Skeletal muscle is dynamic, adapting to environmental needs, continuously maintained and capable of extensive regeneration. These hallmarks diminish with age or disease, 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 leading to a reduction in regenerative capacity of skeletal muscle stem cells, termed satellite cells, are believed to be responsible. Preservation of the satellite cell niche in combination with FGF-2 pretreatment generates a permanent, self-renewing population of donor satellite cells in transplanted skeletal muscle from injection of as few as 30 myofiber associated satellite cells. Donor satellite cells efficiently engraft into both the myonuclear and satellite cell compartments where ≥70% of host myofibers express the donor cell marker or dystrophin in mdx muscle, and 80% of the total satellite cell population is donor-derived. Further, we demonstrate that engraftment of myofiber associated satellite cells, dramatically alters the environment of young adult host muscle, abrogating the onset of age-related muscle atrophy evidenced by a lifelong enhancement in muscle mass, stem cell number, and force generation. These lifelong, physiological changes present a new paradigm for the amelioration of muscle atrophy and diminished functionality that arise with aging and disease through myofiber-associated satellite cell transplantation. Future work is aimed at further elucidating the mechanisms regulating this response, where FGFR-1 is implicated as essential for the self-renewal and maintenance of satellite cells.