RXRα overexpression in cardiomyocytes causes dilated cardiomyopathy but fails to rescue myocardial hypoplasia in RXRα-null fetuses
Vemparala Subbarayan, … , Pierre Chambon, Philippe Kastner
Vemparala Subbarayan, … , Pierre Chambon, Philippe Kastner
Published February 1, 2000
Citation Information: J Clin Invest. 2000;105(3):387-394. https://doi.org/10.1172/JCI8150.
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Article

RXRα overexpression in cardiomyocytes causes dilated cardiomyopathy but fails to rescue myocardial hypoplasia in RXRα-null fetuses

Abstract

Retinoid X receptor α–null (RXRα-null) mutants exhibit hypoplasia of their ventricular myocardium and die at the fetal stage. In the present study, we wished to determine whether transgenic re-expression of RXRα in mutant cardiac myocytes could rescue these defects. Two transgenic mouse lines specifically overexpressing an RXRα protein in cardiomyocytes were generated, using the cardiac α-myosin heavy chain (α-MHC) promoter. Breeding the high copy number transgenic line onto an RXRα-null genetic background did not prevent the myocardial hypoplasia and fetal lethality associated with the RXRα–/– genotype, even though the transgene was expressed in the ventricles as early as 10.5 days post-coitum. These data suggest that the RXRα function involved in myocardial growth may correspond to a non–cell-autonomous requirement forsignal orchestrating the growth and differentiation of myocytes. Interestingly, the adult transgenic mice developed a dilated cardiomyopathy, associated with myofibrillar abnormalities and specific deficiencies in respiratory chain complexes I and II, thus providing an additional model for this genetically complex disease.

Authors

Vemparala Subbarayan, Manuel Mark, Nadia Messadeq, Pierre Rustin, Pierre Chambon, Philippe Kastner

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Figure 5

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Abnormal myocytes in dilated hearts. (a and c) Semithin sections through...
Abnormal myocytes in dilated hearts. (a and c) Semithin sections through the ventricles of a WT and a dilated transgenic heart (2-month-old mice). Note the degenerating cardiomyocytes (asterisks) in the transgenic heart. (b, d–f) Electron microscopy of longitudinally sectioned cardiac muscle cells from ventricles of a WT (b) and dilated (d–f) transgenic heart. In d, note the swelling of the transgenic cardiomyocytes, manifested by the absence of compaction of the myofibrils (MF) and the loss of myofibrils resulting in a relative increase of intervening sarcoplasm (S) and a more dispersed arrangement of mitochondria (MT). e and f illustrate 2 different aspects of cardiomyocytes undergoing necrolysis (asterisks), as well as the abnormal, duplicated aspect of some Z lines (large arrows). C, capillaries; M, myofibers; N, nuclei; MT, mitochondria; MF, myofibrils; S, sarcoplasm. ×340 (a and c); ×4,200 (b and d); ×10,000 (e and f).