Effects of Enhanced Physical Activity on Hematopoietic Stem Cell Aging in PEPCK-C^mus Transgenic Mice

Abstract 1297

Hematopoietic stem cells (HSCs) are self-renewing multipotent precursor cells that give rise to all blood cell lineages. As HSCs age, expansion of the pool of HSCs and abnormal production of blood cells occur, resulting in a loss of immune function and an increased incidence of myeloid leukemia. Exercise has been associated with an extended lifespan, yet the connection between HSC fitness and enhanced physical exercise is currently unclear. Transgenic mice that over-express the gene for the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C) in their skeletal muscle (PEPCK-C^mus mice) have remarkable endurance, can run five to six kilometers at a speed of 20 meters per minute without stopping, and have a markedly longer lifespan. We thus determined the effects of enhanced physical activity on HSC aging by measuring the pool size and functional ability of HSCs in both aged PEPCK-C^mus transgenic and control mice. Cell surface immunostaining and flow cytometric analysis were performed to determine the total quantity of HSCs within the bone marrow cell population of both groups of animals. Preliminary studies showed that age-associated expansion of the HSC pool was absent in PEPCK-C^mus mice. However, the efficiency of HSCs to produce B lymphoid progenitors in PEPCK-C^mus mice was surprisingly 11-fold higher than that in control mice while the age-associated skewness of HSC differentiation toward the myeloid lineage was diminished in PEPCK-C^mus mice. Furthermore, reactive oxygen species (ROS), known to be associated with aging when at high levels, were lower in the HSCs of PEPCK-C^mus mice than was noted in the HSCs of control animals. Together, these preliminary data imply that the functional capacity of HSCs is maintained in old PEPCK-C^mus mice when compared to that of the HSCs in control animals of the same age. This suggests that enhanced physical activity may slow HSC aging, possibly attributed in part to decreased ROS levels.