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Muscle wasting and weakness are common features of patients with critical illnesses, and may impair their recovery. This study examines whether cytoskeletal and contractile proteins are damaged, and which proteolytic mechanisms might be involved, in the muscle fibre atrophy or necrosis associated with the acute myopathy of critically ill patients. Ninety-eight muscle biopsies were obtained by the conchotome method from 57 critically ill patients and examined morphometrically and by immunohistochemical labelling. Sequential biopsies showed a mean reduction in fibre cross-sectional areas of 3-4% per day. More intense immunolabelling for desmin was seen in the smaller fibres of 52% of the biopsies, while immunolabelling for dystrophin, actin and myosin heavy chains was maintained. Myosin ATPase activity was weak in the smaller fibres in some biopsies, and electron microscopy showed the loss of myosin filaments in atrophic fibres. These changes suggest that loss of the filamentous structure of myosin, without degradation of the immunolabelled epitopes, leads to the collapse of the intermyofibrillar desmin network. Fibres with abnormal desmin labelling showed increased cathepsin B, lysozyme and ubiquitin immunolabelling. Nine cases showed increased immunolabelling for heat shock protein 72. The changes in desmin immunolabelling were more prevalent in patients with higher APACHE II scores on admission, but were not related to other clinical features. The results indicate that fibre atrophy is associated with myosin filament depolymerization and the presence of several proteolytic enzymes. In our study, these changes occurred in patients who were critically ill but who did not receive large doses of steroids or neuromuscular blocking agents.
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PMID:Muscle fibre atrophy in critically ill patients is associated with the loss of myosin filaments and the presence of lysosomal enzymes and ubiquitin. 988 61

According to the treadmill hypothesis, the rate of growth cone advance depends upon the difference between the rates of protrusion (powered by actin polymerization at the leading edge) and retrograde F-actin flow, powered by activated myosin. Myosin II, a strong candidate for powering the retrograde flow, is activated by myosin light chain (MLC) phosphorylation. Earlier results showing that pharmacological inhibition of myosin light chain kinase (MLCK) causes growth cone collapse with loss of F-actin-based structures are seemingly inconsistent with the treadmill hypothesis, which predicts faster growth cone advance. These experiments re-examine this issue using an inhibitory pseudosubstrate peptide taken from the MLCK sequence and coupled to the fatty acid stearate to allow it to cross the membrane. At 5-25 microM, the peptide completely collapsed growth cones from goldfish retina with a progressive loss of lamellipodia and then filopodia, as seen with pharmacological inhibitors, but fully reversible. Lower concentrations (2.5 microM) both simplified the growth cone (fewer filopodia) and caused faster advance, doubling growth rates for many axons (51-102 microm/h; p <.025). Rhodamine-phalloidin staining showed reduced F-actin content in the faster growing growth cones, and marked reductions in collapsed ones. At higher concentrations, there was a transient advance of individual filopodia before collapse (also seen with the general myosin inhibitor, butanedione monoxime, which did not accelerate growth). The rho/rho kinase pathway modulates MLC dephosphorylation by myosin-bound protein phosphatase 1 (MPP1), and manipulations of MPP1 also altered motility. Lysophosphatidic acid (10 microM), which causes inhibition of MPP1 to accumulate activated myosin II, caused a contracted collapse (vs. that due to loss of F-actin) but was ineffective after treatment with low doses of peptide, demonstrating that the peptide acts via MLC phosphorylation. Inhibiting rho kinase with Y27632 (100 microM) to disinhibit the phosphatase increased the growth rate like the MLCK peptide, as expected. These results suggest that: varying the level of MLCK activity inversely affects the rate of growth cone advance, consistent with the treadmill hypothesis and myosin II powering of retrograde F-actin flow; MLCK activity in growth cones, as in fibroblasts, contributes strongly to controlling the amount of F-actin; and the phosphatase is already highly active in these cultures, because rho kinase inhibition produces much smaller effects on growth than does MLCK inhibition.
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PMID:Myosin light chain phosphorylation and growth cone motility. 1221 Jan 2

