Abstract Body (Do not enter title and authors here): Introduction: Physical exercise induces physiological cardiac growth and protects the heart against pathological stresses. However, the molecular mechanisms underlying these cardiac benefits of exercise remain incompletely understood. Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor that plays a critical role in the heart’s response to cellular injury. However, its role in exercise-induced cardiac benefits is largely unknown.

Hypothesis: STAT3 is essential for exercise-induced physiological cardiac growth.

Methods: STAT3 floxed mice were crossed with aMHC-Cre mice to generate cardiomyocyte (CM)-specific STAT3 knockout (KO) mice. Eight-week-old CM-specific STAT3 KO mice and STAT3 floxed mice either underwent eight weeks of voluntary wheel running (Run) or were kept sedentary (Sed). Cardiac RNA-sequencing was performed to identify potential mechanisms by which CM STAT3 regulates the cardiac response to exercise.

Results: No differences were observed in cardiac size and function at baseline between floxed and KO mice. At the end of 8 weeks, floxed and KO mice ran similar daily distances (5.68±0.21 in floxed vs 5.59±0.23 km/day in KO, p=0.65, n=6/group). In floxed mice, running increased the heart weight to tibial length ratio (HW/TL, 6.15±0.18 in Sed vs 7.41±0.52 in Run, p<0.01, n=6/group) and CM size without affecting fractional shortening (FS), consistent with physiological remodeling. In KO mice, running also increased HW/TL (6.57±0.22 in Sed vs 7.82±0.35 in Run, p<0.01, n=6/group) and CM size but reduced FS (39.78±0.31 in Sed vs 25.82±0.42% in Run, p<0.01, n=6/group) and increased LV size (LVIDs: 3.41±0.27 in Sed vs 4.03±0.43 mm in Run, p<0.05, n=6/group) while reducing wall thickness, suggesting a maladaptive cardiac remodeling response to running in KO animals. RNA sequencing analysis revealed that in floxed mice, running upregulated expression of pathways associated with glycogenolysis and beta-oxidation of very long-chain fatty acids. In contrast, hearts from running KO mice had downregulation in gene expression in these pathways.

Conclusions: STAT3 is essential for exercise-induced mitochondrial energy metabolism, CM hypertrophy, and adaptive remodeling. STAT3 deficiency leads to maladaptive cardiac remodeling under physiological stress.