Ursolic Acid Induces Beneficial Changes in Skeletal Muscle mRNA Expression and Increases Exercise Participation and Performance in Dogs with Age-Related Muscle Atrophy

Simple Summary Dogs often experience a significant deterioration in skeletal muscle health and activity when they become older, ill, or injured. Here, we sought to identify a new nutritional approach to maintaining healthy skeletal muscle in dogs. To this end, we developed a novel canine dietary supplement containing ursolic acid, a natural dietary compound that has been shown to be beneficial for skeletal muscle health in non-canine species. We found that dietary supplementation with ursolic acid was safe and well tolerated by dogs. In addition, we found that dietary supplementation with ursolic acid generated numerous beneficial molecular changes in skeletal muscle of older dogs, which was associated with significant improvements in exercise participation and performance. These results identify a new nutritional approach to maintaining skeletal muscle health and activity in dogs.Abstract Muscle atrophy and weakness are prevalent and debilitating conditions in dogs that cannot be reliably prevented or treated by current approaches. In non-canine species, the natural dietary compound ursolic acid inhibits molecular mechanisms of muscle atrophy, leading to improvements in muscle health. To begin to translate ursolic acid to canine health, we developed a novel ursolic acid dietary supplement for dogs and confirmed its safety and tolerability in dogs. We then conducted a randomized, placebo-controlled, proof-of-concept efficacy study in older beagles with age-related muscle atrophy, also known as sarcopenia. Animals received placebo or ursolic acid dietary supplements once a day for 60 days. To assess the study's primary outcome, we biopsied the quadriceps muscle and quantified atrophy-associated mRNA expression. Additionally, to determine whether the molecular effects of ursolic acid might have functional correlates consistent with improvements in muscle health, we assessed secondary outcomes of exercise participation and T-maze performance. Importantly, in canine skeletal muscle, ursolic acid inhibited numerous mRNA expression changes that are known to promote muscle atrophy and weakness. Furthermore, ursolic acid significantly improved exercise participation and T-maze performance. These findings identify ursolic acid as a natural dietary compound that inhibits molecular mechanisms of muscle atrophy and improves functional performance in dogs.