A mechanistic, multiscale kinetic model of leucine-mediated signaling and protein metabolism in human skeletal muscle — built from published experimental data and validated through global sensitivity analysis and virtual population simulations — found that no single age-related impairment reproduces the blunted muscle protein synthesis (MPS) response seen in older adults. Anabolic resistance emerged only when multiple dysregulations in nutrient sensing and intracellular signaling operated simultaneously. Sensitivity analyses identified intracellular signaling processes controlling MPS as the dominant drivers of net protein balance, distinguishing anabolic-sensitive from anabolic-resistant phenotypes. Restoring MPS required coordinated, multi-target therapeutic strategies rather than any single intervention.
This is a conceptually important finding that reframes decades of reductionist sarcopenia research. Investigators have long debated whether blunted mTORC1 signaling, reduced amino acid transport, impaired satellite cell activity, or mitochondrial dysfunction is the primary culprit in age-related muscle loss — and single-target trials (leucine supplementation, testosterone, resistance exercise alone) have delivered only modest benefits in older adults. This systems model provides a computational explanation for those clinical disappointments. The study's chief limitation is that it is entirely simulation-based, relying on parameter estimates from heterogeneous published datasets rather than prospectively collected cohort data. Predictions await experimental validation in aged human subjects. Nevertheless, the framework is paradigm-clarifying: it shifts the therapeutic target from a single node to a network, strengthening the rationale for combined nutritional, pharmacological, and exercise strategies in sarcopenia management.
