Sarcopenia as a manifestation of systemic energetic failure with ageing.

Abstract

Sarcopenia remains underdiagnosed and undertreated, partly because it continues to be mainly conceptualised as a disorder intrinsic to skeletal muscle. Although current definitions incorporate muscle strength and physical performance, they are not intended to explain the integrated physiological processes that underlie age-related impairment of muscle function. In this Personal View, we propose that sarcopenia is more appropriately understood as a manifestation of systemic energetic failure. In this framework, muscle function is considered an emergent property of integrated physiology that progressively deteriorates as ageing disrupts the coordination among energetic demand (determined by neural activation), the delivery of oxygen and metabolic substrates, their mitochondrial transformation into ATP, and their efficient utilisation. The resulting mismatch between physiological demand and available energy manifests clinically as reduced strength in physical performances, increased fatigability, impaired recovery, and mobility disability. Independent lines of evidence have shown that muscle dysfunction reflects a failure of integrated physiological systems rather than isolated tissue degeneration. First, epidemiological data show that muscle strength is more closely linked to disability and mortality than muscle mass. Second, interventional studies show that increasing muscle mass does not reliably improve function. Third, emerging findings indicate that mitochondrial performance is constrained by upstream physiological processes that regulate oxygen and substrate delivery. Reframing sarcopenia considering the failure of these integrated physiological systems has important clinical implications. Fatigability and recovery can provide early indicators of dysfunction, risk stratification should account for multisystem impairment, and effective interventions should focus on restoring coordinated physiological function rather than targeting muscle tissue recovery alone. This framework should be viewed as a physiological hypothesis that integrates current evidence and generates testable predictions regarding the mechanisms, assessment, and treatment of sarcopenia.