Spatially distinct ECM-producing fibroblasts and myonuclei orchestrate early adaptation to mechanical loading in the human muscle-tendon unit

We provide the first high-resolution, in vivo single-nucleus map of the acute human muscle-tendon response to mechanical loading. Within 4 hours of resistance exercise, spatially distinct tendon fibroblasts and myonuclei activate coordinated extracellular matrix programs. Interfascicular fibroblasts upregulate PRG4 and VCAN in the tendon, while myonuclei at the myotendinous junction induce COL22A1 and LAMA2. These findings reveal a new principle of human mechanobiology, where exercise rapidly engages niche-specific programs to initiate extracellular matrix adaptation.