Aging is associated with a diminished ability to regenerate skeletal muscle and is partly due to age-related changes to muscle stroma. The immune system is essential for efficient muscle regeneration, however, it is unknown how aging of the immune system contributes to the decline in muscle regeneration with age. Regulatory T cells (Tregs) are indispensable in maintaining immune system homeostasis. Unpublished data from our laboratory demonstrated that Tregs accumulated in injured muscle and was necessary for efficient muscle regeneration. However, there was a strikingly diminished capacity in Tregs from aged mice to accumulate in injured muscle. Thus, we hypothesize that age-related changes in either the muscle stroma/parenchyma or in Tregs themselves limit Treg accumulation in injured muscle, and contribute to the demonstrated decline in regeneration with age. To address this, we will: (1) Determine whether age-related changes in Treg trafficking, proliferation or survival contribute to diminished Treg accumulation in injured muscle from aged mice. (2) Determine whether the age-associated defect lies solely in Tregs themselves. (3) Attempt to reverse the decline in regeneration by increasing the Treg population. (1) First, the kinetics of Treg accumulation in injured muscle will be compared between young and aged mice. Next, Treg trafficking dynamics (will use Kaede mouse model which enables tracking of UV light labeled cells), proliferation, and survival will be compared between young and aged mice to determine the relative contribution of each factor to diminished Treg accumulation in aged injured muscle. (2) To determine the effect of age-related changes in the muscle stroma/parenchyma, immune system and systemic factors on Treg accumulation in injured muscle, Treg accumulation will be studied in conjoined aged and young mice such that they share a closed circulatory system and thus access to a similar pool of systemic factors, and mice treated with young or aged systemic factors. To determine age-related Treg- autonomous effects on muscle regeneration, Treg accumulation in injured muscle and muscle regeneration will be compared between aged and young mice receiving transferred young or aged Tregs. (3) To potentially reverse the age-related decline in muscle regeneration, regeneration will be compared in mice receiving a vehicle control or IL-2:anti-IL-2 complexes to expand Tregs. Results from this experiment will inform us on whether the age-related decline in muscle regeneration may be enhanced by expanding the Treg population while providing further evidence for the novel role of this critical immune system regulator in regeneration. This could eventually lead to further studies to manipulate Tregs in other settings that require enhanced muscle regeneration such as sarcopenia and cachexia, or in the various muscular dystrophies.

Public Health Relevance

In mammals, aging is associated with a diminished capacity to regenerate tissue. The immune system is not only essential for the defense against pathogens, but also for efficient regeneration. The goal of this project is to better understand how aging affects multiple systems involved in the regeneration process with the hope that we may use this knowledge to (1) comprehend the contributions of age-related changes in multiple systems to the decline in tissue regeneration with age, (2) potentially develop novel therapeutics to enhance the regeneration process in the elderly or in pathologic situations, and (3) predict how modulating immune responses impact regeneration.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Williams, John
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Harvard Medical School
Internal Medicine/Medicine
Schools of Medicine
United States
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Li, Chaoran; DiSpirito, Joanna R; Zemmour, David et al. (2018) TCR Transgenic Mice Reveal Stepwise, Multi-site Acquisition of the Distinctive Fat-Treg Phenotype. Cell 174:285-299.e12
Kuswanto, Wilson; Burzyn, Dalia; Panduro, Marisella et al. (2016) Poor Repair of Skeletal Muscle in Aging Mice Reflects a Defect in Local, Interleukin-33-Dependent Accumulation of Regulatory T Cells. Immunity 44:355-67