Partial deletion of the Akap1 gene promotes abnormalities in gut barrier function, gut microbiota composition and cardiac function during cardiovascular aging in mice

Abstract Background Cardiovascular aging is characterized by mitochondrial dysfunction, changes in intestinal permeability and microbiota composition. Mitochondria-targeted A-kinase anchoring proteins (mitoAKAPs) are a group of structurally diverse proteins binding the regulatory subunits of protein kinase A (PKA), and targeting PKA at discrete intracellular locations. We analyzed the effects of global partial genetic deletion of Akap1 on intestinal barrier permeability, microbiota composition, inflammation, and cardiac function during aging in mice. Purpose The proposal of this study was to determine the role of mitoAKAPs in the gut-heart axis during cardiovascular aging. Methods Young (4-6-month) and old (18-24-month) genetically modified Akap1+/+ and Akap1+/− mice of either sex underwent evaluation of cardiac function by transthoracic echocardiography. To evaluate gut barrier integrity, we analyzed expression levels of intestinal junction proteins occludin (Ocln), zonulin (Tjp1) in colonic samples and FITC-dextran permeability in vivo, circulating levels of Tumor Necrosis Factor-alpha (TNF-alpha), Lipopolysaccharide (LPS), Interleukin-1 (IL-1) and Interleukin-10 (IL-10). Fecal microbial composition was evaluated by Illumina Mi-Seq, Gut microbiota differences based on 16S rDNA sequencing at genus and species taxonomic levels were identified using linear discriminant analysis (LDA) combined with effect size (LEfSe) algorithm. Finally, faecal microbiota transplantation (FMT) was performed for five weeks to test whether modification of gut microbiota composition can affect cardiac function. Results A reduction in % left ventricular shortening (FS%) was observed in young and old Akap1+/- mice compared to Akap1+/+ mice. This finding was associated to increased intestinal permeability, as indicated by reduced mRNA levels of Ocln and Tjp1, increased LPS traslocation across intestinal epitelium into blood in 24m Akap1+/- mice compared to Akap1+/+. Through the analysis of the microbial signature, we observed the different bacterial species present in the microbiota of the experimental groups. FMT of bacteria species from old Akap1+/− to young Akap1+/+ mice induced gut abnormalities and cardiac dysfunction, while FMT from young Akap1+/+ donors ameliorated cardiac dysfunction in old Akap1+/+ mice. Conclusions MitoAKAPs play a crucial role in the maintenance of intestinal barrier function, gut microbiota composition and cardiac function during aging. Modulation of the composition of the intestinal microbiota influences intestinal permeability and cardiac function. MitoAKAPs could represent an important diagnostic and therapeutic target for cardiac and intestinal dysfunction.