BackgroundSarcopenia is the gradual decrease in skeletal muscle mass, strength and function in elderly individuals. Gamma‐aminobutyric acid (GABA) is a neurotransmitter naturally produced from glutamate by the enzyme glutamic acid decarboxylase. Age‐related decline in GABA is linked to age‐related motor and sensory decline and seems to affect sarcopenia, yet no detailed study has been conducted. In this study, we aimed to investigate the effect of GABA on improving sarcopenia by suppressing muscle protein degradation through supplementing decreased GABA in old mice.MethodsGABA (10 or 30 mg/kg/day) was orally administered daily to young (3 months) and old (21–23 months) C57BL/6 mice for 7 weeks. The body weight and grip strength of the mice were measured weekly at the same time. After sacrificing the mice, the quadriceps and gastrocnemius muscles were excised from their hind limbs, and the spleen and serum were collected. Histological, biochemical and molecular analyses were conducted in various experiments.ResultsThe administration of GABA increased muscle strength (+41%, +70% compared to the aged mouse control group, GABA at doses of 10 or 30 mg/kg/day respectively, p < 0.05) and muscle mass (quadriceps: +28%, +46%; gastrocnemius: +12%, +19%, p < 0.05) in old mice. This increase was accompanied by a cross‐sectional area (CSA) increase in the quadriceps and gastrocnemius muscle (p < 0.05). The administration of GABA increased IGF‐1 levels in serum (p < 0.05), leading to the activation of muscle protein synthesis. We found that GABA inhibits sarcopenia by regulating muscle protein degradation through the activation of Akt/mTOR/FoxO3a signalling pathways. GABA also regulates inflammaging, which is a hallmark of age‐related muscle atrophy. There was a significant increase in the F4/80 + CD11b + total macrophage ratio in gastrocnemius and spleen, especially the M1 macrophage ratio increased in old mice. However, GABA administration was effective in suppressing M1 macrophages (gastrocnemius: −40%, − 53%; spleen: −22%, −26%, p < 0.05). Pro‐inflammatory cytokines such as TNF‐α and IL‐6, primarily secreted by M1 macrophages, are also decreased by treatment with GABA (TNF‐α: −24%, −27%; IL‐6: −45%, −59%, p < 0.05).ConclusionsTogether, this study demonstrates the importance of GABA in maintaining muscle and low‐chronic inflammation during ageing. We suggest that GABA shows potential as a substance that can effectively address sarcopenia and enhance the overall lifespan and well‐being of older individuals.

中文翻译：

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GABA 通过调节 23 至 25 个月大雌性小鼠的肌肉蛋白降解和炎症来预防肌肉减少症


背景肌肉减少症是老年人骨骼肌质量、力量和功能的逐渐下降。γ-氨基丁酸 （GABA） 是一种由谷氨酸通过谷氨酸脱羧酶天然产生的神经递质。GABA 的年龄相关性下降与年龄相关性的运动和感觉下降有关，并且似乎会影响肌肉减少症，但尚未进行详细研究。在这项研究中，我们旨在通过补充降低的老年 GABA 来抑制肌肉蛋白降解，从而研究 GABA 对改善肌肉减少症的影响。方法每天口服 GABA （10 或 30 mg/kg/天） 给年轻 （3 个月） 和老年 （21-23 个月） C57BL/6 小鼠，持续 7 周。每周同时测量小鼠的体重和握力。献祭小鼠后，从其后肢切除股四头肌和腓肠肌，并收集脾脏和血清。在各种实验中进行了组织学、生化和分子分析。结果GABA 的施用增加了老年小鼠的肌肉力量（+41%，+70%，与老年小鼠对照组相比，GABA 的剂量分别为 10 或 30 mg/kg/天，p < 0.05）和肌肉质量（股四头肌：+28%，+46%;腓肠肌：+12%，+19%，p < 0.05）。这种增加伴随着股四头肌和腓肠肌的横截面积 （CSA） 增加 （p < 0.05）。GABA 的给药增加了血清中 IGF-1 水平 （p < 0.05），导致肌肉蛋白质合成的激活。我们发现 GABA 通过激活 Akt/mTOR/FoxO3a 信号通路调节肌肉蛋白降解来抑制肌肉减少症。GABA 还调节炎症，这是与年龄相关的肌肉萎缩的标志。 腓肠肌和脾脏 F4/80 + CD11b + 总巨噬细胞比值显著升高，尤其是老年小鼠 M1 巨噬细胞比值升高。然而，GABA 给药可有效抑制 M1 巨噬细胞 （腓肠肌： -40%， -53%;脾脏： -22%， -26%，p < 0.05）。主要由 M1 巨噬细胞分泌的促炎细胞因子如 TNF-α 和 IL-6 也通过用 GABA 处理而降低（TNF-α：-24%，-27%;IL-6： -45%， -59%， p < 0.05）。结论总之，本研究证明了 GABA 在衰老过程中维持肌肉和低慢性炎症的重要性。我们认为 GABA 显示出作为一种可以有效解决肌肉减少症并提高老年人整体寿命和健康状况的物质的潜力。