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Issues

Editorials

The July 2021 issue of JGP is a collection of peer-reviewed articles focused on the function and dynamic regulation of contractile systems in muscle and non-muscle cells.

Research News

JGP study shows that the phosphorylation state of cMyBPC modulates the ability of omecamtiv mecarbil to enhance myocardial force generation.

Commentary

Stronczek et al. investigate the structure of titin–N2A and how it affects the binding of signaling proteins.

Iorga and Kraft discuss a recent investigation on force inhibition by mavacamten in ventricular and skeletal myofibrils.

Reviews

This review focuses on thin filament regulatory mechanisms with emphasis on cardiac-specific mechanisms in the three-state model of sarcomere activation and on signaling cascades at the barbed and pointed ends.

Articles

In Special Collection:
Cardiac Physiology 2021

Cardiac myosin-binding protein C (cMyBP-C) is thought to regulate cardiac muscle and heart contraction. Hanft et al. show that cMyBP-C phosphorylation regulates length dependence of power output in murine permeabilized cardiac myocytes, which translates to in vivo Frank–Starling relationships.

Mamidi et al. investigate the effect of cardiac myosin-binding protein C (cMyBPC) phosphorylation on the response to omecamtiv mecarbil (OM), a candidate heart failure therapy. They show that OM uncouples myocardial force dynamics from cMyBPC phosphorylation, suggesting important therapeutic constraints.

In Special Collection:
Cardiac Physiology 2021

Rasicci et al. investigate the mechanochemical properties of distinct isoforms of cardiac myosin carrying the K104E regulatory light chain mutation, previously associated with hypertrophic cardiomyopathy. They demonstrate that the mutation does not affect the ATPase or motor properties of human cardiac myosin subfragment-1 (M2β-S1), but the mutation increases the sliding velocity and disrupts RLC incorporation in full-length α-cardiac myosin.

Using mutations associated with cardiomyopathy, Sitbon et al. study the transition between the super relaxed state of myosin and the disordered-relaxed state. Their findings suggest that the N terminus of myosin essential light chain controls the transition between these two states.

Stronczek et al. analyze the structure of the titin-N2A poly-Ig segment, a key signaling element in the sarcomere. They reveal a unique topography for the I81-I83 tandem, but they could not confirm the presence of Ca2+ binding sites in I81-I83 or the interaction of N2A with actin.

Scellini et al. show that mavacamten, a preclinical inhibitor of sarcomeric myosins, has a fast and reversible mechanical action on skeletal and cardiac myofibers that is mediated by a shift of motor heads out of a force-generating cycle, with no effect on the kinetics of cardiac force development.

Contractility of smooth muscle is of vital importance. Pütz et al. reveal that the actin filament–linked protein caldesmon is indispensable for abdominal wall closure, and that in smooth muscle it promotes a relaxed state and supports the integrity of the contractile apparatus.

Passive force generated in titin plays an important role in maintaining sarcomere structure. In this paper, van der Pijl et al. describe a mechanism by which muscle ankyrin repeat protein 1 (MARP1) locks titin to the thin filament to increase passive force.

Communications

Fazlollahi et al. show that contraction and relaxation remain tightly coupled in intact canine myocardium after exercise training and/or myocardial infarction. They postulate that the action of cardiac myosin binding protein C on actin and myosin may play a key role in this process.

Posttranslational modifications in microtubules affect cytoskeletal mechanics and mechanotransduction. In this study, Coleman et al. show that acetylated α-tubulin affects cytoskeletal stiffness and viscoelastic resistance, thus revealing another regulator of striated muscle mechanotransduction.

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