-GPA treatment leads to elevated basal metabolic rate and enhanced hypoxic exercise tolerance in mice.

Treatments that increase basal metabolic rate (BMR) and enhance exercise capacity may be useful therapeutic approaches for treating conditions such as type 2 diabetes, obesity, and associated circulatory problems. -guanidinopropionic acid (-GPA) supplementation decreases high-energy phosphate concentrations, such as ATP and phosphocreatine (PCr) resulting in an energetic challenge that is similar to both exercise programs and hypoxic conditions. In this study, we administered -GPA to mice for 2 or 6 weeks, and investigated the effect on muscle energetic status, body and muscle mass, muscle capillarity, BMR, and normoxic and hypoxic exercise tolerance (NET and HET, respectively). Relative [PCr] and PCr/ATP ratios significantly decreased during both treatment times in the -GPA fed mice compared to control mice. Body mass, muscle mass, and muscle fiber size significantly decreased after -GPA treatment, whereas muscle capillarity and BMR were significantly increased in -GPA fed mice. NET significantly decreased in the 2-week treatment, but was not significantly different in the 6-week treatment. HET significantly decreased in 2-week treatment, but in contrast to NET, significantly increased in the 6-week-treated mice compared to control mice. We conclude that -GPA induces a cellular energetic response in skeletal muscle similar to that of chronic environmental hypoxia, and this energetic perturbation leads to elevated BMR and increased hypoxic exercise capacity in the absence of hypoxic acclimation.