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

Retinoid X receptor alpha-null (RXR alpha-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 RXR alpha in mutant cardiac myocytes could rescue these defects. Two transgenic mouse lines specifically overexpressing an RXR alpha protein in cardiomyocytes were generated, using the cardiac alpha-myosin heavy chain (alpha-MHC) promoter. Breeding the high copy number transgenic line onto an RXR alpha-null genetic background did not prevent the myocardial hypoplasia and fetal lethality associated with the RXR alpha(-/-) genotype, even though the transgene was expressed in the ventricles as early as 10.5 days post-coitum. These data suggest that the RXR alpha function involved in myocardial growth may correspond to a non-cell-autonomous requirement for a signal 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.