Sarcopenia as a Disorder of Skeletal Muscle Homeostasis: A Five-Pillar Translational Framework Linking Mechanisms, Diagnosis, and Treatment

Abstract

Sarcopenia is a progressive skeletal muscle disorder in which clinically relevant muscle failure is expressed primarily as reduced muscle strength, with low muscle quantity or quality used to confirm the diagnosis and impaired physical performance indicating greater severity in the EWGSOP2 (European Working Group on Sarcopenia in Older People 2) framework. This narrative review first defines the clinical phenotype and its current diagnostic operationalization and then uses an author-proposed five-pillar framework: energy, structure, regeneration, neuromuscular control, and systemic communication, to organize the interacting biological mechanisms that may generate that phenotype. The framework is intended as a translational heuristic rather than a validated classification and is positioned within broader geroscience and hallmarks-of-ageing concepts. Particular emphasis is placed on the distinction between muscle mass, strength, power, and physical performance; context-dependent mTORC1 signaling; the limited specificity of candidate biomarkers; and the uncertain causal direction of several mechanistic associations. Resistance exercise and adequate energy and protein intake remain the foundations of management, whereas pharmacological and regenerative strategies have not yet demonstrated sufficiently consistent improvements in patient-relevant functional outcomes to replace these interventions. Linking biological mechanisms to measurable muscle failure may improve interpretation of current evidence and help define priorities for future mechanistic and clinical studies.