Involvement of receptor for advanced glycation end products in microgravity-induced skeletal muscle atrophy in mice
Involvement of receptor for advanced glycation end products in microgravity-induced skeletal muscle atrophy in mice
复制标题
DOI：
10.1016/j.actaastro.2020.07.002
复制
发表时间：
2020-11
影响因子：
3.5
通讯作者：
T. Egawa;K. Kido;Takumi Yokokawa;M. Fujibayashi;K. Goto;Tatsuya Hayashi
中科院分区：
文献类型：
--
作者：
T. Egawa;K. Kido;Takumi Yokokawa;M. Fujibayashi;K. Goto;Tatsuya Hayashi
晚期糖基化终末产物(AGEs)的积聚可能参与了骨骼肌萎缩的机制。然而，AGEs受体(RAGE)轴在微重力诱导的骨骼肌萎缩中的作用尚未被研究。因此，本研究的目的是探讨RAGE抑制对微重力诱导的骨骼肌萎缩的影响及其相关的分子反应。C57BL/6NCr雄性小鼠后肢悬吊1周后，比目鱼肌和足底肌萎缩，趾长伸肌未见萎缩，RAGE表达增加。然而，在后肢悬吊期间使用RAGE拮抗剂(FPS-ZM1，每天1 mg/kg)可改善比目鱼肌的萎缩反应。此外，肌肉质量与比目鱼肌中AGEs(甲基乙二醛修饰蛋白和N-ε-(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症细胞因子、肿瘤坏死因子-α、白介素1β和白介素6的表达增强，但这些变化被FPS-ZM1处理后减弱。后肢悬吊后比目鱼肌蛋白质泛素化和泛素E3连接酶(肌环指1)表达增加，FPS-ZM1可抑制这些增加。我们的发现表明，在非负荷性萎缩的骨骼肌中，AGE-RAGE轴上调，RAGE的抑制通过减少促炎细胞因子的表达和泛素-蛋白酶体系统的激活来改善微重力引起的骨骼肌萎缩。
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 Nε-(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.