Short-chain fatty acids enhance muscle mass and function through the activation of mTOR signalling pathways in sarcopenic mice.

IF 8.9 1区 医学 Journal of Cachexia, Sarcopenia and Muscle Pub Date : 2024-10-31 DOI:10.1002/jcsm.13573
Chaoran Liu, Pui Yan Wong, Qianjin Wang, Hei Yuet Wong, Tao Huang, Can Cui, Ning Zhang, Wing Hoi Cheung, Ronald Man Yeung Wong
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Abstract

Background: Sarcopenia is a prevalent muscle disorder in old people leading to higher fracture rate, mortality, and other adverse clinical outcomes. Evidence indicates that short-chain fatty acids (SCFAs), which are beneficial gut microbial metabolites, were reduced in old people with sarcopenia. This study aimed to determine whether the use of SCFAs as a supplement can be a therapeutic strategy of sarcopenia in a pre-clinical model.

Methods: Seven-month-old pre-sarcopenic senescent accelerated mouse prone 8 (SAMP8) mice received daily SCFAs cocktail (acetate, butyrate, and propionate) for 3 months. Age-matched senescence accelerated mouse resistant 1 (SAMR1) and SAMP8 mice receiving sodium-matched drinking water were control groups. The gut microbiota composition analysis of aged mice with or without sarcopenia was conducted by 16S rDNA sequencing. Gut barrier-related proteins and lipopolysaccharide (LPS) concentration were biomarkers of gut permeability. Colon inflammation levels, circulatory SCFAs concentration, muscle quality, function, and underlying pathways were detected by cell number counting, RT-qPCR, gas chromatography-mass spectrometry, measurements of muscle wet weight and grip strength, ex vivo functional test, treadmill endurance test, transcriptomic sequencing, morphological and immunofluorescent staining, as well as western blot. To investigate the role of mTOR signalling pathways in SCFAs treatment, C2C12 myotubes were treated with rapamycin.

Results: Aged SAMP8 mice had different microbiota composition, and lower serum butyric acid compared with SAMR1 mice (P < 0.05). SCFAs treatment reversed the increment of colon inflammation (2.8-fold lower of il-1β) and gut barrier permeability (1.7-fold lower of LPS) in SAMP8 mice. Increased muscle mass, myofibre cross-sectional area, grip strength, twitch and tetanic force were found in SCFAs-treated mice compared with control SAMP8 mice (P < 0.05). Anti-fatigue capacity (1.6-fold) and muscle glycogen (2-fold) also improved after SCFAs treatment (P < 0.05). Transcriptomic analysis showed that AMPK, insulin, and mTOR pathways were involved in SCFAs treatment (P < 0.05). Regulation of AKT/mTOR/S6K1 and AMPK/PGC1α pathways were found. SCFAs attenuated fat infiltration and improved mitochondria biogenesis of atrophic muscle. In vitro studies indicated that SCFAs inhibited FoxO3a/Atrogin1 and activated mTOR pathways to improve myotube growth (P < 0.05), and rapamycin attenuated the effect of SCFAs through the inhibition of mTOR pathways.

Conclusions: This study demonstrated that bacterial metabolites SCFAs could attenuate age-related muscle loss and dysfunction, and protein synthesis-related mTOR signalling pathways were involved both in vivo and in vitro.

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短链脂肪酸通过激活肌肉疏松小鼠的 mTOR 信号通路提高肌肉质量和功能。
背景:肌肉疏松症是一种常见的老年人肌肉疾病,会导致较高的骨折率、死亡率和其他不良临床结果。有证据表明,患有肌肉疏松症的老年人体内有益的肠道微生物代谢产物短链脂肪酸(SCFAs)会减少。本研究旨在确定在临床前模型中使用 SCFAs 作为补充剂是否可作为肌肉疏松症的治疗策略:方法:7 个月大的前肌肉疏松性衰老加速小鼠易感基因 8(SAMP8)小鼠每天接受 SCFAs 鸡尾酒(乙酸盐、丁酸盐和丙酸盐)治疗,为期 3 个月。与年龄相匹配的衰老加速小鼠抗性1(SAMR1)和SAMP8小鼠接受与钠匹配的饮用水作为对照组。通过 16S rDNA 测序分析了患有或未患有肌肉疏松症的老年小鼠的肠道微生物群组成。肠道屏障相关蛋白和脂多糖(LPS)浓度是肠道通透性的生物标志物。通过细胞数量计数、RT-qPCR、气相色谱-质谱、肌肉湿重和握力测量、体外功能测试、跑步机耐力测试、转录组测序、形态学和免疫荧光染色以及 Western 印迹,检测了结肠炎症水平、循环 SCFAs 浓度、肌肉质量、功能和潜在通路。为了研究mTOR信号通路在SCFAs治疗中的作用,用雷帕霉素处理C2C12肌管:结果:与 SAMR1 小鼠相比,老年 SAMP8 小鼠的微生物群组成不同,血清丁酸含量也较低(P 结论:SAMP8 小鼠的血清丁酸含量低于 SAMR1 小鼠:本研究表明,细菌代谢产物 SCFAs 可减轻与年龄相关的肌肉损失和功能障碍,而且体内和体外均涉及与蛋白质合成相关的 mTOR 信号通路。
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来源期刊
Journal of Cachexia, Sarcopenia and Muscle
Journal of Cachexia, Sarcopenia and Muscle Medicine-Orthopedics and Sports Medicine
自引率
12.40%
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期刊介绍: The Journal of Cachexia, Sarcopenia, and Muscle is a prestigious, peer-reviewed international publication committed to disseminating research and clinical insights pertaining to cachexia, sarcopenia, body composition, and the physiological and pathophysiological alterations occurring throughout the lifespan and in various illnesses across the spectrum of life sciences. This journal serves as a valuable resource for physicians, biochemists, biologists, dieticians, pharmacologists, and students alike.
期刊最新文献
Short-chain fatty acids enhance muscle mass and function through the activation of mTOR signalling pathways in sarcopenic mice. Sucla2 Knock-Out in Skeletal Muscle Yields Mouse Model of Mitochondrial Myopathy With Muscle Type-Specific Phenotypes. Prognostic Impact and Prevalence of Cachexia in Patients With Heart Failure: A Systematic Review and Meta-Analysis. The Impact of SGLT1 Inhibition on Frailty and Sarcopenia: A Mediation Mendelian Randomization Study. Associations of Serum Lipid Traits With Fracture and Osteoporosis: A Prospective Cohort Study From the UK Biobank.
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