RXR alpha overexpression in cardiomyocytes causes dilated cardiomyopathy but fails to rescue myocardial hypoplasia in RXR alpha-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 mous e lines specifically overexpressing an RXR alpha protein in cardiomyocytes were generated, using the cardiac alpha-myosin heavy chain (alpha-MHC) prom oter. Breeding the high copy number transgenic line onto an RXR alpha-null genetic background did not prevent the myocardial hypoplasia and fetal leth ality associated with the RXR alpha(-/-) genotype, even though the transgen e 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 transg enic mice developed a dilated cardiomyopathy, associated with myofibrillar abnormalities and specific deficiencies in respiratory chain complexes I an d II, thus providing an additional model for this genetically complex disea se.