Abstract A key determinant of geriatric frailty is sarcopenia, the age-associated loss of skeletal muscle mass and strength. Although the etiology of sarcopenia remains to be determined, studies in humans and rodents have reported a strong correlation between the loss and/or dysfunction of satellite cells and sarcopenia. Despite the correlation between declining satellite cell-dependent regenerative capacity and age, no studies to date have directly tested this relationship to determine if the loss of satellite cells causes sarcopenia. To test this idea, we depleted (>85%) satellite cells in five month old mice to a level dramatically lower than that observed with normal aging. A detailed analysis of multiple muscles through 24 months of age revealed that, despite significantly reduced regenerative capacity, the life-long depletion of satellite cells did not accelerate nor exacerbate sarcopenia; however, the depletion of satellite cells at a young age was associated with a significant increase in fibrosis in old mice. These highly provocative findings, together with our data on the fiber-type specific role of satellite cells in response to exercise, reveal our limited understanding of how aging affects the function of satellite cells in skeletal muscle maintenance, the development of fibrosis and in response to a growth stimulus; addressing these fundamental gaps in our knowledge clearly requires new tools. Towards this end, we will utilize a novel mouse strain (Pax7-H2B-GFP) that will allow us to track satellite cell dynamics for the first time in adult skeletal muscle aging. To better understand how aging and exercise affects satellite cell dynamics and the regulation of fibrosis, the following aims will be pursued: 1) determine how age and life-long exercise affects satellite cell dynamics in the maintenance of skeletal muscle, 2) determine how age and life-long exercise affects satellite cell regulation of fibrosis and 3) determine how age affects satellite cell dynamics in response to a growth stimulus. The approaches described herein use powerful, new genetic tools to determine how aging and life-long exercise alters the function of satellite cells in skeletal muscle homeostasis, regulation of fibrosis and adaptability. The development of the Pax7-H2B-GFP mouse represents a long sought-after method for tracking satellite cells, especially following fusion into the myofiber. This novel mouse strain will allow us to address formally intractable questions regarding how satellite cell dynamics are affected by age and life-long exercise. Such fundamental knowledge is necessary to critically evaluate the therapeutic value of satellite cells for the treatment of muscle mass loss and function associated with aging.

Relevance A hallmark of aging in humans is the progressive loss of skeletal muscle mass and strength which is known to have a negative impact on an individual's quality of life by robbing them of their daily independence, as well as increasing the occurrence of falls and other diseases. The primary goal of the proposed research is to understand how stem cell dynamics change with age, how stems cells influence the muscle environment and the impact of exercise on satellite cell function during aging. This knowledge is required to evaluate the therapeutic potential of these cells to treat the loss of skeletal muscle mass and fucntion duirng aging.