The March 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.
Colson discusses a recent investigation of the localization of N-terminal myosin-binding protein C in cardiac muscle.
Reconditi reviews research into the role temperature plays on motor disorders.
Thousands of variants are associated with genetic cardiomyopathies; however, the mechanisms driving these progressive, heterogeneous diseases are not well understood. Functional molecular studies are necessary for both mechanistically understanding disease pathogenesis and realizing the promise of precision medicine–based therapeutics.
This review article focuses on how intra- and extracellular factors influence myosin filament formation and how the assembly state of myosin determines contractile function in smooth muscle.
Making waves: A proposed new role for myosin-binding protein C in regulating oscillatory contractions in vertebrate striated muscle
A new role for myosin-binding protein C in damping sarcomere force oscillations is proposed that has implications for mechanical feedback and cell-to-cell communication in the heart.
Using super-resolution fluorescence microscopy and in silico simulations, Rahmanseresht et al. demonstrate that the N terminus of myosin-binding protein C (MyBP-C) tends to bind to actin filaments in both active and relaxed muscle. Binding to the myosin head also appears possible but only when the myosin head is near the actin filament.
cMyBP-C phosphorylation modulates the time-dependent slowing of unloaded shortening in murine skinned myocardium
Giles et al. show that the phosphorylation status of cardiac myosin-binding protein-C (cMyBP-C) modulates Ca2+ activation–dependent unloaded shortening velocity of skinned myocardium. The results suggest that cMyBP-C phosphorylation regulates cooperative binding of myosin to actin, and thus the activation state of the thin filament.
Tobacman and Cammarato identified locations of pathogenic and nonpathogenic troponin mutations in a thin-filament atomic model. Both mutation types had nonrandom distributions. 95% of pathogenic sites were in troponin regions that inhibit contraction via direct contacts with actin or tropomyosin.
Evidence for S2 flexibility by direct visualization of quantum dot–labeled myosin heads and rods within smooth muscle myosin filaments moving on actin in vitro
Brizendine et al. directly visualized quantum dot–labeled myosin heads and rods in vitro to understand the flexibility of the S2 subdomain. Their results confirm theoretical predictions about the range of motion of S2 and its effect on the relative movement of myosin on actin in vitro.
The arrangement of myosin heads in mammalian relaxed striated muscle becomes disordered at low temperatures. Ma et al. show that the myosin heads of tarantula relaxed striated muscle become disordered at low and high temperatures and propose a thermosensing mechanism by which, in addition to superrelaxation, the structural changes at low temperature also save energy.
Dependence of thick filament structure in relaxed mammalian skeletal muscle on temperature and interfilament spacing
Caremani et al. use x-ray diffraction and interference to characterize the structure of thick filaments in relaxed demembranated and intact resting mammalian muscle, revealing two closely spaced axial periodicities as well as structural changes that occur when filament activation is mimicked by cooling below near-physiological temperature.
In this study, Kawai et al. address the role of inorganic phosphate in muscle cross-bridge kinetics using a subcellular structure called myofibrils. They demonstrate that phosphate binding is a key determinant of oscillatory work and suggest that it may also compete with ATP for binding to the myosin head.
Our multiscale modeling approach incorporates the spatial and chemomechanical properties of sarcomeres for simulation of the mechanical performance of striated muscle. In this study, we demonstrate the ability to simulate the twitch tension and kinetics of cardiac muscle, and this requires inclusion of muscle elasticity and thick-filament regulation. The model provides precise simulations of twitch contractions in rat cardiac muscle, and the parameters used can accurately predict the Ca2+ sensitivity of force in an intact muscle.
van der Horst et al. show that dynein, a microtubule motor protein, carries the voltage-gated potassium channel Kv7.4 away from the cell membrane in vascular smooth muscle cells, thereby reducing its functional impact. These data have implications for our understanding of arterial contractility.
The number of Z-repeats and super-repeats in nebulin greatly varies across vertebrates and scales with animal size
Gohlke et al. compare the structure of the sarcomeric protein nebulin across 53 species. They uncover an association between the number of nebulin structural repeats and animal body size that has implications for muscle mechanics.
Methods and Approaches
A high-throughput fluorescence lifetime-based assay to detect binding of myosin-binding protein C to F-actin
Bunch et al. describe a new assay to rapidly evaluate binding of cMyBP-C to F-actin (with or without tropomyosin) in solution. Changes in labeled actin fluorescence lifetime due to cMyBP-C phosphorylation and/or HCM mutations were consistent with measurements obtained using cosedimentation assays.