Impairment in regeneration process has been suggested as one of the most important contributors for age- related loss of skeletal muscle mass. However, the molecular mechanisms leading to loss of muscle regenerative capacity during aging remain less understood. We have recently reported that levels of TNF receptor associated factor 6 (TRAF6), an adaptor protein involved in context-dependent activation of multiple pathways, are upregulated in injured skeletal muscle. Deletion of TRAF6 in mature differentiated muscle of mice (TRAF6mko) improves regeneration, in part, by increasing the activation of Notch signaling pathway, which promotes satellite cell activation to participate in the regeneration program. However, whether the inhibition of TRAF6 will also improve muscle regeneration in aged animals remain unknown. We will test the hypothesis that muscle-specific inhibition of TRAF6 will augment skeletal muscle regeneration in aged mice through modulating the activity of Notch and Wnt signaling.
AIM 1 : Investigate whether TRAF6 regulates the activity of Wnt and Notch signaling pathways in injured skeletal muscle in adult (3 months) and aged (18 months) mice A decline in Notch signaling activity in combination with accumulation of proinflammatory cellular infiltrates has been shown to account in part to the poor regenerative capacity of aged muscle. Environmental theories of stem cell aging propose that functional impairments that occur in stem cells as they age are potentially reversible when exposed to a young environment as been proven by the parabiotic experiments. We will determine whether the pro-regeneration environment brought about by TRAF6 deletion will carry through in aged muscle and overcome the age-related loss in regenerative capacity.
AIM 2 : Investigate satellite cells versus myofiber role of TRAF6 signaling during skeletal muscle regeneration in adult and aged mice. While the improved regeneration phenotype observed in TRAF6-depleted muscle persisted in vitro, we observed conflicting results when TRAF6 was deleted in satellite cells early during development under a Myf5 promoter (TRAF6dmko). Primary myoblast from TRAF6dmko mice displayed reduced proliferative and differentiation capacities in vitro. By contrast, muscle regeneration is enhanced in response to injury in TRAF6dmko mice. Through generation of tamoxifen-inducible satellite cell-specific TRAF6-knockout mice and an established model of muscle injury, we will delineate the role TRAF6 signaling in satellite cells o both adult and aged mice. Understanding the mechanisms that underlie such debilitation during aging can pave the way to developing novel therapeutics to preventing the loss of muscle mass.

Public Health Relevance

Skeletal muscle damage is a frequent occurrence in normal human population. Regeneration of skeletal muscle is impaired in aged population. Skeletal muscles have an evolutionarily conserved mechanism to repair this damage. However, why muscle regeneration fails in aged subjects remains enigmatic. This proposal will define signaling mechanisms involved in muscle repair with focus on TRAF6, a recently identified regulator of muscle mass. This will lead to a greater understanding of skeletal muscle regeneration associated with defective repair and age- associated loss in muscle mass and regenerative capacity.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Predoctoral Individual National Research Service Award (F31)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Williams, John
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Louisville
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code