β-Guanidinopropionic Acid Stimulates Brain Mitochondria Biogenesis and Alters Cognitive Behavior in Nondiseased Mid-Age Mice

β-guanidinopropionic acid (β-GPA) has been used as a nutritional supplement for increasing physical strength and endurance with positive and predictable results. In muscles, it works as a nonadaptive stimulator of mitochondria biogenesis; it also increases lipid metabolism. There are data indicating that β-GPA can be also neuroprotective, but its mechanisms of action in the brain are less understood. We studied the effects of β-GPA on animal behavior and mitochondrial biogenesis in the cortex and midbrain of mid-age healthy mice. We found that even short-term 3-week-long β-GPA treatment increased the mitochondrial DNA (mtDNA) copy number in the cortex and ventral midbrain, as well as the expression of several key antioxidant and metabolic enzymes-indicators of mitochondria proliferation and the activation of Nrf2/ARE signaling cascade. At the same time, β-GPA downregulated the expression of the β-oxidation genes. Administration of β-GPA in mice for 3 weeks improved the animals' physical strength and endurance health, ie, increased their physical strength and endurance and alleviated anxiety. Thus, β-GPA might be considered an adaptogene affecting both the muscle and brain metabolism in mammals.