Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases
Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases
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DOI：
10.1096/fj.06-6604com
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发表时间：
2007-01-01
期刊：
影响因子：
4.8
通讯作者：
Goldberg, Alfred L.
中科院分区：
文献类型：
--
作者：
Sacheck, Jennifer M.;Hyatt, Jon-Philippe K.;Goldberg, Alfred L.
我们之前发现了一组常见的基因，称为atrogenes，其表达在系统性消耗状态（禁食、癌症恶病质、肾衰竭、糖尿病）时在肌肉中被协调诱导或抑制。为了确定该转录程序是否在收缩活性丧失引起的萎缩中也起作用，以及atrogene的表达是否与肌肉重量减轻的速度相关，我们使用cDNA微阵列和rt聚合酶链反应分析了大鼠腓肠肌在去神经支配或脊髓分离引起的废用性萎缩期间mRNA的变化。Den或SI后3天，肌肉重量减轻的速度最大，在全身分解代谢状态中发现的萎缩中有78%被诱导或抑制。特别令人感兴趣的是关键的泛素连接酶，萎缩素-1（35- 44倍）和MuRF1（12- 22倍）的大量诱导，以及PGC-1 α和PGC-1 β共激活因子的抑制（15倍）。当萎缩减缓时（第14天），92%的这些萎缩基因的表达恢复到基础水平。在28天，诱导萎缩的转录因子fox01仍然被诱导，这可能是维持“萎缩”状态的重要因素。因此，1)与系统分解代谢状态相关的萎缩和随后的废弃涉及类似的转录适应；2)废用性萎缩经历了与快速萎缩和萎缩肌肉相关的多个阶段，涉及不同的转录模式。
We previously identified a common set of genes, termed atrogenes, whose expression is coordinately induced or suppressed in muscle during systemic wasting states ( fasting, cancer cachexia, renal failure, diabetes). To determine whether this transcriptional program also functions during atrophy resulting from loss of contractile activity and whether atrogene expression correlates with the rate of muscle weight loss, we used cDNA microarrays and RT-polymerase chain reaction to analyze changes in mRNA from rat gastrocnemius during disuse atrophy induced by denervation or spinal cord isolation. Three days after Den or SI, the rate of muscle weight loss was greatest, and 78% of the atrogenes identified during systemic catabolic states were induced or repressed. Of particular interest were the large inductions of key ubiquitin ligases, atrogin-1 ( 35- to 44-fold) and MuRF1 ( 12- to 22-fold), and the suppression of PGC-1 alpha and PGC-1 beta coactivators ( 15-fold). When atrophy slowed ( day 14), the expression of 92% of these atrogenes returned toward basal levels. At 28 days, the atrophy-inducing transcription factor, FoxO1, was still induced and may be important in maintaining the "atrophied" state. Thus, 1) the atrophy associated with systemic catabolic states and following disuse involves similar transcriptional adaptations; and 2) disuse atrophy proceeds through multiple phases corresponding to rapidly atrophying and atrophied muscles that involve distinct transcriptional patterns.