Background: The JAK- STAT pathway is a major signal transduction pathway mediating the signaling of extra cellular cytokines that regulate crucial cellular processes. Prominent activation of JAK-STAT signaling in heart diseases highlights its essential role in cardiac physiology and pathology. Although JAK1 is the predominant JAK in cardiomyocytes (CMs), its physiological significance remains unclear. The objective of this study is to define the role of CM JAK1 in cardiac homeostasis and function, with the hypothesis that CM JAK1 is indispensable for maintaining normal cardiac function. Methods: CM-restricted Jak1 deletion (Jak1-cko) was achieved by crossbreeding the Jak1flox/flox mice with transgenic mice overexpressing the Cre recombinase driven by the mouse alpha-myosin heavy chain promoter (Myh6-Cre). Jak1-cko was verified in Jak1flox/flox::Myh6-Cre mice at both gene and protein levels. Cardiac morphometry and function were determined by serial echocardiography (Echo). Results: Western blot analyses showed that Jak1-cko mice showed decreases in myocardial JAK1 (0.56±0.15 vs. 1.00±0.13, p=0.0001), and downstream Tyr705-phosphorylated STAT3 (0.51±0.17 vs. 1.00±0.47, p=0.0623) and total STAT3 (0.51±0.15 vs. 1.00±0.18, p=0.0004) proteins, compared to Myh6-Cre control mice. M-mode Echo has revealed that Jak1-cko mice develop dilated cardiomyopathy and this phenotype is evident at 4.5 months in males and at 6 months in females. Male Jak1-cko mice had decreased ejection fraction compared to male Myh6-Cre control (31.12±6.90 % vs. 36.41±6.61 %, p=0.0493), while females showed no significant difference at 6m of age, which is consistent with a sex-difference in changes of left ventricular (LV) chamber dilatation at 6m of age. In males, Jak1-cko significantly increased LV end-systolic diameter (4.51±0.60 mm vs. 3.99±0.53 mm, p=0.0065) and end-diastolic diameter (5.28±0.54 mm vs. 4.83±0.51 mm, p=0.0116) compared to Myh6-Cre control, whereas female Jak1-cko mice only showed sightly increased LV end-diastolic diameter (4.78±0.28 mm vs. 4.52±0.36mm, p=0.0208) at 6m of age. Kaplan-Meier survival analyses have shown shortened lifespan in Jak1-cko mice compared to Myh6-Cre control (median survival: 242 days vs. 304 days, p< 0.0001). And female Jak1-cko mice survive longer than males (median survival: 256 days vs. 232.5 days, p=0.0254). Conclusions: CM-restricted Jak1 deletion causes dilated cardiomyopathy, heart failure, and premature death in mice, with a more severe phenotype in males than females. These findings suggest that JAK1 is indispensable for maintaining adult heart function Funding sources: American Heart Association (AHA) grant (20TPA35490091), AHA Predoctoral Fellowship (23PRE1023108) This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Cai et al. (Fri,) studied this question.