Language
English (en)
Date of Award
5-15-2025
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Chair and Committee
Gretchen A. Meyer
Committee Members
Matthew R Bersi, Catherine E Lang, Jacob G McPherson, Erica L Scheller, Jennifer A Zellers
Abstract
The expansion of intra-muscular adipose tissue (IMAT) between myofibers and epi-muscular adipose tissue (EMAT) outside of the muscle boundary accompanies numerous pathologies including diabetes, muscular dystrophy, and aging. IMAT and EMAT are anatomically juxtaposed to myofibers. Some evidence supports that IMAT and EMAT impede muscle function. This is potentially due to paracrine factors that are secreted by IMAT/EMAT. Different adipose depots can be classified in numerous ways including where they are located anatomically as well as the factors in which they secrete. Unlike classical white fat, adipose depots classified as brown or beige, noted by the marker uncoupling protein-1 (UCP-1) are typically thought to secrete factors that benefit neighboring tissues. However, it has yet to be substantiated whether IMAT and EMAT have characteristics of brown or beige fat. This dissertation addressed the experimental questions of whether IMAT and EMAT adipocytes are UCP-1 positive, whether UCP-1+ cells play a role in muscle regeneration, and if UCP-1 expression in IMAT and EMAT is modifiable through progressive resistance training in mice.
In Chapter 2, we explored whether development of IMAT is dependent on UCP-1-expressing cells. To do this we utilized a transgenic mouse model that genetically lacks UCP-1+ cells (UCP1-DTA mice). We assessed depot size, adipocyte volume and morphology in naturally occurring and injury-induced IMAT as well as femoral and axillary EMAT depots and traditional white, beige and brown adipose depots in UCP1-DTA and littermate mice. We hypothesized that UCP1-DTA mice would have reduced levels of IMAT. We found that naturally occurring and injury-induced IMAT was qualitatively and quantitatively similar between wild type and UCP1-DTA mice. However, we did find that EMAT located in both the upper and lower body of mice is comprised of UCP-1+ cells. Together, Chapter 2 indicates that IMAT is not comprised of UCP-1+ cells and is thus not a beige adipose depot. However, both EMAT depots were substantially altered by UCP-1+ cell ablation indicating that although frequently grouped together, IMAT and EMAT are phenotypically different muscle-associated adipose depots.
In Chapter 3, the objective was to assess the role that UCP-1+ cells play in muscle regeneration. Current literature suggests that endogenous brown/beige fat and local muscle-resident fibro-adipogenic progenitor cells (FAPs) are UCP-1+ cell sources. Utilizing our previously established UCP1-DTA mouse model where mice genetically lack UCP-1+ cells, we acutely injured hindlimb muscle with glycerol toxin and assessed four stages of regeneration: early (3 and 7 days post-injury; dpi), intermediate (14dpi), and late/complete regeneration (21dpi) for cell population dynamics, structural changes, and contractile function respectively. We found that UCP-1 cell ablation does not result in early cellular changes during muscle regeneration.
However, UCP1-DTA mice had changes in FAP dynamics early in regeneration which correlated with signs of regenerative delay. However, UCP1-DTA mice do show signs of delayed regeneration at 14dpi compared to WT mice. Although at an intermediate timepoint we see this delay, it does not result in any impaired or functional deficit by complete regeneration.
In Chapter 4, we examined whether a twelve-week progressive resistance training protocol in wild type mice could reduce IMAT and/or increase UCP-1 expression of EMAT. We found that twelve weeks of resistance training increased masses of specific muscles in both male and female mice yet did not reduce the total amount of IMAT in muscle. However, resistance training was ineffective at beiging classical adipose depots, IMAT, or EMAT. We also observed an interesting sex-specific difference in adipose masses with more pronounced changes in male mice with resistance training.
These findings contribute foundational knowledge about muscle associated adipose tissue and UCP-1+ cells in muscle regeneration. Due to the numerous clinical populations impacted by expansion of these muscle-associated fat depots, and the potential negative effects that IMAT and EMAT have on skeletal muscle, determining the phenotype and exercise responsiveness of IMAT and EMAT will be informative as to whether these depots may be modified by therapeutic intervention. The collective results indicate that IMAT is not comprised of UCP-1+ cells and has limited potential for beiging, suggestive that beiging is not a promising therapeutic approach for modifying IMAT. However, genetic absence of UCP-1+ cells indicate a potential role for these cell populations in musculoskeletal growth. Contrarily, beiging may successfully modify EMAT, which is comprised of UCP-1+ cells that may have effects on muscle regeneration. Finally, utilizing resistance exercise, rather than pharmacological strategies may have different physiological benefits, particularly with differential capacity for beiging. Despite the ability for pharmacological drug treatment, not resistance training to beige adipose, reduction of average adipocyte mass and appearance of smaller lipids suggest a role of physical exercise on adipose biology. Thus, designing effective therapies including resistance training are of further importance for maintaining skeletal muscle and adipose health.
DOI
https://doi.org/10.48765/75m7-dq37
Recommended Citation
Parson, Jacob C., "Targeting the Beiging of Muscle-Associated Adipose Tissue to Promote Muscle Regeneration" (2025). WUSM Theses and Dissertations – All Programs. 49.
https://digitalcommons.wustl.edu/all_etd/49
