Mice lacking skeletal muscle actin show reduced muscle strength and growth deficits and die during the neonatal period
Mice lacking skeletal muscle actin show reduced muscle strength and growth deficits and die during the neonatal period
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DOI：
10.1128/mcb.22.16.5887-5896.2002
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发表时间：
2002-08-01
影响因子：
5.3
通讯作者：
Lessard, J
中科院分区：
文献类型：
--
作者：
Crawford, K;Flick, R;Lessard, J
高等脊椎动物中的所有四种肌肉肌动蛋白（骨骼肌肌动蛋白、心脏肌动蛋白、血管肌动蛋白和肠肌动蛋白）均显示出不同的表达模式并显示出高度保守的氨基酸序列。虽然假设每种肌肉同肌动蛋白都专门适应其各自的组织，并且它们之间的微小变化具有发育和/或生理相关性，但这些蛋白质的确切功能和发育意义仍然很大程度上未知。为了开始评估这些问题，我们通过同源重组破坏了骨骼肌动蛋白基因。所有缺乏骨骼肌动蛋白的小鼠都会在新生儿早期（第 1 至 9 天）死亡。这些无效动物出生时表现正常，可以呼吸、行走和哺乳，但在 4 天内，它们的体重明显低于正常同窝动物，并且许多出现脊柱侧弯。无效小鼠表现出糖原损失和棕色脂肪减少，这与营养不良导致死亡一致。无效小鼠的新生骨骼肌在大小、纤维类型和超微结构组织方面与野生型小鼠相似。出生时，半合子和纯合子无效动物均显示骨骼肌中心脏和血管肌动蛋白 mRNA 增加，而无效小鼠中不存在骨骼肌动蛋白 mRNA。成年半合子动物后肢肌肉中骨骼肌动蛋白 mRNA 水平升高，但没有明显的表型。与对照同窝小鼠相比，第 2 至 3 天从骨骼肌动蛋白缺陷小鼠分离的趾长伸肌 (EDL) 肌肉显示出力产生显着减少，并且来自半合子动物的 EDL 肌肉显示出中等的力产生。因此，虽然心脏和血管平滑肌肌动蛋白的增加可以部分补偿无效小鼠中骨骼肌动蛋白的缺乏，但这不足以支持足够的骨骼肌生长和/或功能。
All four of the muscle actins (skeletal, cardiac, vascular, and enteric) in higher vertebrates show distinct expression patterns and display highly conserved amino acid sequences. While it is hypothesized that each of the muscle isoactins is specifically adapted to its respective tissue and that the minor variations among them have developmental and/or physiological relevance, the exact functional and developmental significance of these proteins remains largely unknown. In order to begin to assess these issues, we disrupted the skeletal actin gene by homologous recombination. All mice lacking skeletal actin die in the early neonatal period (day 1 to 9). These null animals appear normal at birth and can breathe, walk, and suckle, but within 4 days, they show a markedly lower body weight than normal littermates and many develop scoliosis. Null mice show a loss of glycogen and reduced brown fat that is consistent with malnutrition leading to death. Newborn skeletal muscles from null mice are similar to those of wild-type mice in size, fiber type, and ultrastructural organization. At birth, both hemizygous and homozygous null animals show an increase in cardiac and vascular actin mRNA in skeletal muscle, with no skeletal actin mRNA present in null mice. Adult hemizygous animals show an increased level of skeletal actin mRNA in hind limb muscle but no overt phenotype. Extensor digitorum longus (EDL) muscle isolated from skeletal-actin-deficient mice at day 2 to 3 showed a marked reduction in force production compared to that of control littermates, and EDL muscle from hemizygous animals displayed an intermediate force generation. Thus, while increases in cardiac and vascular smooth-muscle actin can partially compensate for the lack of skeletal actin in null mice, this is not sufficient to support adequate skeletal muscle growth and/or function.