Abstract Body: Background: Using a systems genetics approach in the Hybrid Mouse Diversity Panel, we identified the Motile sperm domain containing 3 (Mospd3) locus as strongly (p=3.49x10^-10) associated with cardiac traits. Previous studies report causal mutations in Mospd3 leading to neonatal lethality with right ventricular defects. However, the role of Mospd3 in the adult heart and its response to pathological stress remains unclear. We investigated the impact of fibroblast specific loss of Mospd3 on beta adrenergic stress induced cardiac remodeling.
Methods: Mospd3 KO was generated using the Col1a2creloxP system, producing complete (CKO) and partial (PKO) knockouts. Mice (n = 40/group; both sexes) received tamoxifen at 9 weeks of age, achieving gene deletion by 12 weeks. This was followed by 3 weeks of isoproterenol (Iso) infusion via Alzet^® pumps to induce adrenergic stress. Control mice (Ctrl) received saline. Echocardiography was performed at 9, 12, and 15 weeks. At study completion, organ weights were recorded and ventricular sections were stained for fibrosis using Picrosirius red. Cre negative littermates served as wild type (WT) controls.
Results: Cardiac function was not significantly altered following tamoxifen induced Mospd3 deletion at 12 weeks compared with pretamoxifen baseline (9 weeks). Following Iso stress, by the end of 15 weeks, all genotypes exhibited stress induced remodeling characterized by increased heart rate (+62-90bpm), left ventricular mass (+25-51mg), dilation, stroke volume (+7-12μL), and cardiac output (+4-7mL/min). However, their magnitude reached significance (p < 0.05) only in CKO mice, although the direction of trend was similar for other genotypes. Males consistently drove the significant Iso response across all genotypes, while females only reached significance (p=0.038) for LV mass and uniquely so in CKO group. Iso stress significantly (p < 0.001) increased heart weight and LV weight compared to Ctrl. Preserved ejection fraction and fractional shortening in these mice indicated a compensated hypertrophy response. Fibrosis showed a pronounced female-specific effect in the CKO (2.86±0.63%(F) vs 0.52±0.29%(M), p = 0.035), a pattern not seen in males (p = 0.333); consistent with HFpEF like phenotype.
Conclusion: Complete loss of Mospd3 aggravates stress induced remodeling in the adult mouse heart. The observed sex specific differences, particularly in fibrotic remodeling, warrant further mechanistic investigation.