Altered Primary and Secondary Myogenesis in the Myostatin-Null Mouse
Altered Primary and Secondary Myogenesis in the Myostatin-Null Mouse
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DOI：
10.1089/rej.2010.1065
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发表时间：
2010-12-01
影响因子：
2.6
通讯作者：
Patel, Ketan
中科院分区：
文献类型：
--
作者：
Matsakas, Antonios;Otto, Anthony;Patel, Ketan
骨骼肌纤维的产生主要发生在两个成肌阶段：（1）当成肌细胞增殖并融合以形成初级肌管时的初级（胚胎）肌发生和（2）当成肌细胞的连续波沿着初级肌管的表面融合时的次级（胎儿）肌发生，产生更小和更多次级肌管的群体。这一系列事件决定了纤维数量，并在小鼠的大多数肌肉中在出生时或出生后不久完成。成年肌生长抑制素基因敲除小鼠（MSTZ-/-）相对于野生型（MSTZ +/+）显示出纤维数量和大小的增加，这表明肌肉过多表型的发育起源。本研究的重点是确定在肌肉发生过程中MMPs-/-动物从MMPs +/+分化的哪个点。为了实现这一点，我们专注于趾长伸肌（EDL）的肌肉，并评估初级肌管数在胚胎天（E）13.0和E14.5和次级初级肌管的比例在E18.5。我们发现，初级肌管的数量和大小显着增加，在MMEN-/-小鼠的E14.5和次级到初级肌管的比例增加在E18.5。这种纤维形成速率的增加导致在E18.5时，MIBI-/-小鼠的最终成年纤维数量为87%，而MIBI +/+小鼠仅为73%。我们发现，在E14.5时，这些动物的EDL肌肉中的肌源性干细胞（通过Pax 7表达鉴定）和成肌细胞（通过肌细胞生成素表达鉴定）细胞库中的初始扩增进一步证实了MIBI-/-小鼠中的加速的肌源性程序，然而，随后在E18.5时，两种细胞群相对于MIBI +/+减少。总之，这些数据表明，肌生长抑制素的遗传丢失加速了初级和次级骨骼肌发生的发育生肌程序。
Skeletal muscle fiber generation occurs principally in two myogenic phases: (1) Primary (embryonic) myogenesis when myoblasts proliferate and fuse to form primary myotubes and (2) secondary (fetal) myogenesis when successive waves of myoblasts fuse along the surface of the primary myotubes, giving rise to a population of smaller and more numerous secondary myotubes. This sequence of events determines fiber number and is completed at or soon after birth in most muscles of the mouse. The adult myostatin null mouse (MSTN-/-) displays both an increase in fiber number and size relative to wild type (MSTN+/+), suggesting a developmental origin for the hypermuscular phenotype. The focus of the present study was to determine at which point during myogenesis do MSTN-/- animals diverge from MSTN+/+. To achieve this, we focused on the extensor digitorum longus (EDL) muscle and evaluated primary myotube number at embryonic day (E) 13.0 and E14.5 and secondary to primary myotube ratios at E18.5. We show that primary myotube number and size were significantly increased in the MSTN-/- mice by E14.5 and the secondary to primary myotube ratio increased at E18.5. This increase in the rate of fiber formation resulted in MSTN-/- mice harboring 87% of their final adult fiber number at E18.5, compared to only 73% in MSTN+/+. An accelerated myogenic program in the MSTN-/- mice was further confirmed by our finding of an initial expansion in the myogenic stem cell (identified through Pax7 expression) and myoblast (identified through myogenin expression) cell pools at E14.5 in the EDL muscle of these animals that was, however, followed by a reduction of both populations of cells at E18.5 relative to MSTN+/+. Overall these data suggest that the genetic loss of myostatin accelerates the developmental myogenic program of primary and secondary skeletal myogenesis.