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.
JGP study shows that the phosphorylation state of cMyBPC modulates the ability of omecamtiv mecarbil to enhance myocardial force generation.
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.
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.
Impact of regulatory light chain mutation K104E on the ATPase and motor properties of cardiac myosin
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.
Cardiomyopathic mutations in essential light chain reveal mechanisms regulating the super relaxed state of 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.
Mavacamten has a differential impact on force generation in myofibrils from rabbit psoas and human cardiac muscle
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.
Caldesmon ablation in mice causes umbilical herniation and alters contractility of fetal urinary bladder smooth muscle
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.
Muscle ankyrin repeat protein 1 (MARP1) locks titin to the sarcomeric thin filament and is a passive force regulator
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.
Contraction–relaxation coupling is unaltered by exercise training and infarction in isolated canine myocardium
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.
Tubulin acetylation increases cytoskeletal stiffness to regulate mechanotransduction in striated muscle
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.