GABA Prevents Sarcopenia by Regulation of Muscle Protein Degradation and Inflammaging in 23‐ to 25‐Month‐Old Female Mice

Abstract

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.