View Program - 63rd Annual Drosophila Research Conference

Heart disease (HD) is a leading cause of mortality for both men and women, currently accounting for approximately 1 of every 4 deaths in the US. Obesity and diabetes greatly increase the risk of HD, although the underlying genetic and metabolic mechanisms remain unclear. CRTC, a CREB (cAMP-responsive element binding protein) - Regulated Transcription Co-activator, has been identified as a “nutrient sensor” and a key regulator of metabolism in mammals and is conserved in Drosophila. In the liver, CRTC mediates signaling from glucagon and insulin, however, a cardiac-specific role for CRTC has yet to be identified. Using our Drosophila heart model, we found that CRTC null mutants (CRTC^-/-)exhibit severe cardiac restriction with reduced stroke volume and tachycardia, accompanied by cardiac fibrosis, a hallmark of heart disease. Cardiac-specific knockdown (KD) of CRTC, or its coactivator CREB, mimics the heart defects of CRTC^-/-. In the liver, CRTC is activated by calcineurin (CN), and in vertebrate hearts CN is known to cause cardiac hypertrophy via activation of NFAT. In the fly, overexpression of CRTC or activated CN, also known as Pp2B, also cause hypertrophy. However, in the fly cardiac KD of NFAT has no effect on function and CRTC knockout (KO) blocks all hypertrophic effect of cardiac- specific overexpression (OE) of Pp2B suggesting that, in the heart, CRTC mediates the downstream effects of CN. We also show that CRTC3 is highly expressed in zebrafish hearts and KD causes cardiac restriction, as in flies. In both fly and fish, CRTC localizes in the Z-bands as well as in myocardial cell nuclei. CRTC 1, 2 & 3 are also expressed in human iPSC-derived cardiomyocytes (hiPSC-CM) and KD of both CRTC 2&3 caused broadened action potentials, further supporting a fundamental role of CRTC in heart function. Comparative analysis of cardiac gene expression revealed that pathways involved in glucose, fatty acid, and amino acid metabolism were contra-regulated between cardiac CRTC KD and OE flies, suggesting that CRTC acts as a metabolic switch in the heart in regulation of lipid, carbohydrate, and protein metabolism. In summary, we have identified CRTC gene and its orthologues as a novel signaling pathway that maintains heart function with likely relevance linking nutrient sensing to heart disease.

A novel role for CRTC linking age-related cardiac dysfunction and fibrosis to metabolic syndrome