Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression
Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression
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DOI：
10.1096/fj.03-0610com
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发表时间：
2004-01-01
期刊：
影响因子：
4.8
通讯作者：
Goldberg, AL
中科院分区：
文献类型：
--
作者：
Lecker, SH;Jagoe, RT;Goldberg, AL
骨骼肌萎缩是对饥饿和许多系统性疾病（包括糖尿病、癌症和肾衰竭）的虚弱反应。我们曾提出，在这些不同状态下，一组共同的转录适应导致了肌肉质量的损失。为了验证这一假设，我们使用cDNA微阵列来比较不同原因引起的肌肉萎缩中特定mrna含量的变化。我们比较了禁食小鼠、癌症恶病质大鼠、链脲霉素诱导的糖尿病大鼠、肾大部切除引起的尿毒症大鼠和成对喂养的对照大鼠的肌肉。尽管bbbb90 %的mrna含量没有改变，包括肌原纤维装置的mrna含量，但我们发现在这四种分解代谢状态下，肌肉中有一组共同的基因（称为atroggins）被诱导或抑制。在强烈诱导的基因中，有许多参与蛋白质降解的基因，包括多泛素、Ub融合蛋白、Ub连接酶atrogin-1/MAFbx和MuRF-1、20S蛋白酶体及其19S调节因子的多个亚基（但不是全部）和组织蛋白酶l。许多ATP生成和糖酵解后期步骤所需的基因被下调，许多细胞外基质蛋白的转录本也被下调。一些先前未涉及肌肉萎缩的基因（脂素、金属硫蛋白、AMP脱氨酶、RNA解旋酶相关蛋白、TG相互作用因子）显著上调，一些生长相关mrna下调（P311、JUN、IGF-1-BP5）。因此，不同类型的肌肉萎缩有一个共同的转录程序，在许多全身性疾病中被激活。
Skeletal muscle atrophy is a debilitating response to starvation and many systemic diseases including diabetes, cancer, and renal failure. We had proposed that a common set of transcriptional adaptations underlie the loss of muscle mass in these different states. To test this hypothesis, we used cDNA microarrays to compare the changes in content of specific mRNAs in muscles atrophying from different causes. We compared muscles from fasted mice, from rats with cancer cachexia, streptozotocin-induced diabetes mellitus, uremia induced by subtotal nephrectomy, and from pair-fed control rats. Although the content of >90% of mRNAs did not change, including those for the myofibrillar apparatus, we found a common set of genes (termed atrogins) that were induced or suppressed in muscles in these four catabolic states. Among the strongly induced genes were many involved in protein degradation, including polyubiquitins, Ub fusion proteins, the Ub ligases atrogin-1/MAFbx and MuRF-1, multiple but not all subunits of the 20S proteasome and its 19S regulator, and cathepsin L. Many genes required for ATP production and late steps in glycolysis were down-regulated, as were many transcripts for extracellular matrix proteins. Some genes not previously implicated in muscle atrophy were dramatically up-regulated (lipin, metallothionein, AMP deaminase, RNA helicase-related protein, TG interacting factor) and several growth-related mRNAs were down-regulated (P311, JUN, IGF-1-BP5). Thus, different types of muscle atrophy share a common transcriptional program that is activated in many systemic diseases.