Abstract 3065: Acute Deactivation of Cardiac PGC-1 Signaling in Adult Mice Causes Cardiomyopathy Associated With Derangements in Mitochondrial Structure
Previously, we found that combined germline deletion of the genes encoding the transcriptional coactivators, PGC-1α and PGC-1β, in mice results in an arrest in cardiac perinatal mitochondrial biogenesis and lethal cardiomyopathy soon after birth. We sought to assess the effect of PGC-1α/PGC-1β deficiency in the adult heart, given that the PGC-1 regulatory circuit has been shown to be downregulated in various forms of heart failure. To accomplish this, generalized PGC-1α-deficient x “floxed” PGC-1β mice were bred with mice expressing a mutant estrogen receptor (ER)-Cre recombinase fusion protein specifically in heart (MHC-Mercre mice) allowing for cardiac-specific, tamoxifen-inducible disruption of the PGC-1β gene, on a PGC-1α-deficient background (PGC-1α−/−βcs−/−Mercre mice). Two doses of tamoxifen were sufficient to delete over 80% of the PGC-1β gene specifically in heart. Survival curves for 2 month old PGC-1α−/−βcs−/−Mercre mice revealed that approximately 50% of the animals died within 7 days post-tamoxifen compared to 100% survival in controls (PGC-1α−/−βf/f mice receiving vehicle or MHC-Mercre mice receiving tamoxifen). Echocardiographic studies demonstrated that at 72–96h after the 1st tamoxifen dose, mean left ventricular (LV) fractional shortening (FS) was markedly reduced in PGC-1α−/−βcs−/−Mercre mice (<5% vs 25–30% for controls). Electron microscopy studies conducted with sections taken from the ventricle of PGC-1α−/−βcs−/−Mercre mice at both the 96h and 1 month timepoints revealed evidence of a dramatic reduction in mitochondrial volume density and size along with evidence of mitoautophagy and abnormalities in cristae structure. Consistent with the observed reduction in mitochondrial density, cardiac mitochondrial DNA levels were reduced by 35–40% in PGC-1α−/− βcs−/−Mercre mice compared to PGC-1α−/−βf/f controls, along with reduced expression of known PGC-1 target genes involved in respiratory function (COX4 and ATP synthase β) and mitochondrial fusion (Mfn1 and Mfn2). We conclude that PGC-1α and PGC-1β cooperate to maintain mitochondrial integrity, quality control, and function in the adult heart, indicating that dysregulation of the PGC-1 circuit is a potential contributor to common forms of heart failure.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).