Peroxisome Proliferator-Activated Receptor-Gamma Coactivator 1 Alpha 1 Induces A Cardiac Excitation-Contraction Coupling Phenotype Without Metabolic Remodelling

The transcriptional coactivator PGC-1 alpha 1 has been identified as a central factor mediating metabolic adaptations of the heart. However, to what extent physiological changes in PGC-1 alpha 1 expression levels actually contribute to the functional adaptation of the heart is still mostly unresolved. The aim of this study was to characterize the transcriptional and functional effects of physiologically relevant, moderate PGC-1 alpha 1 expression in the heart. In vivo and ex vivo physiological analysis shows that expression of PGC-1 alpha 1 within a physiological range in mouse heart does not induce the expected metabolic alterations, but instead induces a unique excitation-contraction (EC) coupling phenotype recapitulating features typically seen in physiological hypertrophy. Transcriptional screening of PGC-1 alpha 1 overexpressing mouse heart andmyocyte cultures with higher, acute adenovirus-induced PGC-1 alpha 1 expression, highlights PGC-1 alpha 1 as a transcriptional coactivator with a number of binding partners in various pathways (such as heat shock factors and the circadian clock) through which it acts as a pleiotropic transcriptional regulator in the heart, to both augment and repress the expression of its target genes in a dose-dependent fashion. At low levels of overexpression PGC-1 alpha 1 elicits a diverse transcriptional response altering the expression state of circadian clock, heat shock, excitability, calcium signalling and contraction pathways, while metabolic targets of PGC-1 alpha 1 are recruited at higher PGC-1 alpha 1 expression levels. Together these findings demonstrate that PGC-1 alpha 1 elicits a dual effect on cardiac transcription and phenotype. Further, our results imply that the physiological role of PGC-1 alpha 1 is to promote a beneficial EC coupling phenotype in the heart.