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

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 crosssectional 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.