Satellite cells are the primary stem cell in skeletal muscle, required for postnatal muscle growth and adult muscle regeneration. Satellite cells are activated to proliferate and normally contribute nuclei to growing myofibers in response to hypertrophic stimuli, although considerable growth can occur in the absence of myonuclear accretion through the expansion of the myonuclear domain. Satellite cells reside within an interstitial niche between myofibers and the basal lamina of the extracellular matrix (ECM). The muscle ECM is largely composed of collagens secreted by fibroblasts. We utilized the discrete expression of Pax7 in satellite cells to develop the Pax7-DTA mouse, whereby the use of Cre-lox technology allows for the specific and inducible depletion of satellite cells following tamoxifen-induced expression of diphtheria toxin. Synergist ablation surgery, where removal of synergist muscles places functional overload on the plantaris, was used to stimulate robust hypertrophy. Depletion of satellite cells in the adult mouse during mechanical overload of muscle resulted in ECM dysregulation and muscle fibrosis. We characterized interactions of activated satellite cells and their daughter cells, myogenic progenitor cells (MPCs), with muscle fibroblasts. We found that MPC-derived exosomes are capable of down-regulating fibroblast collagen expression. Interfering with microRNA processing, resulting in loss of microRNAs in MPC exosomes, reduced their ability to downregulate fibroblast ECM gene expression. These findings provide the first evidence for a new role for satellite cells in the regulation of fibroblast ECM production and suggest MPCs are actively involved in the remodeling of the skeletal muscle extracellular environment during muscle hypertrophy.