๐ค Authors: Xiaomin Wang, Liping Zhu, Ruoyutong Du, Ang Li, Na Li, Xiaoying Liu, Yin Zhang, Xiaoqin Liu, Qiong Wang, Chao Han, Chao Qu, Wei Zou, Jing Liu, Yanfu Wang
Cistanche deserticola extract and its active components, echinacoside, ameliorate sarcopenia by activating the IGF-1/PI3K-AKT pathway to modulate ferroptosis.
<p><b>BACKGROUND</b></p><p>Sarcopenia (SP) is characterized by progressive loss of skeletal muscle mass and function, and is a significant health burden in an aging society. Existing therapies have limited effectiveness.
While ferroptosis plays a key role in sarcopenia, its regulatory mechanism remains unclear. As a traditional tonifying Chinese medicine, Cistanche deserticola has antioxidant potential due to its active ingredient, echinacoside (ECH); however, its mechanism of action in sarcopenia remains to be elucidated.</p><p><b>PURPOSE</b></p><p>To investigate the effects of Cistanche deserticola extract (CDE) and ECH on improving sarcopenia, with a focus on elucidating their molecular mechanisms of inhibiting ferroptosis in C2C12 cells by regulating the IGF-1/PI3K-AKT pathway.</p><p><b>METHODS</b></p><p>HPLC/MS was used to quantify the ECH content in CDE; Predicting common targets of ECH and sarcopenia through network pharmacology and verifying binding ability through molecular docking; Construct an in vitro model of muscle atrophy induced by dexamethasone (DEX) and intervene with CDE and low/high concentrations of ECH (l-ECH/H-ECH) to detect cell viability, ferroptosis markers, and pathway molecules; Establish a sarcopenia mouse model in vivo to evaluate skeletal muscle mass, function, and molecular changes; Combining untargeted metabolomics to analyze muscle metabolic profiles.</p><p><b>RESULTS</b></p><p>HPLC/MS showed that the ECH content in CDE was 43.15 ยฑ 0.2 mg/g.
Network pharmacology analysis revealed that ECH shares 217 core targets with sarcopenia, significantly enriched in the IGF-1/PI3K-AKT pathway and ferroptosis regulation. In vitro, CDE and ECH inhibited dexamethasone-induced myotube atrophy in a concentration-dependent manner, and H-ECH effectively replaced CDE; Simultaneously inhibiting ferroptosis and improving mitochondrial function.
In vivo, H-ECH significantly increased muscle fiber cross-sectional area, grip strength, and endurance, and activated the IGF-1/PI3K-AKT pathway to downregulate ferroptosis-promoting genes. Non-targeted metabolomics showed that ECH reversed dexamethasone-induced energy metabolism disorders and ferroptosis-related metabolite (arachidonic acid and glutathione) imbalance, and enriched pathways such as glutathione and arachidonic acid metabolism.
PI3K inhibitors blocked the protective effects of ECH.</p><p><b>CONCLUSIONS</b></p><p>ECH, the main active ingredient of Cistanche deserticola, inhibits ferroptosis in C2C12 cells and reverses skeletal muscle atrophy through concentration-dependent activation of the IGF-1/PI3K-AKT pathway. This study provides new targets and experimental evidence for the treatment of sarcopenia with traditional Chinese medicine.</p>
