1Universitätsmedizin Greifswald Klinik und Poliklinik für Innere Medizin B Greifswald, Deutschland; 2Interfakultäres Institut für Genetik und Funktionelle Genomforschung Greifswald, Deutschland
Methods: Luciferase assay were performed to verify if TFEB regulates PPARGC1A expression. To investigate the role of TFEB in metabolic remodeling, cardiomyocyte-specific Tfeb knockout (cKO, TfebloxP/loxP; αMHC-CRE) mice were generated. cKO and wildtype (WT, TfebloxP/loxP) male mice were subjected to 27G transverse aortic constriction or sham surgery for 21 and 56 days, respectively, to induce LVH and HFrEF. Echocardiographic, morphological, and histological analyses were performed. Changes in markers of cardiac stress and remodeling, metabolic shift and oxidative phosphorylation were investigated by Western blot analyses, mass spectrometry and quantitative real-time PCR.
Results: Luciferase assays revealed that TFEB increases PPARGC1A/PGC-1α expression, which was inhibited by class IIa histone deacetylases and derepressed by protein kinase D. At baseline, cKO mice showed a reduced cardiac function, increased stress markers and a decrease in FAO and GO genes compared to WT mice. LVH resulted in increased cardiac remodeling and a decreased expression of FAO and GO genes, but a comparable decline in cardiac function in cKO compared to WT mice. In HFrEF, cKO mice showed an improved cardiac function, lower heart weights, smaller myocytes and a reduction in cardiac remodeling compared to WT mice. Proteomic analysis revealed a metabolic shift from FAO to GO in the hearts of both cKO and WT HFrEF mice.
Conclusions: TFEB has minor effects on the metabolic shift in LVH and HFrEF in mice. Deletion of TFEB plays a protective role in HFrEF but does not affect the course of LVH.