Comprehensive transcriptomic profiling reveals impaired polyamine metabolism as a contributor to age-related muscle decline.

Abstract

Sarcopenia, the age-related decline in skeletal muscle mass and function, profoundly affects skeletal muscle structure and performance. We present a spatial transcriptomic atlas of skeletal muscle from young and aged mice, resolving transcriptional reprogramming across fiber types and tissue compartments. Our analyses reveal alterations in sarcomeric organization, excitation-contraction coupling, oxidative stress responses, and fiber type-specific metabolic rewiring. Conserved molecular signatures across muscles and species highlight Car3 as a potential biomarker of sarcopenia. We also uncover a selective downregulation of polyamine biosynthetic enzymes, leading to reduced spermidine levels in aged muscle. This decline affects muscle-resident populations, as limiting polyamine metabolic flux in both murine and human fibro-adipogenic progenitors (hFAPs) induces aging-like features, including myofibroblast differentiation, extracellular matrix dysregulation, and impaired ability to support myogenesis. Together, our findings reveal spatially organized, fiber type-specific, and polyamine-linked mechanisms of muscle aging and position the polyamine pathway as a promising therapeutic target.