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PRINCIPAL PUBLICATION AND AUTHORS

Titin activates myosin filaments in skeletal muscle by switching from an extensible spring to a mechanical rectifier, C. Squarci (a), P. Bianco (a), M. Reconditi (a), I. Pertici (a), M. Caremani (a), T. Narayanan (b), Á.I. Horváth (c,d), A. Málnási-Csizmadia (c,d), M. Linari (a), V. Lombardi (a), G. Piazzesi (a), Proc. Natl. Acad. Sci. USA. 120, 9, e2219346120 (2023); https:/doi.org/10.1073/pnas.2219346120 (a) PhysioLab, University of Florence (Italy) (b) ESRF (c) MTA-ELTE Motor Pharmacology Research Group, Budapest (Hungary) (d) Motorpharma, Ltd., Budapest (Hungary)

REFERENCES

[1] M. Linari et al., Nature 528, 276-279 (2015). [2] M. Reconditi et al., Proc. Natl. Acad. Sci. USA. 114, 3240-3245 (2017). [3] M. Kepiro et al., Angew. Chem. Int. Ed. Engl. 53, 8211-8215 (2014).

It was found that, in the activated cell, a calcium- dependent process switches the I-band titin from an SL-dependent extensible spring (OFF-state) to an SL- independent mechanical rectifier (ON-state) that allows free shortening while resisting stretch with an effective stiffness that, at physiological SL, is two orders of magnitude larger than the stiffness at rest. Under these conditions, an increase in load is efficiently transmitted by the I-band titin to the surface of the thick filament. X-ray analysis revealed that the periodic interactions of A-band titin with myosin motors alter their resting disposition in a load-dependent manner, biasing the azimuthal orientation of the motors toward actin (Figure 13b).

This work demonstrates the mechanism by which titin, acting as a mechano-sensor, drives the myosin motors to interact with the overlapping actin filaments. The results set the stage for future investigations on muscle preparations from animal models and human biopsies to define the scaffold and mechano-sensing-based signalling functions of titin in health and disease and to develop specific therapeutical strategies.

Fig. 13: a) 2D X-ray pattern from a single muscle cell at rest with 1.6 m camera length. SL 2.7 μm, temperature 4°C. b) Schematic of the cross-section of the half-sarcomere. Blue, thick filament;

yellow, thin filaments surrounding the thick filament according to the hexagonal lattice; magenta: titin; brown, orange and ochre ovals represent the motors on three consecutive layers along the filament axis.

Left panel, before, and right panel, after a sudden increase in force.