ORF04-05 - Heart-to-Skeletal Muscle Communication through the Novel Cardiomyokine

The heart’s role as an endocrine organ is increasingly recognized but remains poorly characterized. Most known cardiomyokines (factors secreted by cardiomyocytes) act in an autocrine manner to primarily regulate cardiac function in pathological conditions. In our preliminary studies, six weeks of voluntary wheel running in C57BL/6 (WT) mice selectively increased cardiac expression of a novel secreted protein OSU-SP3. We also detected increased circulating protein levels of OSU-SP3 by mass spectrometry. The role OSU-SP3 plays in regulating systemic metabolism and the mechanism of secretion is unknown. To investigate its function in vivo, we generated cardiac-specific transgenic (cTg) mice using the αMHC promoter to drive OSU-SP3 overexpression in cardiomyocytes. cTg mice exhibited elevated cardiac and circulating OSU-SP3 levels, reduced body weight and adiposity, did not affect cardiac function or food intake, but demonstrated enhanced exercise endurance compared to WT littermates. Mitochondrial function in cTg skeletal muscle was significantly increased compared to WT skeletal muscle from sedentary and exercise-trained mice, while mitochondrial function in cardiac muscle was not significantly changed. When challenged with a high-fat diet (HFD), cTg mice maintained a lower body weight and fat mass without reduced food intake. Additionally, WT mice on HFD displayed decreased cardiac OSU-SP3 expression compared to chow-fed WT controls. Collectively, these findings demonstrate that cardiac OSU-SP3 enhances skeletal muscle mitochondrial function and improves systemic metabolic health without affecting cardiac performance. Our results are the first to demonstrate cardiac-to-skeletal muscle communication through a novel cardiomyokine that improves whole-body energy metabolism.