Changes in muscle mass and phenotype and the expression of autocrine and systemic growth factors by muscle in response to stretch and overload
Changes in muscle mass and phenotype and the expression of autocrine and systemic growth factors by muscle in response to stretch and overload
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DOI：
10.1046/j.1469-7580.1999.19430323.x
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发表时间：
1999-04-01
影响因子：
2.4
通讯作者：
Goldspink, G
中科院分区：
文献类型：
--
作者：
Goldspink, G
对细胞响应机械刺激的潜在机制（即机械刺激与基因表达之间的联系）的研究代表了形态学中的一个新的重要领域。几种细胞类型（“机械细胞”），例如成骨细胞和成纤维细胞以及平滑肌、心肌和骨骼肌细胞都会被机械应变激活，现在有越来越多的证据表明这涉及细胞骨架。肌肉为研究这种类型的机械转导提供了最好的机会之一，因为可以在体外和体内系统中精确控制和测量由肌肉组织产生和施加于肌肉组织的机械活动。肌肉对功能需求的变化高度敏感。过载会导致肥大，而负载力产生的减少和肌肉在缩短位置的固定会导致萎缩。例如，已经表明，拉伸是产生更多肌动蛋白和肌球蛋白丝以及串联和并联添加新肌节的重要机械信号。在此之前，适当基因的转录上调，其中一些基因（例如肌球蛋白亚型）显着改变肌肉表型。事实上，编码不同分子马达的肌球蛋白重链基因的机械活动诱导的表达转换是组织适应给定类型的身体活动的一种手段。就质量的增加而言，我们的小组已经克隆了由活跃肌肉产生的 IGF-1 剪接变体的 cDNA，该变体似乎是控制局部组织修复、维护和重塑的因素。从其序列可以看出，它是由IGF-I基因通过选择性剪接衍生而来，但具有与肝脏亚型不同的外显子。它在 E 结构域中有一个 52 个碱基插入片段，可改变 3' 端的阅读框。因此，IGF-1的这种剪接变体很可能与存在于肌肉、神经组织和骨骼的间质组织空间中的不同结合蛋白结合。预计这将使其作用局部化，因为它在未结合的形式下不稳定，这一点很重要，因为它的产生不会过度干扰葡萄糖稳态。这种新的生长因子被称为机械生长因子（MGF），以区别于具有全身作用模式的肝脏 IGF。虽然肝脏通常被认为是循环 IGF-1 的来源，但最近的研究表明，在运动过程中，骨骼肌不仅产生大量循环 IGF-1，而且活跃的肌肉组织也利用了大部分产生的 IGF-1。我们克隆了自分泌型和内分泌型 IGF-I，当心肌和骨骼肌超负荷时，这两种 IGF-I 的表达都会上调。研究表明，与正常肌肉相比，即使进行拉伸和拉伸结合电刺激，在营养不良的 mdx 肌肉中也检测不到 MGF。对于由于缺乏肌营养不良蛋白（X连锁）和层粘连蛋白缺乏（常染色体）而导致的肌营养不良症来说，情况也是如此，因此表明肌营养不良蛋白细胞骨架复合体可能参与了机械转导机制。当该复合体有缺陷时，局部修复所需的必要的全身生长因子和自分泌 IGF-I 生长因子就不会产生，随后的细胞死亡会导致肌肉质量逐渐丧失。局部产生的 IGF-1 的发现似乎提供了机械刺激和基因表达激活之间的联系。
The study of the underlying mechanisms by which cells respond to mechanical stimuli, i.e. the link between the mechanical stimulus and gene expression, represents a new and important area in the morphological sciences. Several cell types ('mechanocytes'), e.g. osteoblasts and fibroblasts as well as smooth, cardiac and skeletal muscle cells are activated by mechanical strain and there is now mounting evidence that this involves the cytoskeleton. Muscle offers one of the best opportunities for studying this type of mechanotransduction as the mechanical activity generated by and imposed upon muscle tissue can be accurately controlled and measured in both in vitro and in vivo systems. Muscle is highly responsive to changes in functional demands. Overload leads to hypertrophy, whilst decreased load force generation and immobilisation with the muscle in the shortened position leads to atrophy. For instance it has been shown that stretch is an important mechanical signal for the production of more actin and myosin filaments and the addition of new sarcomeres in series and in parallel. This is preceded by upregulation of transcription of the appropriate genes some of which such as the myosin isoforms markedly change the muscle phenotype. Indeed, the switch in the expression induced by mechanical activity of myosin heavy chain genes which encode different molecular motors is a means via which the tissue adapts to a given type of physical activity. As far as increase in mass is concerned, our group have cloned the cDNA of a splice variant of IGF-1 that is produced by active muscle that appears to be the factor that controls local tissue repair, maintenance and remodelling. From its sequence it can be seen that it is derived from the IGF-I gene by alternative splicing but it has different exons to the liver isoforms. It has a 52 base insert in the E domain which alters the reading frame of the 3' end. Therefore, this splice variant of IGF-1 is likely to bind to a different binding protein which exists in the interstitial tissue spaces of muscle, neuronal tissue and bone. This would be expected to localise its action as it would be unstable in the unbound form which is important as its production would not disturb the glucose homeostasis unduly. This new growth factor has been called mechano growth factor (MGF) to distinguish it from the liver IGFs which have a systemic mode of action. Although the liver is usually thought of as the source of circulating IGF-I, it has recently been shown that during exercise skeletal muscle not only produces much of the circulating IGF-1 but active musculature also utilises most of the IGF-1 produced. We have cloned both an autocrine and endocrine IGF-I, both of which are upregulated in cardiac as well as skeletal muscle when subjected to overload. It has been shown that, in contrast to normal muscle, MGF is not detectable in dystrophic mdx muscles even when subjected to stretch and stretch combined with electrical stimulation. This is true for muscular dystrophies that are due to the lack of dystrophin (X-linked) and due to a laminin deficiency (autosomal), thus indicating that the dystrophin cytoskeletal complex may be involved in the mechanotransduction mechanism. When this complex is defective the necessary systemic as well as autocrine IGF-I growth factors required for local repair are not produced and the ensuing cell death results in progressive loss of muscle mass. The discovery of the locally produced IGF-1 appears to provide the link between the mechanical stimulus and the activation of gene expression.