In Vitro Modeling of Sarcopenia-Related Pathology and Exercise-Associated Adaptations: Integration with In Silico Approaches

Sarcopenia is a progressive and generalized skeletal muscle disorder characterized primarily by reduced muscle strength, with low muscle quantity or quality confirming the diagnosis and poor physical performance indicating greater severity. Although human studies and animal models remain essential, their use is constrained by ethical considerations, inter-individual variability, species-specific differences, cost, and the difficulty of isolating individual mechanisms within whole-body systems. This review critically evaluates in vitro models that reproduce selected sarcopenia-related pathological phenotypes, experimental approaches for studying exercise-associated adaptations, and in silico methods for translational benchmarking. We compare myogenic cell cultures, three-dimensional engineered muscle tissues, senescence-inducing systems, and microphysiological platforms according to the phenotypes modeled, principal endpoints, strengths, and limitations. We then assess electrical pulse stimulation, mechanical stretch, and pathway-targeted pharmacological probes as reductionist tools for examining contraction-associated, load-sensitive, humoral, and metabolic responses rather than reproducing whole-body exercise. Finally, we discuss how multi-omics profiling, machine learning, deep learning, public transcriptomic datasets, and cell-type-aware analyses can benchmark in vitro signatures against in vivo data while accounting for batch effects, dataset heterogeneity, cell-composition confounding, overfitting, interpretability, and external validation. Integrating experimentally validated findings with clearly identified hypothesis-generating observations may improve model selection, reduce reliance on animal experiments where appropriate, and accelerate the development of interventions to preserve skeletal muscle function during aging.