AMPK Activation and Exercise Capacity: Mechanisms, Pharmacological Activators, and Performance Implications

Background: Activation of adenosine monophosphate-activated kinase (AMPK) contributes to numerous beneficial effects including improvement of hyperglycemic states in diabetes, reduction of obesity, attenuation of inflammatory processes, and enhancement of metabolic health. Furthermore, stimulation of AMPK activity has been associated with increased exercise capacity. A landmark study published in ۲۰۰۸ demonstrated that the AMPK activator AICAR increased running capacity in untrained mice, prompting the World Anti-Doping Agency to include certain AMPK activators on the list of prohibited substances. This development raises critical questions regarding whether all AMPK activators should be considered for regulatory restriction or whether performance-enhancing effects are limited to specific compounds and mechanisms. Methods: This comprehensive review synthesizes evidence from pharmacology, exercise physiology, and sports science to examine currently published AMPK-activating drugs, their working mechanisms, and their impact on physical fitness and exercise performance. Pharmacological activators including AICAR, metformin, and novel investigational compounds are critically evaluated. Evidence from preclinical and human studies is systematically reviewed to distinguish between general metabolic benefits and specific performance-enhancing effects. Results: AMPK activators demonstrate heterogeneous effects on exercise capacity, with differential impacts depending on compound characteristics, dosage, and physiological context. AICAR and related compounds show potent performance-enhancing effects in animal models, primarily through enhanced fatty acid oxidation and mitochondrial biogenesis. Metformin and other AMPK activators demonstrate more modest effects on exercise performance, with benefits primarily related to metabolic improvements rather than direct performance enhancement. The mechanisms underlying performance enhancement include increased glucose uptake, fatty acid oxidation, mitochondrial function, and altered substrate utilization during exercise. Conclusion: Not all AMPK activators should be considered equivalent regarding performance-enhancing potential. Current evidence suggests that specific compounds, particularly those with direct effects on skeletal muscle AMPK, may confer meaningful performance benefits. Future research should clarify performance effects of different AMPK activators in humans and inform evidence-based regulatory and therapeutic decisions.

کلیدواژه ها:

AMPK activation ، Exercise capacity ، AICAR ، Metabolic regulation ، Performance enhancement ، Pharmacological activators