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首页> 外文期刊>American Journal of Physiology >Inefficient skeletal muscle repair in inhibitor of differentiation knockout mice suggests a crucial role for BMP signaling during adult muscle regeneration
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Inefficient skeletal muscle repair in inhibitor of differentiation knockout mice suggests a crucial role for BMP signaling during adult muscle regeneration

机译：分化抑制基因敲除小鼠中骨骼肌修复的效率低下表明成年肌肉再生过程中BMP信号传导的关键作用

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The bone morphogenetic protein (BMP) pathway is known to be involved in limb myogenesis during development, but whether it is involved in postnatal muscle regeneration is unclear. We have found that adult inhibitor of differentiation (Id)-mutant (Id1+/-Id3-/-) mice display delayed and reduced skeletal muscle regeneration after injury compared with either wild-type littermates or Id3-null mice. Immunoblotting of wild-type muscle lysates revealed that, not only were Id1 and Id3 highly upregulated within 24 h after injury, but other upstream components of the BMP pathway were as well, including the BMP receptor type II and phosphorylated Smad1/5/8 (pSmad1/5/8). Inhibition of BMP signaling in injured skeletal muscle by Noggin injection reduced pSmad1/5/8, Id1, and Id3 protein levels. The mouse myoblast-derived cell line C2C12 also expressed Id1, Id3, BMP receptor type II, and pSmad1/5/8 during proliferation, but all were reduced upon differentiation into myotubes. In addition, these cells secreted mature BMP-4, and BMP signaling could be inhibited with exogenous Noggin, causing a reduction in pSmad1/5/8, Id1, and Id3 levels. Confocal immunofluorescence microscopy revealed that activated Pax7+ myoblasts coexpressed nuclear pSmad1/5/8, Id1, and Id3 in injured mouse skeletal muscle sections. Although we did not observe differences in the numbers of quiescent Pax7+ satellite cells in adult uninjured hindlimb muscles, we did observe a significant reduction in the number of proliferating Pax7+ cells in the Id-mutant mice after muscle injury compared with either wild-type or Id3-null mice. These data suggest a model in which BMP signaling regulates Id1 and Id3 in muscle satellite cells, which directs their proper proliferation before terminal myogenic differentiation after skeletal muscle injury in postnatal animals.
机译：骨形态发生蛋白（BMP）途径在发育过程中与肢体肌生成有关，但尚不清楚其是否与产后肌肉再生有关。我们已经发现，与野生型同窝仔或Id3无效的小鼠相比，成年的分化（Id）突变型（Id1 +/- Id3-/-）抑制剂在小鼠受伤后显示延迟和减少的骨骼肌再生。野生型肌肉溶解产物的免疫印迹显示，不仅Id1和Id3在损伤后24小时内高度上调，而且BMP途径的其他上游成分也是如此，包括II型BMP受体和磷酸化的Smad1 / 5/8（ pSmad1 / 5/8）。通过Noggin注射抑制受伤骨骼肌中BMP信号传导可降低pSmad1 / 5/8，Id1和Id3蛋白水平。小鼠成肌细胞衍生的细胞系C2C12在增殖过程中也表达了Id1，Id3，BMP受体II型和pSmad1 / 5/8，但在分化成肌管后均降低了。此外，这些细胞分泌成熟的BMP-4，并且外源Noggin可以抑制BMP信号传导，从而导致pSmad1 / 5/8，Id1和Id3水平降低。共聚焦免疫荧光显微镜检查显示，活化的Pax7 +成肌细胞在受伤的小鼠骨骼肌切片中共表达核pSmad1 / 5/8，Id1和Id3。尽管我们未观察到成年未受伤后肢肌肉中静态Pax7 +卫星细胞数量的差异，但我们确实观察到与野生型或Id3相比，Id突变小鼠肌肉损伤后增殖的Pax7 +细胞数量显着减少。 -空小鼠。这些数据提出了一种模型，其中BMP信号调节肌肉卫星细胞中的Id1和Id3，从而指导它们在骨骼肌损伤后的终末成肌分化之前的适当增殖。

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