Microbial-Derived Exerkines Outperform Creatine Monohydrate in Enhancing Skeletal Muscle Adaptation to Exercise in Mice

We recently demonstrated that the microbial-derived exerkines (MDEs) pipecolic acid and succinate (PAS) prevent disuse-induced skeletal muscle atrophy and preserve muscle function during hindlimb immobilization in mice. Here, we investigated whether PAS also enhances exercise performance and adaptation and compared its effects with creatine monohydrate (CRE), the current gold-standard ergogenic aid for strength and power performance. Mice received vehicle (VEH), CRE, or PAS during a 7-week progressive weighted-wheel-running training protocol. Exercise performance, body composition, and skeletal muscle size and function were assessed at the conclusion of training. Both CRE and PAS enhanced high-intensity exercise performance relative to VEH, increasing running distance and time spent running during the course of the training protocol. Neither CRE nor PAS enhanced lean mass, muscle mass, or soleus myofiber cross-sectional area relative to VEH. However, PAS-treated mice exhibited greater grip strength and ex vivo soleus force production and rate of force development than both VEH and CRE. These findings demonstrate that PAS enhances strength and power adaptations to exercise beyond those achieved with CRE, identifying PAS as a promising exercise supplement and establishing MDEs as a novel class of ergogenic aids.