Lecker Stewart H, Jagoe R Thomas, Gilbert Alexander, Gomes Marcelo, Baracos Vickie, Bailey James, Price S Russ, Mitch William E, Goldberg Alfred L
Renal Unit, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
FASEB J. 2004 Jan;18(1):39-51. doi: 10.1096/fj.03-0610com.
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.
骨骼肌萎缩是对饥饿以及包括糖尿病、癌症和肾衰竭在内的许多全身性疾病的一种使人衰弱的反应。我们曾提出，一组共同的转录适应性变化是这些不同状态下肌肉质量丧失的基础。为了验证这一假设，我们使用cDNA微阵列来比较因不同原因萎缩的肌肉中特定mRNA含量的变化。我们比较了禁食小鼠、患有癌症恶病质的大鼠、链脲佐菌素诱导的糖尿病大鼠、次全肾切除诱导的尿毒症大鼠以及配对喂养的对照大鼠的肌肉。尽管超过90%的mRNA含量没有变化，包括那些编码肌原纤维装置的mRNA，但我们发现了一组共同的基因（称为萎缩素），在这四种分解代谢状态下，它们在肌肉中被诱导或抑制。在强烈诱导的基因中，有许多参与蛋白质降解，包括多聚泛素、泛素融合蛋白、泛素连接酶萎缩素-1/MAFbx和MuRF-1、20S蛋白酶体及其19S调节因子的多个但并非所有亚基以及组织蛋白酶L。许多ATP生成所需的基因和糖酵解后期步骤的基因被下调，细胞外基质蛋白的许多转录本也被下调。一些先前未涉及肌肉萎缩的基因显著上调（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），一些与生长相关的mRNA被下调（P311、JUN、IGF-1-BP5）。因此，不同类型的肌肉萎缩共享一个在许多全身性疾病中被激活的共同转录程序。
