Mechanisms Underlying Dilated Cardiomyopathy Associated with FKBP12 Deficiency

To define the role of the immunophilin FKBP12 in cardiac function, two conditional models of FKBP12 deficiency were created using Fkbp1a floxed (FL) mice expressing Cre+ recombinase under the control of different promoters (alpha-myosin heavy chain, alpha-MHC, and muscle creatine kinase, MCK) that differ in both developmental stage of expression (E9 versus E 13) and Cre+ expression levels. In adult mice FKBP12 was reduced by 96% and 86% in alpha-MHC-Cre+- and MCK-Cre+-FKBP12 deficient mice, respectively, compared to FL mice. FL mice and mice hemizygous for the alpha-MHC Cre+ recombinase only (to assess potential cytotoxic effects of the Cre+ recombinase) were used as controls. Of these four strains of mice, only the alpha-MHC-Cre+-FKBP12 deficient mice developed an early-onset dilated cardiomyopathy (DCM) and displayed both increased cardiomyocyte sarcoplasmic reticulum Ca2+ leak and large elevations (assessed with RNAseq and western blots) in Ankyrin repeat domain 1 protein (ANKRD1), a negative regulator of cardiac gene expression in response to stress. These data suggest that an FKBP12 deficiency that begins during cardiac development and reduces FKBP12 below a critical level causes RyR2 mediated Ca2+ leak and ANKRD1 elevation, leading to cardiac structural remodeling and the development of DCM. This Ca2+ leak/ANKRD1 pathway may represent a common and targetable mechanism for DCM. To define the role of the immunophilin FKBP12 in cardiac function, two conditional models of FKBP12 deficiency were created using Fkbp1a floxed (FL) mice expressing Cre+ recombinase under the control of different promoters (alpha-myosin heavy chain, alpha-MHC, and muscle creatine kinase, MCK) that differ in both developmental stage of expression (E9 versus E 13) and Cre+ expression levels.