Abstract 270: Loss of S100A1 Protein Negatively Impacts Glucose Metabolism and Energy Homeostasis in Cardiomyocytes

Abstract

Introduction: As a true metabolic omnivore, the heart is able to utilize different substrates for energy production. In the hypertrophied and early failing state, cardiac muscle leans towards glucose as a major carbon substrate to meet its energetic demand. Given that S100A1 gene therapy reverses the compromised energetic balance of the failing heart, we were interested in determining the specific role of the EF-hand calcium sensor S1001A1 in cardiomyocyte energy metabolism. Methods and results: To study metabolic changes in response to different carbon substrates, we used neonatal rat ventricular cardiomyocytes (NRVMs), which were subjected to electrical stimulation (2Hz) in culture and adenoviral-mediated anti-S100A1 shRNA silencing or scr-shRNA, and either fed with glucose, oleate or lactate only for 24hrs. Of note, lack of S100A1 expression only impaired energy metabolism of cardiomyocytes in response to glucose as reflected by a significantly decreased ATP content and subsequently enhanced AMP/ATP and p-AMPK/AMPK ratios with consecutive elevated p-ACC/ACC and Glut4 protein levels. In contrast, energy metabolism appeared to remain normal in response to oleate in S100A1-deprived cells. Targeted metabolomics yielded a tremendous decrease in glucose-6-phosphate levels as the first key step in glucose metabolism despite enhanced AMPK activation in glucose-fed S100A1-defiecient cardiomyocytes. Conclusion: Our novel in vitro data indicate that S100A1 protein may be crucial for cardiomyocytes to meet their energetic demand when glucose is the major substrate. Since the latter becomes the preferred substrate for functionally compromised heart over fatty acids, lack of S100A1 expression - as a result of fetal gene reprogramming - most likely impairs the ability of the heart to sufficiently utilize glucose to meet its energetic demand. These data shed new mechanistic light on the sustained therapeutic efficacy of S100A1 gene therapy of heart failure where S100A1 may be a key factor enabling the heart to sufficiently use glucose to reverse its compromised energetic state. Further studies answering these pressing questions are underway for an informed design of a best-case patient enrollment scenario for a first-in-men clinical study.