Ginsenoside Rg5 improves exercise performance and alleviates exercise-induced fatigue by enhancing mitochondrial function

Abstract

Red ginseng is widely recognized for its anti-fatigue properties, yet the underlying mechanisms remain unclear. Ginsenoside Rg5, a major saponin in red ginseng, was investigated for its role in regulating mitochondrial bioenergetics. Notably, label-free quantitative proteomics revealed that Rg5 selectively upregulated 11 core subunits of mitochondrial respiratory chain complex I. In L-02 hepatocytes, Rg5 significantly enhanced mitochondrial function, as evidenced by increased mitochondrial membrane potential, ATP production, mitochondrial DNA copy number, as well as enzymatic activities of complexes I and II. This effect was accompanied by activation of the LKB1/PGC-1α/TFAM signaling axis, indicating stimulation of mitochondrial biogenesis. In vivo, Rg5 administration markedly prolonged exhaustion time in forced swimming and treadmill tests and improved motor coordination in the rotarod. These functional improvements were associated with elevated ATP levels in the gastrocnemius muscle, liver, and heart, along with increased expression of multiple complex I subunits and enhanced mitochondrial biogenesis. In addition, multiple fatigue-related serum biochemical parameters were significantly improved. Collectively, this study suggests that Rg5 may be associated with the upregulation of key subunits of Complex I and the activation of mitochondrial biogenesis-related processes; these changes appear to collectively lead to enhanced mitochondrial ATP production and contribute to fatigue relief. These findings identify Rg5 as a potential mitochondrial modulator of exercise endurance and support its potential as a natural intervention for fatigue management.