Abstract The accumulation of advanced glycation end-products (AGEs) may be involved in the mechanism of skeletal muscle atrophy. However, the involvement of the receptor for AGEs (RAGE) axis in microgravity-induced skeletal muscle atrophy has not been investigated. Therefore, the purpose of the present study was to investigate the effect of RAGE inhibition on microgravity-induced skeletal muscle atrophy and the related molecular responses. Male C57BL/6NCr mice subjected to a 1-week hindlimb suspension lead to muscle atrophy in soleus and plantaris but not extensor digitorum longus muscle, accompanied by increases in RAGE expression. However, treatment with a RAGE antagonist (FPS-ZM1, intraperitoneal, 1 mg/kg/day) during hindlimb suspension ameliorated the atrophic responses in soleus muscle. Further, muscle mass inversely correlated with the accumulation of AGEs (methylglyoxal-modified proteins and Ne-(carboxymethyl) lysine-modified proteins) in soleus muscle. The expression of proinflammatory cytokines, tumor necrosis factor-α, interleukin-1β, and interleukin-6 in soleus muscle was enhanced in response to hindlimb suspension, but these changes were attenuated by FPS-ZM1 treatment. Protein ubiquitination and ubiquitin E3 ligase (muscle RING finger 1) expression in soleus muscle were elevated following hindlimb suspension, and these increments were suppressed by FPS-ZM1 treatment. Our findings indicate that the AGE-RAGE axis is upregulated in unloaded atrophied skeletal muscle, and that RAGE inhibition ameliorates microgravity-induced skeletal muscle atrophy by reducing proinflammatory cytokine expression and ubiquitin-proteasome system activation.

中文翻译：

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晚期糖基化终产物受体参与微重力诱导的小鼠骨骼肌萎缩

摘要 晚期糖基化终末产物（AGEs）的积累可能与骨骼肌萎缩的机制有关。然而，尚未研究 AGE 受体 (RAGE) 轴在微重力诱导的骨骼肌萎缩中的作用。因此，本研究的目的是研究 RAGE 抑制对微重力诱导的骨骼肌萎缩的影响及相关分子反应。雄性 C57BL/6NCr 小鼠后肢悬吊 1 周会导致比目鱼肌和足底肌肉萎缩，但不会导致趾长伸肌萎缩，并伴有 RAGE 表达增加。然而，在后肢悬吊期间用 RAGE 拮抗剂（FPS-ZM1，腹膜内，1 mg/kg/天）治疗改善了比目鱼肌的萎缩反应。更多，肌肉质量与比目鱼肌中AGEs（甲基乙二醛修饰蛋白和Ne-（羧甲基）赖氨酸修饰蛋白）的积累呈负相关。后肢悬吊后，比目鱼肌中促炎细胞因子、肿瘤坏死因子-α、白细胞介素-1β 和白细胞介素-6 的表达增强，但这些变化通过 FPS-ZM1 处理减弱。后肢悬吊后，比目鱼肌中的蛋白质泛素化和泛素 E3 连接酶（肌肉无名指 1）表达升高，并且这些增量被 FPS-ZM1 处理抑制。我们的研究结果表明 AGE-RAGE 轴在无负荷的萎缩骨骼肌中上调，