TNF-alpha impairs heart and skeletal muscle protein synthesis by altering translation initiation.
TNF-alpha impairs heart and skeletal muscle protein synthesis by altering translation initiation.
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发表时间：
2002
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通讯作者：
C. Lang;R. Frost;A. Nairn;D. MacLean;T. Vary
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作者：
C. Lang;R. Frost;A. Nairn;D. MacLean;T. Vary
这项研究探讨了注射肿瘤坏死因子-α后抑制骨骼肌和心脏蛋白质合成的可能机制。大鼠植入血管导管后，持续输注肿瘤坏死因子-α24小时，体内测定的腓肠肌(39%)和心脏(25%)的蛋白质合成率下降。肿瘤坏死因子-α诱导的腓肠肌蛋白质合成减少涉及肌原纤维和肌浆蛋白合成的减少。为了确定调控mRNA翻译的潜在机制，我们检测了几种真核细胞起始因子(EIF)和延伸因子(EEFS)。肿瘤坏死因子-α可降低肌肉中eIF-2B的活性(39%)，但不能降低心脏中的活性。这种活性的降低不是由于eIF-2B epsilon含量的减少或eIF-2α的含量和磷酸化状态引起的。经TNF-α处理的大鼠骨骼肌和心脏显示：1)翻译抑制物4E结合蛋白-1(4E-BP1)与eIF-4E的结合增加，2)eIF-4E与eIF-4G相关的eIF-4E减少，以及3)过度磷酸化的4E-BP1的伽马型含量减少。相反，输注肿瘤坏死因子-α并不改变EEF-1α或EEF-2的含量，也不改变EEF-2的磷酸化状态。综上所述，这些数据表明，肿瘤坏死因子-α损害了骨骼肌和心脏蛋白质的合成，至少部分是通过降低与eIF-4E可获得性改变相关的翻译起始障碍而导致的mRNA翻译效率。
This study examined potential mechanisms contributing to the inhibition of protein synthesis in skeletal muscle and heart after administration of tumor necrosis factor (TNF)-alpha. Rats had vascular catheters implanted, and TNF-alpha was infused continuously for 24 h. TNF-alpha decreased in vivo-determined rates of global protein synthesis in gastrocnemius (39%) and heart (25%). The TNF-alpha-induced decrease in protein synthesis in the gastrocnemius involved a reduction in the synthesis of both myofibrillar and sarcoplasmic proteins. To identify potential mechanisms responsible for regulating mRNA translation, we examined several eukaryotic initiation factors (eIFs) and elongation factors (eEFs). TNF-alpha decreased the activity of eIF-2B in muscle (39%) but not in heart. This diminished activity was not caused by a reduction in the content of eIF-2B epsilon or the content and phosphorylation state of eIF-2 alpha. Skeletal muscle and heart from TNF-alpha-treated rats demonstrated 1) an increased binding of the translation repressor 4E-binding protein-1 (4E-BP1) with eIF-4E, 2) a decreased amount of eIF-4E associated with eIF-4G, and 3) a decreased content of the hyperphosphorylated gamma-form of 4E-BP1. In contrast, the infusion of TNF-alpha did not alter the content of eEF-1 alpha or eEF-2, or the phosphorylation state of eEF-2. In summary, these data suggest that TNF-alpha impairs skeletal muscle and heart protein synthesis, at least in part, by decreasing mRNA translational efficiency resulting from an impairment in translation initiation associated with alterations in eIF-4E availability.