Sarcopenia beyond muscle: endocrine–metabolic regulation and inter-tissue crosstalk across the muscle–tendon unit

Abstract

Sarcopenia is characterized by a progressive loss of muscle strength and physical performance that frequently exceeds the decline predicted by muscle mass alone. This discrepancy indicates that functional deterioration is shaped not only by the force-generating capacity of skeletal muscle, but also by the tissues responsible for transmitting and integrating that force. In this Review, we examine sarcopenia through the biology of the muscle-tendon unit, encompassing skeletal muscle, tendon, and their specialized interface. We discuss how systemic aging processes, including metabolic dysfunction, inflammaging, and vascular insufficiency, produce tissue-specific and potentially asynchronous effects on muscle contractile capacity, tendon matrix remodeling, and myotendinous junction (MTJ) integrity. Much of the evidence for tendon and MTJ remodeling derives from physiological aging and experimental models, whereas their characteristic phenotypes in clinically defined sarcopenia remain insufficiently characterized. Since muscle, the MTJ, and tendon form a serial force-transmission pathway, differential remodeling across these components may create a mismatch between force-generating and force-transmitting capacities. We further evaluate the strength of evidence for inter-tissue communication, distinguishing experimentally supported muscle-to-tendon regulation from emerging tendon-to-muscle effects demonstrated primarily in co-culture, conditioned-medium, and engineered-interface systems. Particular emphasis is placed on the myotendinous junction as a structurally specialized interface where mechanical forces, extracellular matrix organization, and local signaling converge. Age-related disruption of this interface may reduce force-transfer efficiency and magnify the functional consequences of muscle weakness. Finally, we consider how the muscle–tendon unit framework may refine exercise prescription, functional phenotyping, and the evaluation of future tissue-specific interventions while remaining complementary to established diagnostic criteria and current exercise-based management. Together, these observations identify impaired coordination across the muscle–tendon unit as a potentially important contributor to loss of strength and physical performance in sarcopenia.