Adenylate kinase (AK) and associated AMP-activated protein kinase (AMPK) constitute a major metabolic signaling axis, yet the role of this system in guiding differentiation and lineage specification remains undefined. Methods and Results: Cardiac stem cell differentiation is the earliest event in organogenesis, and a suitable model of developmental bioenergetics. Molecular profiling of embryonic stem cells during cardiogenesis revealed here a distinct expression pattern of adenylate kinase and AMPK genes that encode the AK-AMP-AMPK metabolic surveillance axis. Cardiac differentiation upregulated cytosolic AK1 isoform, doubled AMP-generating adenylate kinase activity, and increased AMP/ ATP ratio. At cell cycle initiation, AK1 translocated into the nucleus and associated with centromeres during energy- consuming metaphase. Concomitantly, the cardiac AMP-signal receptor AMPKa2 was upregulated and redistributed to the nuclear compartment as signaling-competent phosphorylated p-AMPKa(Thr172). The cardiogenic growth factor TGF-b promoted AK1 expression, while knockdown of AK1, AK2 and AK5 activities with siRNA or suppression by hyperglycemia disrupted cardiogenesis compromising mitochondrial and myofibrillar network formation and contractile performance. Induction of cr