Sarcopenia is the age-related loss in skeletal muscle mass and strength; it leads to a host of co-morbidities including loss of physical function and overall resilience. One such perturbation in persons with sarcopenia is the diminished ability to regenerate muscle after injury. Muscle stem cells, referred to as satellite cells, are required to activate, proliferate and differentiate to regenerate muscle and restore physical function. Aged satellite cells are slower to activate upon injury; susceptible to apoptosis; and less efficient in repairing injured muscle. The AMPK/ULK1/p27Kip1 pathway appears critical for successful transition from quiescence to entry into the cell cycle. Our preliminary data identify perturbations in the AMPK/ULK1/p27Kip1 pathway with advanced age. This award period will investigate the role of the AMPK/ULK1/p27Kip1 pathway in the phenotype of satellite cell aging in both human and mouse models.
In Aim1, we will test the hypothesis that activation of AMPK and its downstream targets ULK1 and p27Kip1 regulate the autophagy/apoptosis decision in aged satellite cells. We will use molecular assays to rescue the functional loss of this pathway in aged cells and return proliferative capacity.
In Aim 2, we will test the hypothesis that exercise, a physiological inducer of AMPK and autophagy, stimulates the AMPK/ULK1/p27Kip1 pathway, thereby enhancing proliferation and metabolic function in aging murine and human satellite cells.
Aim 3 will test the hypothesis that AMPK/ULK1/p27Kip1 signaling will regulate the beneficial effects of caloric restriction on aged satellite cells. Together, the experiments in this proposal will test the hypothesis that the AMPK/ULK1/p27Kip1 pathway is impaired in aging satellite cells resulting in a reduction in autophagy and susceptibility to apoptosis. Key aspects of Dr. White's career enhancement will be: to learn how to coordinate clinical exercise trials; to train in methods of satellite cell isolation and metabolic analysis, especially in the context of the aging organism. The training program will entail dedicated internal and external scientific presentations; pertinent course work/workshops in stem cell biology and aging; and intensive career mentorship to ensure progress toward independence. The research and career development plan detailed in this proposal will be conducted with a team of outstanding mentors. Dr. William E. Kraus, a professor at the Duke Medical School is an established expert in clinical exercise studies and muscle/satellite cell biology; he will serve as the primary mentor. Drs. Kenneth Schmader, Deborah Muoio (Duke) and Amy Wagers (Harvard) will serve as co-mentors; they will facilitate training in aging biology, cell metabolism and aging stem cell biology, respectively. The environment at the Duke School of Medicine is ideal for the research and training activities outlined in this proposal. This award will provide Dr. White with optimal training to ensure an outstanding start to his career as an independent investigator.
The loss of muscle mass with aging, referred to as sarcopenia, is associated with lack of independence, metabolic dysfunction, loss of regenerative capacity and increased morbidity. There is an immediate need for treatment options to prevent the development of sarcopenia and all associated disabilities. Improving muscle stem cell function is one target to improve muscle regeneration and subsequent resilience in aged individuals.
| White, James P; Billin, Andrew N; Campbell, Milton E et al. (2018) The AMPK/p27Kip1 Axis Regulates Autophagy/Apoptosis Decisions in Aged Skeletal Muscle Stem Cells. Stem Cell Reports 11:425-439 |
