Tension to Translation: External to Internal Processes in Muscle Hypertrophy

Skeletal muscle is a highly adaptable tissue that plays a central role in overall health. The dynamic balance between muscle protein synthesis and breakdown governs skeletal muscle mass maintenance. Increased loading and hyperaminoacidemia (via protein ingestion) are positive drivers of skeletal muscle protein accretion, which, when combined, drive a hypertrophic phenotypic adaptation. In contrast, unloading (disuse) results in skeletal muscle atrophy and metabolic dysregulation. Hypertrophy enhances metabolic health and functional capacity, underscoring the importance of understanding the mechanisms that regulate this process. External variables, such as resistance exercise and dietary protein, influence hypertrophy; however, resistance exercise is the primary driver, with protein playing a minor supporting role. Signals from external inputs – loading (resistance exercise) and nutritional manipulation (protein ingestion) – are sensed and transduced into intracellular pathways that promote muscle protein synthesis, yet the precise mechanisms underlying their integration remain incompletely understood. This review summarizes current knowledge on how resistance exercise and dietary protein converge on the intracellular level to regulate skeletal muscle hypertrophy in humans.