Mozaffar Tahseen, Haddad Fadia, Zeng Ming, Zhang Li Ying, Adams Greg R, Baldwin Kenneth M
Department of Neurology, University of California, Irvine, 101 City Drive South, Building 22C, Route 13, Orange, California 92868, USA.
Muscle Nerve. 2007 Jan;35(1):55-65. doi: 10.1002/mus.20647.
Muscle denervation and concomitant high-dose dexamethasone treatment in rodents produces characteristic pathologic features of severe muscle atrophy and selective myosin heavy filament (MyHC) depletion, identical to those seen in acute quadriplegic myopathy (AQM), also known as critical illness myopathy. We tested the hypothesis that defective pre-translational processes contribute to the atrophy and selective MyHC depletion in this model. We examined the effects of combined glucocorticoid-denervation treatment on MyHC and actin mRNA populations; we also studied mRNA expression of the myogenic regulatory factors (MRFs), primary transcription factors for MyHC. Adult female rats were subjected to proximal sciatic denervation followed by high-dose dexamethasone (DD) treatment (5 mg/kg body weight daily) for 7 days. Disease controls included rats treated with denervation alone (DN) or dexamethasone alone (DX). At 1 week the plantaris atrophied by approximately 42% in DD muscles. DD treatment resulted in selective MyHC protein depletion; actin protein concentration was not significantly changed. Despite an increase in total RNA concentration in DN and DD muscles, MyHC and actin mRNA concentrations were significantly decreased in these muscles. MyHC mRNA showed a significantly more extensive depletion relative to actin mRNA in DD muscles. Glucocorticoid treatment did not influence a denervation-induced increase in the mRNA expression of the MRFs. We conclude that a deleterious interaction between glucocorticoid and denervation treatments in skeletal muscle is responsible for pre-translational defects that reduce actin and MyHC mRNA substrates in a disproportionate fashion. The resultant selective MyHC depletion contributes to the severe muscle atrophy.
在啮齿动物中，肌肉去神经支配并同时给予高剂量地塞米松治疗会产生严重肌肉萎缩和选择性肌球蛋白重链（MyHC）缺失的特征性病理特征，这与急性四肢瘫性肌病（AQM，也称为危重病性肌病）中所见的特征相同。我们检验了一个假设，即翻译前过程缺陷导致了该模型中的肌肉萎缩和选择性MyHC缺失。我们研究了糖皮质激素 - 去神经支配联合治疗对MyHC和肌动蛋白mRNA水平的影响；我们还研究了生肌调节因子（MRFs）的mRNA表达，MRFs是MyHC的主要转录因子。成年雌性大鼠接受坐骨神经近端去神经支配，随后给予高剂量地塞米松（DD）治疗（每日5mg/kg体重），持续7天。疾病对照组包括仅接受去神经支配治疗（DN）或仅接受地塞米松治疗（DX）的大鼠。1周时，DD组肌肉中比目鱼肌萎缩约42%。DD治疗导致选择性MyHC蛋白缺失；肌动蛋白蛋白浓度无显著变化。尽管DN组和DD组肌肉中总RNA浓度增加，但这些肌肉中的MyHC和肌动蛋白mRNA浓度显著降低。在DD组肌肉中，MyHC mRNA相对于肌动蛋白mRNA的缺失更为广泛。糖皮质激素治疗并未影响去神经支配诱导的MRFs mRNA表达增加。我们得出结论，骨骼肌中糖皮质激素和去神经支配治疗之间的有害相互作用导致了翻译前缺陷，以不成比例的方式减少了肌动蛋白和MyHC mRNA底物。由此产生的选择性MyHC缺失导致了严重的肌肉萎缩。
