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Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner.
Circ Res. 2004 Mar 05; 94(4):525-33.CircR

Abstract

Recent evidence has identified the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) as a regulator of cardiac energy metabolism and mitochondrial biogenesis. We describe the development of a transgenic system that permits inducible, cardiac-specific overexpression of PGC-1alpha. Expression of the PGC-1alpha transgene in this system (tet-on PGC-1alpha) is cardiac-specific in the presence of doxycycline (dox) and is not leaky in the absence of dox. Overexpression of PGC-1alpha in tet-on PGC-1alpha mice during the neonatal stages leads to a dramatic increase in cardiac mitochondrial number and size coincident with upregulation of gene markers associated with mitochondrial biogenesis. In contrast, overexpression of PGC-1alpha in the hearts of adult mice leads to a modest increase in mitochondrial number, derangements of mitochondrial ultrastructure, and development of cardiomyopathy. The cardiomyopathy in adult tet-on PGC-1alpha mice is characterized by an increase in ventricular mass and chamber dilatation. Surprisingly, removal of dox and cessation of PGC-1alpha overexpression in adult mice results in complete reversal of cardiac dysfunction within 4 weeks. These results indicate that PGC-1alpha drives mitochondrial biogenesis in a developmental stage-dependent manner permissive during the neonatal period. This unique murine model should prove useful for the study of the molecular regulatory programs governing mitochondrial biogenesis and characterization of the relationship between mitochondrial dysfunction and cardiomyopathy and as a general model of inducible, reversible cardiomyopathy.

Authors+Show Affiliations

Department of Medicine, Washington University School of Medicine, St Louis, Mo 63110, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14726475

Citation

Russell, Laurie K., et al. "Cardiac-specific Induction of the Transcriptional Coactivator Peroxisome Proliferator-activated Receptor Gamma Coactivator-1alpha Promotes Mitochondrial Biogenesis and Reversible Cardiomyopathy in a Developmental Stage-dependent Manner." Circulation Research, vol. 94, no. 4, 2004, pp. 525-33.
Russell LK, Mansfield CM, Lehman JJ, et al. Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner. Circ Res. 2004;94(4):525-33.
Russell, L. K., Mansfield, C. M., Lehman, J. J., Kovacs, A., Courtois, M., Saffitz, J. E., Medeiros, D. M., Valencik, M. L., McDonald, J. A., & Kelly, D. P. (2004). Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner. Circulation Research, 94(4), 525-33.
Russell LK, et al. Cardiac-specific Induction of the Transcriptional Coactivator Peroxisome Proliferator-activated Receptor Gamma Coactivator-1alpha Promotes Mitochondrial Biogenesis and Reversible Cardiomyopathy in a Developmental Stage-dependent Manner. Circ Res. 2004 Mar 5;94(4):525-33. PubMed PMID: 14726475.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cardiac-specific induction of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha promotes mitochondrial biogenesis and reversible cardiomyopathy in a developmental stage-dependent manner. AU - Russell,Laurie K, AU - Mansfield,Carolyn M, AU - Lehman,John J, AU - Kovacs,Attila, AU - Courtois,Michael, AU - Saffitz,Jeffrey E, AU - Medeiros,Denis M, AU - Valencik,Maria L, AU - McDonald,John A, AU - Kelly,Daniel P, Y1 - 2004/01/15/ PY - 2004/1/17/pubmed PY - 2004/5/22/medline PY - 2004/1/17/entrez SP - 525 EP - 33 JF - Circulation research JO - Circ. Res. VL - 94 IS - 4 N2 - Recent evidence has identified the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) as a regulator of cardiac energy metabolism and mitochondrial biogenesis. We describe the development of a transgenic system that permits inducible, cardiac-specific overexpression of PGC-1alpha. Expression of the PGC-1alpha transgene in this system (tet-on PGC-1alpha) is cardiac-specific in the presence of doxycycline (dox) and is not leaky in the absence of dox. Overexpression of PGC-1alpha in tet-on PGC-1alpha mice during the neonatal stages leads to a dramatic increase in cardiac mitochondrial number and size coincident with upregulation of gene markers associated with mitochondrial biogenesis. In contrast, overexpression of PGC-1alpha in the hearts of adult mice leads to a modest increase in mitochondrial number, derangements of mitochondrial ultrastructure, and development of cardiomyopathy. The cardiomyopathy in adult tet-on PGC-1alpha mice is characterized by an increase in ventricular mass and chamber dilatation. Surprisingly, removal of dox and cessation of PGC-1alpha overexpression in adult mice results in complete reversal of cardiac dysfunction within 4 weeks. These results indicate that PGC-1alpha drives mitochondrial biogenesis in a developmental stage-dependent manner permissive during the neonatal period. This unique murine model should prove useful for the study of the molecular regulatory programs governing mitochondrial biogenesis and characterization of the relationship between mitochondrial dysfunction and cardiomyopathy and as a general model of inducible, reversible cardiomyopathy. SN - 1524-4571 UR - https://www.unboundmedicine.com/medline/citation/14726475/Cardiac_specific_induction_of_the_transcriptional_coactivator_peroxisome_proliferator_activated_receptor_gamma_coactivator_1alpha_promotes_mitochondrial_biogenesis_and_reversible_cardiomyopathy_in_a_developmental_stage_dependent_manner_ L2 - http://www.ahajournals.org/doi/full/10.1161/01.RES.0000117088.36577.EB?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -