The smooth muscle titin filament system regulates uterus contractility and implantation

Coordinated uterine peristalsis positions embryos for implantation, but the mechanotransduction pathways controlling uterine wave coordination are not well defined. We combined smooth-muscle-specific deletion of titin M-band exons 1 and 2 with vertical agarose gel electrophoresis, mass spectrometry, uterine ring myography, imaging, transcriptomics, spatial proteomics, and targeted immunoblotting. We show that the myometrium expresses smooth-muscle titin and low-abundance full-length titin including the M-band kinase region. Conditional M-band deletion increased oxytocin-evoked force and area-under-the-curve while reducing coordinated wall motion, yielding fewer as well as crowded/mislocalized implantation sites and heavier placentas. Proteomics and immunoblotting identified disruption of an NBR1/p62 autophagy hub with downstream remodeling of excitability, metabolism, and wall mechanics. Reduced telokin and MLCK levels are consistent with impaired relaxation and increased Ca2+-sensitization. Together, these findings establish the titin M-band as a mechanotransductive signaling hub regulating peri-implantation motility with potential clinical relevance for optimizing implantation after in vitro fertilization and preventing ectopic pregnancy.