PI: Fabrisia Ambrosio, Bennett Van Houten
Co-I: Aaron Barchowsky, Mauricio Rojas, Donna Stolz
Title: The Anti-Aging Effect of Klotho on Skeletal Muscle Regeneration
Description: An age-related impairment of the regenerative capacity of aged muscle is a major contributor to declines in functional mobility and is associated with an increased morbidity in an elderly population. Following an acute injury, young skeletal muscle initiates a highly effective regenerative response, which largely restores the original architecture of the damaged fibers. Conversely, with increasing age, the regenerative response to injury results in a considerable scar tissue deposition at the expense of functional contractile tissue. Much of this healing defect has been attributed to an age-related decrease in muscle stem, or satellite, cell (MuSC) functionality. In response to skeletal muscle injury, MuSCs become activated from a quiescent state to repair damaged myofibers. However, it has been suggested that the increased fibrosis deposition following injury is a result of a myogenic-to-fibrogenic conversion of MuSCs. Fortunately, these age-related changes are reversible.
Elegant studies employing heterochronic parabiosis, in which the circulatory systems of young and aged animals are conjoined, have revealed that rejuvenation of the systemic microenvironment significantly restores both whole tissue and MuSC regenerative capacity in aged muscle. These findings implicate that circulating factors, such as the longevity protein Klotho, play a critical role in dictating skeletal muscle regenerative potential over time. Elucidation of the origin and nature of circulating factors contributing to the aged muscle phenotype is critical for the development of strategies to prevent, delay or reverse age-related declines. These studies will evaluate the role of circulating Klotho as a key anti-geronic protein contributing to the benefit of heterochronic parabiosis on aged muscle regeneration.
In Specific Aim 1, we will test the hypothesis that aged parabionts paired with young mice heterozygously deficient for Klotho will display significantly impaired skeletal muscle regeneration when compared to aged parabionts paired with young wild type mice. In Specific Aim 2, we will test the hypothesis that restoration of circulating Klotho to youthful levels reverse age-related declines in skeletal muscle regenerative capacity. We anticipate that success in these aims will have a long and lasting impact on the field as they will establish Klotho as an important anti-geronic factor that regulates MuSC activity essential for functional muscle regeneration after injury.
Source: National Institute on Aging