Sarcoplasmic reticulum (SR)
calcium (Ca) leak can be reduced by enhancing
FKBP12.6 binding to SR Ca release channels (
RyR2) and expression of a "sticky"
FKBP12.6(D37S) mutant may correct reduced binding stoichiometry in
RyR2 from failing hearts. Both
calcium/calmodulin-dependent protein kinase IIδc (CaMKIIδc) and
protein kinase A (PKA) are activated in
heart failure and promote SR Ca leak at
RyR2. It is possible that
FKBP12.6 dissociation from
RyR2 may promote remodeling and that interventions to reassociate
FKBP12.6 with
RyR2 reflect a future therapeutic strategy. We created transgenic (TG) mice expressing
FKBP12.6(D37S) and tested their capacity to improve intracellular Ca handling and pathological remodeling in vivo.
FKBP12.6(D37S) TG mice were cross-bred with CaMKIIδc TG mice, which are known to exhibit pronounced
RyR2 dysfunction and
heart failure. We observed a significant improvement of post-rest Ca transients and a higher SR Ca content in
FKBP12.6(D37S) TG mice. In double-TG mice, a marked reduction of SR Ca spark frequency indicated reduced SR Ca leak but neither SR Ca transient amplitude, SR Ca content nor morphological or functional parameters improved in vivo. Likewise,
FKBP12.6(D37S) TG mice subjected to increased afterload after aortic banding exhibited higher SR Ca load but did not exhibit any improvement in hypertrophic growth or functional decline. Enhancement of FKBP12.6-RyR2 binding markedly reduced
RyR2 Ca leak in CaMKIIδc-induced
heart failure and in pressure overload. Our data suggest that activation of CaMKIIδc and pressure overload confer significant resistance towards approaches aiming at FKBP12.6-RyR2 reconstitution in
heart failure and maladaptive remodeling, although
RyR2 Ca leak can be reduced.