Atractylodes macrocephala Koidz. water extract alleviates exercise-induced fatigue by activating mitochondrial biogenesis via the PGC-1α/NRF1/TFAM axis.

In Traditional Chinese Medicine (TCM), Atractylodes macrocephala Koidz. (Baizhu) is a fundamental herb for fortifying the spleen and replenishing qi, specifically used to treat syndromes characterized by weakness, and poor appetite due to spleen qi deficiency. Despite its long-standing use, the scientific basis for its anti-fatigue effect remains unclear. This study aimed to systematically evaluate the anti-peripheral fatigue activity of AMWE and elucidate its underlying mechanisms, thereby providing a scientific basis for its development as a functional food ingredient. A mouse model of peripheral fatigue was established over 33 days using forced swimming combined with intermittent fasting. During this period, mice were administered AMWE at doses of 0.75-3.0 g/kg body weight. The chemical composition of AMWE was characterized, and its effects on exercise performance, metabolic markers, muscle histology, and mitochondrial function were assessed. AMWE primarily contained 23.84 % polysaccharides (composed of 62.20 % glucose), 2.44 % Atractylenolide II, and 7.22 % Atractylenolide III. Treatment with AMWE improved physical condition, enhanced grip strength and exercise endurance, and increased liver and muscle glycogen storage. It also reduced anaerobic metabolites such as lactic acid (LA), lactate dehydrogenase (LDH), and blood urea nitrogen (BUN). AMWE ameliorated damage to the gastrocnemius and soleus muscles and elevated blood amino acid levels. Importantly, AMWE up-regulated the mRNA and protein expression of the PGC-1α/NRF1/TFAM axis, improved mitochondrial function, increased substrate levels of pyruvate (PA) and acetyl-CoA (A-CoA) in the TCA cycle, enhanced the activity of key enzymes pyruvate dehydrogenase (PDH) and citrate synthase (CS), and promoted ATP synthesis. AMWE exhibits significant anti-fatigue activity, which is achieved by promoting mitochondrial biogenesis and enhancing mitochondrial function via activation of the PGC-1α/NRF1/TFAM axis. The underlying mechanism is associated with the activation of the AMPK/SIRT1/PGC-1α signaling axis and the subsequent upregulation of downstream NRF1/TFAM, leading to improved TCA cycle flux and ATP production.