The goal of this proposal is to develop and characterize a novel mouse line which will allow for the conditional, genetic labeling of satellite cells in adult skeletal muscle. Satellite cells are the myogenic stem cell of adult skeletal muscle and have been most studied during post-natal growth and during muscle regeneration following injury. Beyond speculation, the role of satellite cells in the maintenance of skeletal muscle throughout life has yet to be directly studied due to the difficulty of accurately identifying satellite cells and the inability to stably track their frequency and behavior over time. To overcome this obstacle, in Aim 1 we will generate the Pax7-GNZ mouse by crossing the conditional, satellite cell-specific driver/inducer mouse line (Pax7-CreER) with a nuclear-localized GFP-lacZ reporter mouse line (Rosa26-GNZ). A major strength of the proposal is that the parental strains required to generate the Pax7-GNZ line already exist. Characterization of the Pax7-GNZ mouse line will entail quantifying the specificity and magnitude to which the reporter gene effectively marks satellite cells. The role of satellite cells in maintaining muscle mass will then be determined by inducing reporter gene expression in 3 month old mice which will be analyzed at later time points throughout the lifespan of the mice. Aim 2 will begin to determine the contribution of satellite cells to the compromised ability of aging muscle to adapt to changes in demand. The Pax7-GNZ mice will be used to quantify satellite cell dynamics with muscle hypertrophy induced by synergist ablation and re-growth following muscle atrophy induced by hindlimb unloading. The Pax7-GNZ mouse line represents a powerful, unique genetic tool that will allow for the first time, a comprehensive and accurate quantification of satellite cell dynamics in the maintenance of muscle during normal muscle aging, as well as during periods of altered demand such as hypertrophy and restoration of mass following atrophy. Furthermore, results obtained will serve as the foundation for future studies using a genetic mouse model to examine the impact on muscle plasticity of specifically ablating satellite cells in adult skeletal muscle. These studies will define the function of satellite cells in skeletal muscle plasticity and homeostasis and how it may change with age.

PUBLIC HEALTH RELEVANCE: Almost one-third of the elderly suffer from the debilitating condition of frailty. The cause of geriatric frailty is not known but a contributing factor is sarcopenia, the progressive loss of muscle mass with age. Defects in satellite cells, the primary stem cell of adult skeletal muscle, are thought to play a central role. The goal of this proposal is to develop and characterize a novel mouse model to track satellite cells in aging skeletal muscle with the aim to better understand their role in sarcopenia. The long-term goal of the research project is to develop a therapeutic intervention to prevent sarcopenia and reduce the incidence of frailty in the elderly.

R21AG034453

2009-08-15

2012-07-31