Compensatory Growth of Healthy Cardiac Cells in the Presence of Diseased Cells Restores Tissue Homeostasis during Heart Development

Energy generation by mitochondrial respiration is an absolute requirement for cardiac function. Here, we used a heart-specific conditional knockout approach to inactivate the X-linked gene encoding Holocytochrome c synthase ( Hccs), an enzyme responsible for activation of respiratory cytochromes c a...

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Bibliographic Details
Published in:Developmental cell 2008-10, Vol.15 (4), p.521-533
Main Authors: Drenckhahn, Jörg-Detlef, Schwarz, Quenten P., Gray, Stephen, Laskowski, Adrienne, Kiriazis, Helen, Ming, Ziqiu, Harvey, Richard P., Du, Xiao-Jun, Thorburn, David R., Cox, Timothy C.
Format: Article
Language:English
Subjects:
Animals
beta-Galactosidase - genetics
Biological and medical sciences
Cell differentiation, maturation, development, hematopoiesis
Cell physiology
CELLCYCLE
DEVBIO
Embryo, Mammalian
Female
Fetal Heart - embryology
Fundamental and applied biological sciences. Psychology
Genes, Reporter
Green Fluorescent Proteins - genetics
Green Fluorescent Proteins - metabolism
Heart - embryology
Heterozygote
Homeostasis
HUMDISEASE
Lyases - genetics
Male
Mice
Mice, Knockout
Models, Cardiovascular
Molecular and cellular biology
Mosaicism - embryology
Myocardium - cytology
Myocardium - pathology
Myocardium - ultrastructure
Myocytes, Cardiac - physiology
Myocytes, Cardiac - ultrastructure
Organogenesis - genetics
Pregnancy
Transgenes
X Chromosome Inactivation
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Summary:Energy generation by mitochondrial respiration is an absolute requirement for cardiac function. Here, we used a heart-specific conditional knockout approach to inactivate the X-linked gene encoding Holocytochrome c synthase ( Hccs), an enzyme responsible for activation of respiratory cytochromes c and c1. Heterozygous knockout female mice were thus mosaic for Hccs function due to random X chromosome inactivation. In contrast to midgestational lethality of  Hccs knockout males, heterozygous females appeared normal after birth. Analyses of heterozygous embryos revealed the expected 50:50 ratio of Hccs deficient to normal cardiac cells at midgestation; however, diseased tissue contributed progressively less over time and by birth represented only 10% of cardiac tissue volume. This change is accounted for by increased proliferation of remaining healthy cardiac cells resulting in a fully functional heart. These data reveal an impressive regenerative capacity of the fetal heart that can compensate for an effective loss of 50% of cardiac tissue.
ISSN:1534-5807
1878-1551
DOI:10.1016/j.devcel.2008.09.005