Polygonatum sibiricum polysaccharide ameliorates skeletal muscle aging and mitochondrial dysfunction via PI3K/Akt/mTOR signaling pathway.

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL Phytomedicine Pub Date : 2024-12-09 DOI:10.1016/j.phymed.2024.156316

Yang Li, Zhongyuan Liu, Hongyu Yan, Tianle Zhou, Liming Zheng, Feng Wen, Guanghui Guo, Zhiwen Zhang

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Abstract

Background: Sarcopenia is currently a life-threatening disease for the elderly. Polygonatum sibiricum polysaccharide (PSP) has anti-oxidative stress and anti-inflammatory effects. However, the effects of PSP on skeletal muscle aging, myoblast differentiation and mitochondrial dysfunction through PI3K/Akt/mTOR signaling pathway has not been explored.

Purpose: To explore the effects and related mechanisms of PSP on muscle aging, myoblast differentiation and mitochondrial dysfunction.

Methods: The chemical components of Polygonatum sibiricum were determined using the UHPLC-MS/MS method. The common targets and biological pathways between PSP and sarcopenia were investigated by network pharmacology analysis. In vitro C2C12 cells experiments were performed to reveal the effects of PSP on muscle aging, myotube differentiation, and mitochondrial damage. In addition, in vivo experiments were designed with the mouse model of D-gal-induced aging to evaluate the ameliorative impact of PSP on the skeletal muscle mass and function.

Results: Polygonatum sibiricum mainly included 466 bioactive components. Polygonatum sibiricum and sarcopenia had 278 common targets by network pharmacology analysis, which were associated with mitochondrial function and PI3K/Akt/mTOR pathway. In vitro experiment indicated that PSP significantly enhanced the viability of C2C12 cells and myotube differentiation by down-regulating p21, p53, p16, MuRF1 and Atrogin-1and up-regulating MyoD, Myogenin, and MyHC. However, the addition of LY294002, PI3K/Akt/mTOR pathway inhibitor, partially reversed the anti-aging and anti-oxidative stress effects of PSP. PSP also significantly improved mitochondrial membrane potential and decreased mitochondrial ROS levels by upregulating the phosphorylation of the PI3K/Akt/mTOR pathway. In vivo experimental data indicated that PSP significantly enhanced muscle strength, endurance, mass of skeletal muscle (quadriceps and gastrocnemius) and cross-sectional area (CSA) of skeletal muscle in D-gal induced aging mice.

Conclusion: PSP exhibits significant ameliorative effects on skeletal muscle aging and atrophy, as well as mitochondrial dysfunction by activating the PI3K/Akt/mTOR signaling pathway. Our study uniquely investigates the effects of PSP on skeletal muscle aging and mitochondrial dysfunction with a specific focus on the PI3K/Akt/mTOR signaling pathway, which highlights the potential of PSP as a novel therapeutic agent for sarcopenia, offering an alternative to current treatment strategies.

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背景：目前，"肌肉疏松症 "是一种威胁老年人生命的疾病。何首乌多糖（PSP）具有抗氧化应激和抗炎作用。目的：探讨何首乌多糖对肌肉衰老、肌母细胞分化和线粒体功能障碍的影响及相关机制：方法：采用超高效液相色谱-质谱/质谱（UHPLC-MS/MS）方法测定何首乌中的化学成分。方法：采用超高效液相色谱-质谱/质谱法测定了何首乌的化学成分，并通过网络药理学分析研究了 PSP 与肌肉疏松症之间的共同靶点和生物通路。体外 C2C12 细胞实验揭示了 PSP 对肌肉衰老、肌管分化和线粒体损伤的影响。此外，还利用 D-gal 诱导的小鼠衰老模型设计了体内实验，以评估 PSP 对骨骼肌质量和功能的改善作用：结果：何首乌主要含有466种生物活性成分。通过网络药理学分析，何首乌与肌肉疏松症有 278 个共同靶点，这些靶点与线粒体功能和 PI3K/Akt/mTOR 通路有关。体外实验表明，PSP 通过下调 p21、p53、p16、MuRF1 和 Atrogin-1，上调 MyoD、Myogenin 和 MyHC，显著增强了 C2C12 细胞的活力和肌管分化。然而，加入 PI3K/Akt/mTOR 通路抑制剂 LY294002 会部分逆转 PSP 的抗衰老和抗氧化应激作用。通过上调 PI3K/Akt/mTOR 通路的磷酸化，PSP 还能明显改善线粒体膜电位并降低线粒体 ROS 水平。体内实验数据表明，PSP 能显著增强 D-gal 诱导的衰老小鼠的肌力、耐力、骨骼肌（股四头肌和腓肠肌）质量和骨骼肌横截面积（CSA）：结论：PSP 通过激活 PI3K/Akt/mTOR 信号通路，对骨骼肌衰老和萎缩以及线粒体功能障碍有明显的改善作用。我们的研究独特地探讨了 PSP 对骨骼肌衰老和线粒体功能障碍的影响，并特别关注 PI3K/Akt/mTOR 信号通路，这凸显了 PSP 作为治疗肌肉疏松症的新型药物的潜力，为当前的治疗策略提供了一种替代方案。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.