Abstract
BackgroundMyofibers with an abnormal branching cytoarchitecture are commonly found in muscular dystrophy and in regenerated or aged nondystrophic muscles. Such branched myofibers from dystrophic mice are more susceptible to damage than unbranched myofibers in vitro, suggesting that muscles containing a high percentage of these myofibers are more prone to injury. Little is known about the regulation of myofiber branching.MethodsTo gain insights into the formation and fate of branched myofibers, we performed in-depth analyses of single myofibers isolated from dystrophic and nondystrophic (myotoxin-injured or aged) mouse muscles. The proportion of branched myofibers, the number of branches per myofiber and the morphology of the branches were assessed.ResultsAged dystrophic mice exhibited the most severe myofiber branching as defined by the incidence of branched myofibers and the number of branches per myofiber, followed by myotoxin-injured, wild-type muscles and then aged wild-type muscles. In addition, the morphology of the branched myofibers differed among the various models. In response to either induced or ongoing muscle degeneration, branching was restricted to regenerated myofibers containing central nuclei. In myotoxin-injured muscles, the amount of branched myofibers remained stable over time.ConclusionWe suggest that myofiber branching is a consequence of myofiber remodeling during muscle regeneration. Our present study lays valuable groundwork for identifying the molecular pathways leading to myofiber branching in dystrophy, trauma and aging. Decreasing myofiber branching in dystrophic patients may improve muscle resistance to mechanical stress.
Highlights
Myofibers with an abnormal branching cytoarchitecture are commonly found in muscular dystrophy and in regenerated or aged nondystrophic muscles
Despite the fact that branched myofibers are observed in several muscular dystrophies in human, dog, cat and mouse [3,4,5,6,7,8,9,10,11], myofiber branching has been studied predominantly studied in mdx mice, a mouse model of Duchenne muscular dystrophy (DMD) [10,12,13,14,15]
Ca2+ signaling is altered in branched myofibers compared to unbranched myofibers, suggesting that contractile activity is impaired in branched myofibers [13]
Summary
Myofibers with an abnormal branching cytoarchitecture are commonly found in muscular dystrophy and in regenerated or aged nondystrophic muscles. Such branched myofibers from dystrophic mice are more susceptible to damage than unbranched myofibers in vitro, suggesting that muscles containing a high percentage of these myofibers are more prone to injury. Isolated branched myofibers of mdx mice are more susceptible to damage at the branch point in response to eccentric contraction [14,15,18], suggesting that muscles containing a high percentage of these myofibers are more prone to injury. Branched myofibers can occur in nondystrophic muscles in response to aging, weightlifting or muscle injury induced by myotoxins [12,19,20,21,22,23,24,25], but only limited quantitative analyses of myofiber branching were performed in previously described experiments [12,19,24,25]
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