biostudies-literatureHessel ALDeutsche ForschungsgemeinschaftHHS | NIH | National Institute of General Medical SciencesIZKF Muenstere2209441119https://www.ebi.ac.uk/biostudies/studies/S-EPMC9860331biostudies-literatureUnknown119(48)Skeletal muscle force production is increased at longer compared to shorter muscle lengths because of length-dependent priming of thick filament proteins in the contractile unit before contraction. Using small-angle X-ray diffraction in combination with a mouse model that specifically cleaves the stretch-sensitive titin protein, we found that titin cleavage diminished the length-dependent priming of the thick filament. Strikingly, a titin-sensitive, length-dependent priming was also present in thin filaments, which seems only possible via bridge proteins between thick and thin filaments in resting muscle, potentially myosin-binding protein C. We further show that these bridges can be forcibly ruptured via high-speed stretches. Our results advance a paradigm shift to the fundamental regulation of length-dependent priming, with titin as the key driver.Proceedings of the National Academy of Sciences of the United States of AmericaTitin force in muscle cells alters lattice order, thick and thin filament protein formation.PMC9860331Li1/029/20P30 GM138395SFB1002 A08P41 GM103622454867250Rice PELinke WANissen DKuehn MHessel ALMazara NIrving TGong HMa WfalseTitin force in muscle cells alters lattice order, thick and thin filament protein formation.Skeletal muscle force production is increased at longer compared to shorter muscle lengths because of length-dependent priming of thick filament proteins in the contractile unit before contraction. Using small-angle X-ray diffraction in combination with a mouse model that specifically cleaves the stretch-sensitive titin protein, we found that titin cleavage diminished the length-dependent priming of the thick filament. Strikingly, a titin-sensitive, length-dependent priming was also present in thin filaments, which seems only possible via bridge proteins between thick and thin filaments in resting muscle, potentially myosin-binding protein C. We further show that these bridges can be forcibly ruptured via high-speed stretches. Our results advance a paradigm shift to the fundamental regulation of length-dependent priming, with titin as the key driver.2022-01-01T00:00:00Z2022 Nov2025-04-04T08:06:24.912Z2025-04-04T08:06:24.912ZS-EPMC98603313640988710.1073/pnas.2209441119