Prevention of Muscle Aging by Myofiber-Associated Satellite Cell Transplantation

Transplantation of myofibers and associated stem cells into injured muscle protects against age-related muscle degeneration in mice. Perpetually Powerful Muscles It is plain from the biceps of any bodybuilder that muscles can show startling growth—except when they do not. Patients with muscular dystrophies or the frail elderly could benefit from some of the bodybuilder’s myofiber hypertrophy. In an effort to understand the process by which muscles become weak with age and how that might be reversed, Hall et al. have harnessed the power of muscle stem cells. By augmenting the stem cell supply early in the life of mice through transplantation of myofibers and their companion satellite stem cells, they are able to prevent the age-related wasting of muscle. The key to muscle regeneration in adulthood is the satellite cell, stem cells that reside just outside each myofiber, below the basement membrane. These cells divide and contribute myoblasts to build young muscle and, although usually quiescent in adults, they regenerate muscle damaged from injury or disease. The authors found that if they transplanted intact myofibers, with their associated satellite cells, into young 3-month-old mice whose muscles had been injured (by BaCl2 or cardiotoxin), the mice did not experience the usual age-related decrease in muscle mass and strength 21 months later. When the authors investigated why this occurred, they found that many of the transplanted cells fused to form new myofibers, as revealed by incorporation into myofibers of a green fluorescent protein (GFP) marking the donor cells. In addition, there was a large increase in the number of satellite cells, a result of engraftment and proliferation of these cells from the donor. The excess satellite cells continuously supplied new nuclei to the myofibers so that by 21 months after transplantation, the GFP-positive myofibers were larger than the myofibers derived from the hosts’ own satellite cells. These hypertrophied myofibers, derived from self-renewing donor satellite cells, conferred on these aged muscles youthful mass, force, and allotment of fast twitch fibers. The authors attribute their success in slowing down the clock for these mouse muscles to the manipulation of two critical aspects of satellite cell biology. By injuring the host muscle, they created a general tissue environment in which satellite cell engraftment and function is activated. And, second, by supplying the donor satellite cells still in their intact niches on the donor myofiber, they ensured that the satellite cells were competent to respond. Although what happens in aging muscle to cause the loss of satellite cell function is not clear, the conditions enforced on the young muscles in this study reverse this process or allow the aging muscle to compensate. A better understanding of the hormonal or cellular interactions that allow this to take place will facilitate the use of transplanted stem cells in the treatment of muscular disease and the disability that accompanies the weakened muscles in the elderly. 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.