Myosin II is an intracellular force-generating enzyme with no known extracellular action. In the course of experiments involving trituration loading of skeletal myosin II into embryonic sensory neurons we observed that extracellular application of myosin II to neurons resulted in a robust increase in the number of axons initiated by each neuron, but did not alter the rate of axon extension. Substratum bound myosin II in the presence of laminin was sufficient to elicit increases in axon formation. However, in the absence of laminin, extracellular myosin II alone was not sufficient to promote axon formation, although it allowed neuron survival in the presence of neurotrophin. Myosin II promoted the attachment of neurons to the substratum in the absence or presence of laminin. In addition to promoting the initiation of axons, extracellular myosin II also increased the frequency of axon collateral branching. Finally, extracellular myosin II did not affect growth cone collapse in response to semaphorin-IIIA, but attenuated the inhibitory action of chondroitin sulfate proteoglycans on axon extension. Surprisingly, these results demonstrate that extracellular myosin II promotes attachment of neurons and increases axon formation and branching. The potential significance of these observations is discussed in the context of myosin II release from injured muscle and a previous demonstration of extracellular myosin II association with the extracellular matrix.
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PMID:Extracellular Muscle Myosin II Promotes Sensory Axon Formation. 1600 12

Axon guidance is mediated by the effects of attractant and repellent guidance cues on the cytoskeleton of growth cones and axons. During development, axon retraction is an important aspect of the pruning of inappropriately targeted axons in response to repellent guidance cues. I investigated the roles of RhoA-kinase and myosin II in semaphorin-3A-induced growth cone collapse and axon retraction. I report that semaphorin 3A activates myosin II in growth cones and axons. Myosin II activity is required for axon retraction but not growth cone collapse. Furthermore, semaphorin 3A promotes the formation of intra-axonal F-actin bundles in concert with the loss of F-actin in growth cone lamellipodia and filopodia. Formation of axonal F-actin bundles was independent of myosin II, but partially required RhoA-kinase activity. Conversely, RhoA-kinase activity was required to shut down F-actin polymerization underlying protrusive activity. Collectively, these observations suggest that guidance cues cause axon retraction through the coordinated activation of myosin II and the formation of intra-axonal F-actin bundles for myosin-II-based force generation. I suggest that in the context of semaphorin 3A signaling, RhoA-kinase serves as a switch to change the function of the F-actin cytoskeleton from promoting protrusive activity to generating contractile forces.
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PMID:RhoA-kinase coordinates F-actin organization and myosin II activity during semaphorin-3A-induced axon retraction. 1689 19

Neuronal dynamics result from the integration of forces developed by molecular motors, especially conventional myosins. Myosin IIC is a recently discovered nonsarcomeric conventional myosin motor, the function of which is poorly understood, particularly in relation to the separate but coupled activities of its close homologues, myosins IIA and IIB, which participate in neuronal adhesion, outgrowth and retraction. To determine myosin IIC function, we have applied a comparative functional knockdown approach by using isoform-specific antisense oligodeoxyribonucleotides to deplete expression within neuronally derived cells. Myosin IIC was found to be critical for driving neuronal process outgrowth, a function that it shares with myosin IIB. Additionally, myosin IIC modulates neuronal cell adhesion, a function that it shares with myosin IIA but not myosin IIB. Consistent with this role, myosin IIC knockdown caused a concomitant decrease in paxillin-phospho-Tyr118 immunofluorescence, similar to knockdown of myosin IIA but not myosin IIB. Myosin IIC depletion also created a distinctive phenotype with increased cell body diameter, increased vacuolization, and impaired responsiveness to triggered neurite collapse by lysophosphatidic acid. This novel combination of properties suggests that myosin IIC must participate in distinctive cellular roles and reinforces our view that closely related motor isoforms drive diverse functions within neuronal cells.
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PMID:Myosin IIC: a third molecular motor driving neuronal dynamics. 1861

Growth cone responses to guidance cues provide the basis for neuronal pathfinding. Although many cues have been identified, less is known about how signals are translated into the cytoskeletal rearrangements that steer directional changes during pathfinding. Here we show that the response of dorsal root ganglion (DRG) neurons to Semaphorin 3A gradients can be divided into two steps: growth cone collapse and retraction. Collapse is inhibited by overexpression of myosin IIA or growth on high substrate-bound laminin-1. Inhibition of collapse also prevents retractions; however collapse can occur without retraction. Inhibition of myosin II activity with blebbistatin or by using neurons from myosin IIB knockouts inhibits retraction. Collapse is associated with movement of myosin IIA from the growth cone to the neurite. Myosin IIB redistributes from a broad distribution to the rear of the growth cone and neck of the connecting neurite. High substrate-bound laminin-1 prevents or reverses these changes. This suggests a model for the Sema 3A response that involves loss of growth cone myosin IIA to facilitate actin meshwork instability and collapse, followed by myosin IIB concentration at the rear of the cone and neck region where it associates with actin bundles to drive retraction.
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PMID:Dorsal root ganglion neurons react to semaphorin 3A application through a biphasic response that requires multiple myosin II isoforms. 1910 30

