Skeletal muscle stem cell activation : aging and rejuvenation
Abstract/Contents
- Abstract
- Aging stymies wound healing. This is pronounced in skeletal muscle, a tissue repaired by muscle stem cells (MuSCs). In adults, MuSCs are normally quiescent but respond to muscle damage by activating and regenerating muscle fibers. In old organisms, MuSC activation is far less efficient, yet much is still unknown about mechanisms and potential mitigating strategies. In this thesis, we dissect the cellular events of activation in young and old MuSCs, uncovering an early delay, before S-phase, in old MuSC activation. We perform unbiased metabolomic and transcriptional profiling, discovering oxidative stress as a reversible cause of the slower activation of old MuSCs. Next, we test the hypothesis that voluntary exercise is a practicable intervention that can benefit old MuSCs and muscle repair. We demonstrate that exercise rejuvenates old MuSC activation and muscle regeneration ability in a cell-intrinsic manner. Molecular profiling followed by genetic manipulation of MuSCs in the contexts of aging and exercise reveals Cyclin D1 as a protein vital for MuSC activation that is decreased during aging and restored by exercise. In quiescent MuSCs, loss of Cyclin D1 liberates the pro-aging pathways TGFβ-Smad3 and NF-κB, whose pharmacologic inhibition ameliorates the activation deficits of old and genetically Cyclin D1-deficient MuSCs. In summary, this work combines molecular profiling and in vivo rejuvenation to discover new mechanisms of MuSC aging and strategies to improve old MuSC activation.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2018; ©2018 |
| Publication date | 2018; 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Brett, Jamie O |
|---|---|
| Degree supervisor | Rando, Thomas A |
| Thesis advisor | Rando, Thomas A |
| Thesis advisor | Beachy, Philip Arden |
| Thesis advisor | Palmer, Theo |
| Thesis advisor | Sage, Julien |
| Degree committee member | Beachy, Philip Arden |
| Degree committee member | Palmer, Theo |
| Degree committee member | Sage, Julien |
| Associated with | Stanford University, Program in Stem Cell Biology and Regenerative Medicine. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Jamie O. Brett. |
|---|---|
| Note | Submitted to the Program in Stem Cell Biology and Regenerative Medicine. |
| Thesis | Thesis Ph.D. Stanford University 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Jamie Or Brett
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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