The molecular memory of exercise in skeletal muscle

Weidenhamer, Clay Jackson

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https://hdl.handle.net/2142/132758 Copy

Description

Title

The molecular memory of exercise in skeletal muscle

Author(s)

Weidenhamer, Clay Jackson

Issue Date

2025-11-26

Doctoral Committee Chair(s)

Hernandez-Saavedra, Diego

Committee Member(s)

• Burd, Nicholas
• Allen, Jacob
• Kalsotra, Auinash

Department of Study

Health and Kinesiology

Discipline

Kinesiology

Degree Granting Institution

University of Illinois Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Exercise
• Hypertrophy
• Mitochondria
• Muscle Memory
• Skeletal Muscle

Abstract

Skeletal muscle constitutes nearly half of our body weight and reduction of muscle mass is linked to increased risk of mortality and metabolic disorders. Further, skeletal muscle mass and function decline with age, a term known as sarcopenia. These reductions in muscle mass and function can be combated through increased physical activity and exercise. Both endurance and resistance exercise have been shown to enhance performance and increase overall health. While the study of how these types of exercise lead to adaptation in skeletal muscle is quite extensive, how exercise leads to lasting adaptation following the cessation of exercise is still largely unknown. In chapter 2 of this dissertation, we investigated how endurance exercise leads to skeletal muscle adaptations and encodes a memory of exercise in skeletal muscle. Using a novel TRAIN-DETRAIN-RETRAIN paradigm under control or high-fat diets, we investigated which adaptations occurred with exercise TRAINing, whether these adaptations persisted after DETRAINing and if they could be recalled upon RETRAINing. Our results suggests that endurance TRAINing encodes a memory of exercise that leads to the optimization of the mitochondria, regardless of diet, to support hypertrophic remodeling with RETRAINing. Furthermore, our results highlight that prior exercise potentiates muscle growth greater than age-matched exercise (naïve exercise). This characterization of the memory of exercise after endurance exercise and identifies mechanisms by which exercise may combat overnutrition to promote whole muscle and fiber hypertrophy. In chapter 3, we investigated how progressive overloaded wheel running (hiPoWeR) mediates skeletal muscle adaptations and encodes a memory. The utilization of weighted wheel running allows for the characterization of the skeletal muscle memory with a different stimulus than endurance exercise. Here, we developed a hiPoWeR protocol in which wheel weight progressively increased up to 15g of added weight in a 4wk period. Mice conducted training (PoWeR), detraining (DEPoWeR), and retraining (REPoWeR) phases to assess how exercise modality altered hypertrophic and metabolic responses. These results suggest that recurrent hiPoWeR enhances whole-body glucose handling, reduces fat mass, and enhances relative muscle weight. This PoWeR protocol also induces more myofiber adaptations than endurance exercise and resulted in retention of mitochondrial oxidative phosphorylation complexes following PoWeR throughout the DEPoWeR phase. While these were not enhanced following the REPoWeR phase, these results suggest that recurrent hiPoWeR results in greater muscle growth than age-matched hiPoWeR. This highlights the necessity of a bout of prior hiPoWeR exercise to kick-start the mitochondria and result in greater muscle adaptation with retraining. These findings suggest that this novel hiPoWeR protocol could have greater implications for future investigation into high intensity and resistance-type exercise. The single nucleus RNA-seq (snRNA-seq) data presented in chapter 4 allowed me to investigate the potential of a cell specific memory of exercise following endurance exercise. Utilizing isolated nuclei from the gastrocnemius muscle of mice fed a control diet from the endurance TRAIN-DETRAIN-RETRAIN in chapter 2, we highlight the differences between RETRAINing and age-matched (naïve) exercise compared to age-matched sedentary controls. While this dissertation highlighted how RETRAINing elicits a shift toward more oxidative myonuclei, the most striking finding is the supportive role of fibro-adipogenic progenitors (FAPs) and stromal cells in mediating the cellular memory of exercise. This finding challenges the typical myonucleus-centric view of the memory of exercise in skeletal muscle and highlights the potential role of supportive cells. Our results provide a foundational framework for future investigations into how exercise encodes a cell specific memory of exercise and offers a reproducible pipeline for cell-specific transcriptomic analysis within physiological contexts. In the final chapter of this dissertation, chapter 5, we investigated the therapeutic potential of prior exercise training. Utilizing Landscape In Silico deletion Analysis (LISA), our gene expression data suggests that the glucocorticoid receptor (GR) may mediate the memory of exercise in skeletal muscle, regardless of diet or exercise modality. Thus, I developed an experiment to test this intersection in which male mice were injected with a GR agonist, prednisone, once weekly for 4wks under sedentary conditions, following prior endurance or high intensity exercise, or alongside endurance or high intensity retraining. Our results show that exercise is necessary to enhance whole-body metabolism and mediate muscle growth as intermittent prednisone injections did not recapitulate these adaptations. Furthermore, retraining alongside prednisone injections did not produce a synergistic effect regardless of exercise modality. Future studies may investigate longer duration of intermittent injections and include female mice to determine if time or sex plays a role in the GR mediated memory of exercise in skeletal muscle.

Graduation Semester

2025-12

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/132758

Copyright and License Information

Copyright 2025 Clay Weidenhamer

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