Sex Dimorphic Myofilament Function and AMPK Expression in R403Q Hearts

Abstract

Male mice expressing an autosomal dominant mutation in alpha-myosin heavy chain (R403Q) develop hypertrophic cardiomyopathy characterized by progressive left-ventricular dilation and cardiac dysfunction whereas females do not. We wished to determine whether these sex dimorphisms were due to underlying differences in myofilament contractile function. Therefore, we determined the sensitivity of the myofilaments to Ca2+ in demembranated cardiac trabeculae (CT) from wild-type (WT) and R403Q male and female mice (10-12 months of age). We demonstrate that the R403Q mutation did not affect Ca2+-sensitive tension development in CT from males. While Ca2+-sensitivity was greater in both male WT and R403Q CT compared to WT females, they were less sensitive to Ca2+ than CT from female R403Q hearts. We also determined rates of tension redevelopment (ktr) following a release-restretch protocol in CT from WT and R403Q male and female hearts at the same age. CT from R403Q male hearts exhibited an enhanced ktr compared to WT males. The ktr in WT female CT was similar to WT males. The ktr in R403Q female CT measured between WT and R403Q males. We hypothesized that the sex dimorphisms in myofialment function reflect an increase in the energetic cost of contraction when expressing the R403Q mutation. Therefore, we measured levels of Adenosine monophosphate-activated kinase (AMPK), a central sensor of the cellular energy state. Total AMPK protein levels were significantly increased in 10-12 month male R403Q hearts compared to WT controls. Female R403Q hearts showed the opposite: total AMPKα expression was lower compared to WT controls. We conclude that (1) the increased Ca2+-sensitivity may provide sufficient contractile support in female R403Q hearts maintaining a compensated state, and (2) the increased AMPK expression in male R403Q hearts is indicative of an increased energetic demand caused by the mutation.