COMPLEX SYSTEMS AND BIOMEDICAL SCIENCES

72 ESRF

Myosin filament-based regulation of the dynamics of contraction in heart muscle, E. Brunello (a), L. Fusi (a), A. Ghisleni (a), S.J. Park-Holohan (a), J.G. Ovejero (a),

T. Narayanan (b) and M. Irving (a), Proc. Natl. Acad. Sci. U.S.A. 117, 8177- 8186 (2020); https://doi.org/10.1073/ pnas.1920632117.

(a) Randall Centre for Cell and Molecular Biophysics, King s College London, London (UK) (b) ESRF

[1] M. Linari et al., Nature 528, 276-279 (2015). [2] A.M. Gordon et al., Physiol. Rev. 80, 853-924 (2000).

PRINCIPAL PUBLICATION AND AUTHORS

REFERENCES

of the filament closer to the midpoint, and activating the more central motors by a filament mechano-sensing mechanism first described in skeletal muscle [1]. At the peak of contraction (Figure 58b) the active motors (green) are confined to the C-zone, and these C-zone motors control the dynamics of relaxation in each beat.

This new picture of the regulation of contractility during the heartbeat is in marked contrast to the long-standing view that the strength and speed of contraction were controlled by structural changes in the actin filament, triggered by an increase in calcium concentration in the muscle cell [2]. It is now clear as a result of these X-ray interference measurements that, although the intracellular calcium transient provides the start signal for the heartbeat, the strength and the speed of contraction and relaxation in the heart are controlled by the zonal dynamics of the myosin filament. With the EBS, these studies can be extended to transgenic mouse models and faster timescales to further elucidate the mechanisms of myosin-based regulation of contractility in the heart.

Fig. 57: Confocal fluorescence micrograph (a) and schematic (b) of sarcomeres inside a heart muscle cell. Each sarcomere, delimited by

Z-bands (magenta), contains overlapping actin (dark grey) and myosin filaments (white). Myosin binding protein-C containing C-zone, green; myosin filament midpoint, M; layers of myosin motors (vertical lines on myosin filament); interference distance ID, blue. Scale bar, 2 μm.

Generation of X-ray interference subpeaks (c and d, black) by diffraction from the ordered layers of myosin motors within each half-filament (b and c, red) multiplied by the interference fringes (b and c, blue).

Fig. 58: Schematic of the half-sarcomere showing myosin motor conformations in the C-zone and in the distal D-zone of the myosin filament in heart muscle in the relaxed phase between beats (a) and at peak force (b) of the heartbeat. Folded motors, pink; folded and helically ordered motors, dark pink; actin- attached motors, green, and their partners, yellow; isotropic, gray. Myosin binding protein-C, blue.