Myosin binding protein C (MyBP-C) is thought to regulate the contraction of skeletal muscle. Robinett et al. show that phosphorylation of slow skeletal MyBP-C modulates contraction by recruiting cross-bridges, modifying cross-bridge kinetics, and altering internal drag forces in the C-zone.

from actin is faster during relaxation from tetanic contraction. The rate of the recovery of the intensity of the first-order myosin layer line (MLL1) after contraction was used to estimate the relaxation time. In WT soleus, the MLL1 intensity took about 0.9s to reach its pre-contraction value after the end of stimulation, compared to 0.67s in the RNR mice. When fit to the Hill equation, the Hill coefficient for the recovery of MLL1 intensity WT muscle was 2.574, compared to 4.476 in RNR muscle, indicating that dATP increases the rate of return of the myosin heads to an ordered resting state. In the resting state, the radii to the center of mass of the myosin heads (Rm) and equatorial intensity ratio (I1,1/I1,0) were larger in RNR muscle than in WT muscle, indicating that myosin heads were extended closer to actin with elevated dATP. Molecular dynamics simulations of post-powerstroke myosin showed that relative to ADP, dADP is more mobile, forms altered interactions within the nucleotide binding pocket, and induces altered conformations of the actin binding residues of myosin. Our results indicate that dATP significantly increases the rate of myosin detachment after tetanic contraction. Thus dATP enhances both myosin binding and detachment, and suggests therapeutic strategies for cardiomyopathies caused by hypo-contraction and incomplete cardiac or skeletal muscle relaxation. Central to the functional use of muscles is the active perturbation response that transitions between a stiff solid-like and a yielding fluid-like material depending on its neural activation. The solid-like response enables muscle to transmit stresses to tendons without stretching appreciably. A fluid-like response is essential to minimally resist being stretched during fast motions, without internal damage to the muscle. This transition manifests as a stress relaxation timescale of the perturbation response, where the muscle is solid-like for times shorter than this timescale and fluid-like for longer times. Behavioral evidence shows that muscle can dissipate stresses in less than 100ms during a fast motion such as a baseball pitch. But it can also maintain stresses for several minutes to stabilize a posture. The relaxation timescale must therefore vary by 1000-fold or more, depending on the neural input that modulates intracellular calcium concentration. We find that Huxley-based models of crossbridge mechanics, irrespective of the number of internal states, fail to capture this vast change in the relaxation timescale unless non-physiological dependence on calcium are assumed for the kinetics. Other resolutions involve either titin or stretch reflexes, and we examine the experimental evidence for each. We also posit a third crossbridge based hypothesis, namely, a calcium-dependent glass transition in population dynamics of active crossbridges. At a glass transition, the material's viscosity increases by many orders of magnitude over a small parameter change, and a characteristic of the glassy state is a slower than exponential stress relax...

Heart failure (HF) often includes changes in myocardial contractile function. This study addressed the myofibrillar basis for contractile dysfunction in failing human myocardium. Regulation of contractile properties was measured in cardiac myocyte preparations isolated from frozen, left ventricular mid-wall biopsies of donor (n = 7) and failing human hearts (n = 8). Permeabilized cardiac myocyte preparations were attached between a force transducer and a position motor, and both the Ca 2+ dependence and sarcomere length (SL) dependence of force, rate of force, loaded shortening, and power output were measured at 15 ± 1 • C. The myocyte preparation size was similar between groups (donor: length 148 ± 10 µm, width 21 ± 2 µm, n = 13; HF: length 131 ± 9 µm, width 23 ± 1 µm, n = 16). The maximal Ca 2+-activated isometric force was also similar between groups (donor: 47 ± 4 kN • m −2 ; HF: 44 ± 5 kN • m −2), which implicates that previously reported force declines in multi-cellular preparations reflect, at least in part, tissue remodeling. Maximal force development rates were also similar between groups (donor: k tr = 0.60 ± 0.05 s −1 ; HF: k tr = 0.55 ± 0.04 s −1), and both groups exhibited similar Ca 2+ activation dependence of k tr values. Human cardiac myocyte preparations exhibited a Ca 2+ activation dependence of loaded shortening and power output. The peak power output normalized to isometric force (PNPO) decreased by ∼12% from maximal Ca 2+ to half-maximal Ca 2+ activations in both groups. Interestingly, the SL dependence of PNPO was diminished in failing myocyte preparations. During submaximal Ca 2+ activation, a reduction in SL from ∼2.25 to ∼1.95 µm caused a ∼26% decline in PNPO in donor myocytes but only an ∼11% change in failing myocytes. These results suggest that altered length-dependent regulation of myofilament function impairs ventricular performance in failing human hearts.

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