Skeletal muscle is dynamic, adapting to environmental needs, continuously maintained, and capable of extensive regeneration. These hallmarks diminish with age, resulting in a loss of muscle mass, reduced regenerative capacity, and decreased functionality. Although the mechanisms responsible for this decline are unclear, complex changes within the local and systemic environment that lead to a reduction in regenerative capacity of skeletal muscle stem cells, termed satellite cells, are believed to be responsible. We demonstrate that engraftment of myofiber-associated satellite cells, coupled with an induced muscle injury, markedly alters the environment of young adult host muscle, eliciting a near-lifelong enhancement in muscle mass, stem cell number, and force generation. The abrogation of age-related atrophy appears to arise from an increased regenerative capacity of the donor stem cells, which expand to occupy both myonuclei in myofibers and the satellite cell niche. Further, these cells have extensive self-renewal capabilities, as demonstrated by serial transplantation. These near-lifelong, physiological changes suggest an approach for the amelioration of muscle atrophy and diminished function that arise with aging through myofiber-associated satellite cell transplantation.