Abstract Body: The heart’s role as an endocrine organ is beginning to be appreciated but is not well-understood. Most Cardiomyokines (factors secreted from cardiomyocytes) act in an autocrine manner primarily regulating cardiac function and are upregulated in pathological conditions. In our preliminary findings, we subjected C57BL/6 (WT) mice to voluntary wheel cage running for six weeks, causing elevated levels of a novel cardiac secreted protein, OSU-SP3. The role OSU-SP3 plays in regulating systemic metabolism and the mechanism of secretion is unknown. To determine the role of enhanced levels of the novel secreted cardiomyokine we generated cardiac transgenic mice (cTg) using the aMHC promoter to drive increased expression in cardiomyocytes. We observed a significant increase in the protein levels in the heart and in the serum of cTg mice. Mitochondrial function in cTg skeletal muscle was significantly increased compared to WT skeletal muscle in sedentary and exercise-trained conditions, while mitochondrial function in cardiac muscle was not significantly changed. In conclusion, overexpression of our novel cardiomyokine does not alter cardiac function but improves skeletal muscle mitochondrial function. Our results are the first to demonstrate cardiac-to-skeletal muscle communication through a novel cardiomyokine.