Abstract
Skeletal muscle formation and regeneration require myoblast fusion to form multinucleated myotubes or myofibers, yet their molecular regulation remains incompletely understood. We show here that the levels of extra- and/or pericellular chondroitin sulfate (CS) chains in differentiating C2C12 myoblast culture are dramatically diminished at the stage of extensive syncytial myotube formation. Forced down-regulation of CS, but not of hyaluronan, levels enhanced myogenic differentiation in vitro. This characteristic CS reduction seems to occur through a cell-autonomous mechanism that involves HYAL1, a known catabolic enzyme for hyaluronan and CS. In vivo injection of a bacterial CS-degrading enzyme boosted myofiber regeneration in a mouse cardiotoxin-induced injury model and ameliorated dystrophic pathology in mdx muscles. Our data suggest that the control of CS abundance is a promising new therapeutic approach for the treatment of skeletal muscle injury and progressive muscular dystrophies.
Highlights
Expression level of chondroitin sulfate (CS) is important in embryonic development
Temporal Reduction in CS Levels Is Required for Myogenic Differentiation—To test our assumption, we took advantage of an in vitro culture system, in which mouse C2C12 myoblasts can be induced to differentiate into multinucleated myotubes by serum withdrawal [9]
C and D, degree of myogenesis was quantified based on the MHCϩ cell density (C) and on the fusion index of MHCϩ cells (D) in parental C2C12 cells and its stable clones in DM culture at each time point (n ϭ 5, parental cells; n ϭ 3, OE #1; n ϭ 4, OE #5; n ϭ 3, KD #1; n ϭ 3, KD #8; at each time point; results are expressed as means Ϯ S.D.; *, p Ͻ 0.05; **, p Ͻ 0.001)
Summary
Expression level of chondroitin sulfate (CS) is important in embryonic development. its involvement in skeletal myogenesis is unknown. Results: The CS level is temporally decreased during skeletal muscle development, and its forced reduction enhances myogenic differentiation/regeneration. Insufficient CS production at immediate-early stages of division results in undesirable embryonic cell death due to frequent reversion of cytokinesis accompanied by abnormal multinucleation. These findings suggested the seemingly paradoxical notion that a temporal reduction in CS levels was required for normal cell fusion processes to form multinucleated syncytia in somatic cells, including in skeletal myogenesis [5, 6]. Our data suggest that strategies aimed at lowering CS abundance open promising new therapeutic approaches for the treatment of skeletal muscle injury and progressive muscular dystrophies. We have previously shown that CS in mammals, or its nonsulfated form in Caenorhabditis elegans, is
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