Issues

The first of two special issues dedicated to contractile systems highlights an emerging consensus that regulatory mechanisms involve thick and thin filaments.

JGP paper explores how a mutated troponin T causes cardiac hypertrophy.

The detachment of myosin from actin is associated with tropomyosin adopting a blocked or closed state, but the mechanism is unclear. Using MD simulations, Kiani et al. show that tropomyosin undergoes spontaneous transitions on the F-actin surface toward blocked or closed positions.

Cardiac troponin activators could be beneficial in systolic heart failure. Tikunova et al. demonstrate that, unlike previously known calcium sensitizers, the small molecule 3-chlorodiphenylamine does not activate isolated cardiac troponin C but instead activates the intact troponin complex.

Hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomeric proteins, but the pathogenic mechanism is unclear. Piroddi et al. find impairment of cross-bridge kinetics and energetics in human sarcomeres with a TNNT2 mutation, suggesting that HCM involves inefficient ATP utilization.

Increases in sarcomere length cause enhanced force generation in cardiomyocytes by an unknown mechanism. Li et al. reveal that titin-based passive tension contributes to length-dependent activation of myofilaments and that tightly bound myosin–actin cross-bridges are associated with this effect.

Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by increased diastolic stiffness, for which effective therapies are lacking. Slater et al. show that metformin lowers titin-based passive stiffness in an HFpEF mouse model and may therefore be of therapeutic benefit.

Thick filament mechanosensing has been proposed as the mechanism by which myosin motors in cardiac muscle become available to bind actin. Accordingly, Caremani et al., using x-ray diffraction from intact rat trabeculae, show that myosin motors fully return to their OFF state during diastole independently of inotropic interventions.

Contraction of cardiac muscle is regulated by sarcomere length and proteins that comprise the sarcomeric filaments. Breithaupt et al. find that phosphorylation of myosin regulatory light chain augments length-dependent activation of contraction when β-cardiac myosin heavy chain predominates.

Knockdown of cardiac myosin binding protein C (cMyBP-C), which is the cause of many cases of hypertrophic cardiomyopathy in humans, results in left ventricular dilation, cardiac hypertrophy, and impaired ventricular function, but it is unclear whether these effects can be reversed. Using the Tet-Off system, Giles et al. show that these phenotypes can be induced and reversed with reexpression of cMyBP-C on the null background.