Multifactorial nature of anabolic resistance in ageing skeletal muscle: A systems modelling study

Sarcopenia, the age-related loss of skeletal muscle mass and function, is primarily caused by anabolic resistance, which is the blunted stimulation of muscle protein synthesis (MPS) and impaired suppression of muscle protein breakdown following anabolic stimuli such as feeding. Multiple age-related impairments have been implicated, but none alone explains reduced MPS in older adults, suggesting that anabolic resistance arises from interacting dysregulated processes. Studying these interactions experimentally is challenging, motivating systems approaches. Here, we applied a mechanistic, multiscale kinetic model of leucine-mediated signalling and protein metabolism in human skeletal muscle to study anabolic resistance mechanisms. Parameter values were estimated from published data. Global sensitivity analysis identified key controllers of MPS and net protein balance (NB). Virtual population simulations of MPS responses to amino acid feeding were classified as anabolic sensitive or anabolic resistant. We quantified individual and combined age-related impairments and simulated therapeutic interventions to restore anabolic responsiveness. Sensitivity analyses revealed that intracellular signalling processes controlling MPS dominate NB. Feeding simulations indicated that dysregulation of these processes distinguished anabolic-sensitive from anabolic-resistant phenotypes. No single dysregulated mechanism reproduced age-related reductions in MPS. Instead, anabolic resistance emerged only when multiple impairments operated together. Restoring MPS from multifactorial dysregulation required co-ordinated, multitarget therapeutic strategies. These findings demonstrate that anabolic resistance arises from multiple interacting dysregulations in nutrient sensing and signalling. By quantifying their contributions in a systems framework, this work advances mechanistic understanding of sarcopenia and supports the design of combined interventions to restore muscle protein metabolism in older adults. KEY POINTS: Anabolic resistance is a key contributor to sarcopenia, but no single age-related physiological impairment fully explains the reduced muscle protein synthesis response observed in older adults. Systems modelling identified intracellular signalling processes that directly control muscle protein synthesis as dominant drivers of net protein balance, distinguishing anabolic-sensitive from anabolic-resistant phenotypes. Simulations reveal that anabolic resistance emerges from the combined effects of multiple dysregulated mechanisms rather than from single impairments acting independently. Clinically, interventions targeting single mechanisms are unlikely to fully restore muscle anabolism in older adults, particularly when multiple impairments coexist. Simulations predict combinations of age-related impairments that are most important to address to restore anabolic responsiveness, thereby informing multimodal therapeutic strategies for sarcopenia.