Dystrophin and calcium current are decreased in cardiomyocytes expressing Cre enzyme driven by αMHC but not TNT promoter.

The Cre/lox system is a potent technology to control gene expression in mouse tissues. However, cardiac-specific Cre recombinase expression alone can lead to cardiac alterations when no loxP sites are present, which is not well understood. Many loxP-like sites have been identified in the mouse genome that might be Cre sensitive. One of them is located in the Dmd gene encoding dystrophin, a protein important for the function and stabilization of voltage-gated calcium (Ca_v1.2) and sodium (Na_v1.5) channels, respectively. Here, we investigate whether Cre affects dystrophin expression and function in hearts without loxP sites in the genome. In mice expressing Cre under the alpha-myosin heavy chain (MHC-Cre) or Troponin T (TNT-Cre) promoter, we investigated dystrophin expression, Na_v1.5 expression, and Ca_v1.2 function. Compared to age-matched MHC-Cre^- mice, dystrophin protein level was significantly decreased in hearts from MHC-Cre⁺ mice of more than 12-weeks-old. Quantitative RT-PCR revealed decreased mRNA levels of Dmd gene. Unexpectedly, calcium current (I_CaL), but not Na_v1.5 protein expression was altered in those mice. Surprisingly, in hearts from 12-week-old and older TNT-Cre⁺ mice, neither I_CaL nor dystrophin and Na_v1.5 protein content were altered compared to TNT-Cre^-. Cre recombinase unpredictably affects cardiac phenotype, and Cre-expressing mouse models should be carefully investigated before experimental use.

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