Here, we produced cytoplasmic protrusions with optical tweezers in mature BY-2 suspension cultured cells to study the parameters involved in the movement of actin filaments during changes in cytoplasmic organization and to determine whether stiffness is an actin-related property of plant cytoplasm. Optical tweezers were used to create cytoplasmic protrusions resembling cytoplasmic strands. Simultaneously, the behavior of the actin cytoskeleton was imaged. After actin filament depolymerization, less force was needed to create cytoplasmic protrusions. During treatment with the myosin ATPase inhibitor 2,3-butanedione monoxime, more trapping force was needed to create and maintain cytoplasmic protrusions. Thus, the presence of actin filaments and, even more so, the deactivation of a 2,3-butanedione monoxime-sensitive factor, probably myosin, stiffens the cytoplasm. During 2,3-butanedione monoxime treatment, none of the tweezer-formed protrusions contained filamentous actin, showing that a 2,3-butanedione monoxime-sensitive factor, probably myosin, is responsible for the movement of actin filaments, and implying that myosin serves as a static cross-linker of actin filaments when its motor function is inhibited. The presence of actin filaments does not delay the collapse of cytoplasmic protrusions after tweezer release. Myosin-based reorganization of the existing actin cytoskeleton could be the basis for new cytoplasmic strand formation, and thus the production of an organized cytoarchitecture.
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PMID:Actin and myosin regulate cytoplasm stiffness in plant cells: a study using optical tweezers. 1976 43

Schwann cells migrate along axons before initiating myelination during development and their migration facilitates peripheral nerve regeneration after injury. Axon guidance molecule Slit-2 is highly expressed during peripheral development and nerve regeneration; however, whether Slit-2 regulates the migration of Schwann cells remains a mystery. Here we show that Slit-2 receptor Robo-1 and Robo-2 were highly expressed in Schwann cells in vitro and in vivo. Using three distinct migration assays, we found that Slit-2 repelled the migration of cultured Schwann cells. Furthermore, frontal application of a Slit-2 gradient to migrating Schwann cells first caused the collapse of leading front, and then reversed soma translocation of Schwann cells. The repulsive effects of Slit-2 on Schwann cell migration depended on a Ca(2+) signaling release from internal stores. Interestingly, in response to Slit-2 stimulation, the collapse of leading front required the loss of F-actin and focal adhesion, whereas the subsequent reversal of soma translocation depended on RhoA-Rock-Myosin signaling pathways. Taken together, we demonstrate that Slit-2 repels the migration of cultured Schwann cells through RhoA-Myosin signaling pathways in a Ca(2+)-dependent manner.
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PMID:Repulsive migration of Schwann cells induced by Slit-2 through Ca2+-dependent RhoA-myosin signaling. 2336 95

Myosin-V is a highly processive dimeric protein that walks with 36-nm steps along actin tracks, powered by coordinated adenosine triphosphate (ATP) hydrolysis reactions in the two myosin heads. No previous theoretical models of the myosin-V walk reproduce all the observed trends of velocity and run length with adenosine diphosphate (ADP), ATP and external forcing. In particular, a result that has eluded all theoretical studies based upon rigorous physical chemistry is that run length decreases with both increasing [ADP] and [ATP]. We systematically analyze which mechanisms in existing models reproduce which experimental trends and use this information to guide the development of models that can reproduce them all. We formulate models as reaction networks between distinct mechanochemical states with energetically determined transition rates. For each network architecture, we compare predictions for velocity and run length to a subset of experimentally measured values, and fit unknown parameters using a bespoke Monte Carlo simulated annealing optimization routine. Finally we determine which experimental trends are replicated by the best-fit model for each architecture. Only two models capture them all: one involving [ADP]-dependent mechanical detachment, and another including [ADP]-dependent futile cycling and nucleotide pocket collapse. Comparing model-predicted and experimentally observed kinetic transition rates favors the latter.
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PMID:Detachment, futile cycling, and nucleotide pocket collapse in myosin-V stepping. 2576 41