PubMed · 8553065
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P Cossart, P Boquet, S Normark, R Rappuoli. 1996-01-19. Cellular microbiology emerging.. https://doi.org/10.1126/science.271.5247.315
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Myoblast fusion is crucial for the formation, growth, maintenance and regeneration of healthy skeletal muscle. Unfortunately, the molecular machinery, cell behaviors, and membrane and cytoskeletal remodeling events that govern fusion and myofiber formation remain poorly understood. Using time-lapse imaging approaches on mouse C2C12 myoblasts, we identify discrete and specific molecular events at myoblast membranes during fusion and myotube formation. These events include rearrangement of cell shape from fibroblast to spindle-like morphologies, changes in lamellipodial and filopodial extensions during different periods of differentiation, and changes in membrane alignment and organization during fusion. We find that actin-cytoskeleton remodeling is crucial for these events: pharmacological inhibition of F-actin polymerization leads to decreased lamellipodial and filopodial extensions and to reduced myoblast fusion. Additionally, shRNA-mediated inhibition of Nap1, a member of the WAVE actin-remodeling complex, results in accumulations of F-actin structures at the plasma membrane that are concomitant with a decrease in myoblast fusion. Our data highlight distinct and essential roles for actin cytoskeleton remodeling during mammalian myoblast fusion, provide a platform for cellular and molecular dissection of the fusion process, and suggest a functional conservation of Nap1-regulated actin-cytoskeleton remodeling during myoblast fusion between mammals and Drosophila.
Hydrogen peroxide, coming from polymorphonuclear leukocytes, causes severe oxidative injury on actin molecules with the disarrangement of cortical actin cytoskeleton followed by plasmalemma blebbing. In this paper we demonstrate that actin oxidation does not simply develop into denaturation, but oxidative injuries on actin are specific and related to the chemical characteristics of the oxidant. Experiments on purified actin in solution have shown that actin behavior to oxidation depends on (i) the amino acidic targets of the oxidant and (ii) on the structural plasticity of the actin molecule, which differently responds to different chemical modifications. Therefore, hydrogen peroxide (that presents a broad oxidative activity) affects actin dynamics by markedly inhibiting the assembly of actin monomers, by forcing the disassembly of actin polymers, and, moreover, by affecting the interaction between oxidant-stressed actin and DNase I. Diamide (a specific thiol oxidant), in contrast, mainly lowers the actin polymerization extent, while it slightly influences the polymerization rate and results uneffective on both F-actin disassembly and actin-related DNase I inhibition. Actin response to oxidative stresses likely depends on the "structural connectivity in actin," the property allowing it to finely modulate the actin filament architecture. The potential cellular relevance of the alterations in the interaction between oxidized actin and DNase I has been briefly discussed.
Gelatinase A (GL-A) is a matrix metalloproteinase (MMP) involved in both connective tissue remodeling and tumor invasion. GL-A activation is mediated by a membrane-type MMP (MT-MMP) that cleaves the GL-A propeptide. In this study, we examined the role of the actin cytoskeleton in regulating GL-A activation and MT-MMP-1 expression. Human palmar fascia fibroblasts and human fetal lung fibroblasts were cultured on a planar substratum or within different types of collagen lattices. Fibroblasts that formed stress fibers, either on a planar substratum or within an attached collagen lattice, showed reduced GL-A activation compared with fibroblasts lacking stress fibers, within either floating or stress-released collagen lattices. To determine whether changes in the organization of the actin cytoskeleton could promote GL-A activation, fibroblasts with stress fibers were treated with cytochalasin D. Within 24 h after treatment, GL-A activation was dramatically increased. Associated with this GL-A activation was an increase in MT-MMP-1 mRNA as determined by Northern blot analysis. Treatment with nocodazole, which induced microtubule depolymerization and cell shape changes without affecting stress fibers, did not promote GL-A activation. These results suggest that the extracellular matrix and the actin cytoskeleton transduce signals that modulate GL-A activation and regulate tissue remodeling.