The Role of Mammalian Target of Rapamycin (mTOR) and Adenosine Monophosphate-Activated Protein Kinase (AMPK) Signaling in Skeletal Muscle Hypertrophy: A Literature Review With Implications for Health and Disease.

Maintaining skeletal muscle mass is fundamental not only for strength and mobility but also for metabolic health, disease prevention, and healthy aging. Skeletal muscle functions as a dynamic metabolic organ, and its maintenance depends on the delicate equilibrium between mammalian target of rapamycin (mTOR), which drives anabolic processes, such as protein synthesis and hypertrophy, and adenosine monophosphate-activated protein kinase (AMPK), which promotes catabolic renewal through mitochondrial biogenesis, autophagy, and energy conservation. Sustained mTOR hyperactivation contributes to obesity, insulin resistance, neurodegeneration, and cancer, while AMPK activation counterbalances these effects by restoring cellular energy balance and enhancing metabolic resilience. Thus, optimal muscle and metabolic health depend not on dominance of one pathway, but on the strategic balance between mTOR and AMPK activity. Human trials and meta-analyses show that for individuals engaged in resistance training, a total protein intake of approximately 1.6 g/kg/day effectively maximizes muscle protein synthesis, with diminishing returns beyond that level. Distributing protein evenly across meals enhances anabolic efficiency, about 0.25 g/kg per meal in younger adults and 0.40 g/kg per meal in older adults, which helps overcome age-related anabolic resistance. Protein quality is equally critical: leucine-rich, rapidly absorbed sources such as whey elicit the most robust mTOR activation and muscle-building response. Exercise mode and energy timing further shape this anabolic-catabolic balance. Concurrent endurance and resistance training may attenuate hypertrophy depending on session order, intensity, and training status, whereas intermittent fasting and time-restricted feeding improve body composition and cardiometabolic health when total energy and protein needs are still met. Together, these findings suggest that integrating structured resistance exercise, well-distributed, high-quality protein intake, and periodic AMPK activation through fasting or aerobic training provides a practical framework for sustaining muscle mass, optimizing metabolic function, and promoting longevity.