Cardiac Physiology

Understanding a Broken Heart

Science Signaling  11 Sep 2012:
Vol. 5, Issue 241, pp. ec241
DOI: 10.1126/scisignal.2003590

Cardiac myosin-binding protein C (cMyBP-C) is a thick filament–associated sarcomeric protein that modulates cardiac contractility in a phosphorylation-dependent manner; mutations in the MYBC3 gene are the leading cause of hypertrophic cardiomyopathy. Previs et al. (see the Perspective by Burghardt and Ajtai) have isolated native myosin thick filaments from transgenic mouse hearts, which retained the spatial distribution of cMyBP-C in the thick filament. Imaging of a single actin filament being propelled along the thick filament showed that the N-terminal 29-kD domain of cMyBP-C slows actomyosin motion in parts of the thick filament corresponding to the C-zones in which the thick filaments are cross-bridged. This effect on actomyosin contractility was tuned by graded phosphorylation of four serines adjacent to the 29-kD domain. The findings may explain the appearance of a cMyBP-C fragment in the serum of patients with cardiac ischemia and why cMyBP-C haploinsufficiency associated with cardiomyopathy patients might trigger a hypertrophic response.

M. J. Previs, S. Beck Previs, J. Gulick, J. Robbins, D. M. Warshaw, Molecular mechanics of cardiac myosin-binding protein C in native thick filaments. Science 337, 1215–1218 (2012). [Abstract] [Full Text]

T. P. Burghardt, K. Ajtai, Heart brakes. Science 337, 1182–1183 (2012). [Abstract] [Full Text]