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Developmental Restructuring of the Creatine Kinase System Integrates Mitochondrial Energetics with Stem Cell Cardiogenesis
Author(s) -
Chung Susan,
Dzeja Petras P.,
Faustino Randolph S.,
Terzic Andre
Publication year - 2008
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1427.004
Subject(s) - embryonic stem cell , sarcolemma , microbiology and biotechnology , stem cell , embryoid body , biology , mitochondrion , induced pluripotent stem cell , creatine kinase , myofibril , myocyte , cellular differentiation , biochemistry , gene
Differentiation of pluripotent low‐energy requiring stem cells into the high‐energy expenditure cardiac lineage requires coordination of genomic programming and energetic system maturation. Here, in a murine embryonic stem cell cardiac differentiation model, emergence of electrical and beating activity in cardiomyocytes developing within embryoid bodies was coupled with the establishment of the mitochondrial network and expansion of the creatine kinase (CK) phosphotransfer system. Stem cell cardiogenesis was characterized by increased total CK activity, an isoform shift manifested by amplified muscle CK‐M mRNA levels and protein content, and the appearance of cardiac‐specific CK‐MB dimers. Treatment of differentiating stem cells with BMP2, a cardiogenic growth factor, promoted CK activity. CK‐M clustered around developing myofibrils, sarcolemma, and the perinuclear compartment, whereas CK‐B was tightly associated with myofibrillar α‐actinin, forming wire‐like structures extending from the nuclear compartment to the sarcolemma. Developmentally enhanced phosphotransfer enzyme‐anchoring protein FHL2 coalesced the myofibrillar CK metabolic signaling circuit, providing an energetic continuum between mitochondria and the nascent contractile machinery. Thus, the evolving CK‐catalyzed phosphotransfer network integrates mitochondrial energetics with cardiogenic programming, securing the emergence of energy‐consuming cardiac functions in differentiating embryonic stem cells.

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