Glycogen synthase kinase 3β localizes to the Z-disc to maintain length dependent activation

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Glycogen synthase kinase 3β (GSK-3β) can modulate myofilament function in vitro. However, it’s in vivo role, mechanism, and translational relevance are unknown, which we investigated using inducible cardiomyocyte-specific GSK-3β KO mice. Compared to tamoxifen-treated GSK-3βfl/fl/Cre-mice (Con), skinned myocytes from KO mice had reduced calcium sensitivity at long sarcomere lengths (SL = 2.2 μm), but there were no differences at short SL (∼1.9 μm). Thus, myocytes from KO mice did not sensitize to calcium with stretch, a mechanism called length dependent activation (LDA) underlying the organ-level Frank-Starling law.