Shortening the thick filament by partial deletion of titin's C-zone alters cardiac function by reducing the operating sarcomere length range. (April 2022)

• Record Type: Journal Article
• Authors: Methawasin, Mei; Farman, Gerrie P.; Granzier-Nakajima, Shawtaroh; Strom, Joshua; Kiss, Balazs; Smith, John E.; Granzier, Henk
• Is Part Of: Journal of molecular and cellular cardiology. Volume 165(2022)
• Page Start: 103
• Page End: 114
• Publication Date: 2022-04
• Subjects: Diastolic stiffness -- Contractile function -- Myofilament function -- titin's C-zone -- Heart disease; LV left ventricle -- SL sarcomere length -- cMyBP-C cardiac myosin-binding protein C -- ESPVR end-systolic pressure-volume relation -- EDPVR end-diastolic pressure-volume relation -- E(t) elastance -- En(t) normalized elastance -- Toe time to the onset of ejection -- Tes time to the end-systole -- Eoe elastance at the onset of ejection -- Ees elastance at end-systole -- dS/dtmax maximal rate of stress rise -- dS/dtmin maximal rate of stress decline -- ES-SSLR end-systolic stress-sarcomere length relation -- ED-SSLR end-diastolic stress-sarcomere length relation -- LDA length dependence of activation -- IVRT Isovolumic relaxation time; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2022.01.002
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Titin's C-zone is an inextensible segment in titin, comprised of 11 super-repeats and located in the cMyBP-C-containing region of the thick filament. Previously we showed that deletion of titin's super-repeats C1 and C2 ( Ttn ΔC1–2 model) results in shorter thick filaments and contractile dysfunction of the left ventricular (LV) chamber but that unexpectedly LV diastolic stiffness is normal. Here we studied the contraction-relaxation kinetics from the time-varying elastance of the LV and intact cardiomyocyte, cellular work loops of intact cardiomyocytes, Ca 2+ transients, cross-bridge kinetics, and myofilament Ca 2+ sensitivity. Intact cardiomyocytes of Ttn ΔC1–2 mice exhibit systolic dysfunction and impaired relaxation. The time-varying elastance at both LV and single-cell levels showed that activation kinetics are normal in Ttn ΔC1–2 mice, but that relaxation is slower. The slowed relaxation is, in part, attributable to an increased myofilament Ca 2+ sensitivity and slower early Ca 2+ reuptake. Cross-bridge dynamics showed that cross-bridge kinetics are normal but that the number of force-generating cross-bridges is reduced. In vivo sarcomere length (SL) measurements revealed that in Ttn ΔC1–2 mice the operating SL range of the LV is shifted towards shorter lengths. This normalizes the apparent cell and LV diastolic stiffness but further reduces systolic force as systole occurs further down on the ascending limb of the force-SL relation. We propose that the reduced working SLs reflect titin's role in regulating diastolic stiffness by altering the number of sarcomeres in series. Overall, our study reveals that thick filament length regulation by titin's C-zone is critical for normal cardiac function. Graphical abstract: Unlabelled Image Highlights: Deletion of titin's super-repeats C1 and C2 ( Ttn ΔC1-2 mice ) results in shorter thick filaments and contractile dysfunction. This contractile dysfunction is more pronounced than expected based on the reduced thick filament length per se. Diastolic stress is expected to be increased in Ttn ΔC1-2 mice, but instead is unaltered. These findings can be explained by the discovered shift in the operating sarcomere-length (SL) range of Ttn ΔC1-2 mice. The shift in operating SL range towards the shorter lengths further depresses contractility but normalizes titin-based passive stress. It appears that titin regulates passive stress at the detriment of contractile function.