Development of an extracellular vesicle therapy to recover skeletal muscle after disuse

Exercise plays a fundamental role in promoting human health and mitigating disease. Muscle contraction during exercise facilitates the release of proteins into the bloodstream which may confer the benefits of exercise. However, the molecular mechanisms underlying exercise adaptation remain largely unknown. Sedentary lifestyles and prolonged periods of inactivity often results in a significant loss of skeletal muscle mass (disuse atrophy) and higher rates of communicable diseases. While extended periods of inactivity may be necessary for recovery from surgery, illnesses, or injuries, the loss of skeletal muscle correlates with increased likelihood of metabolic disorders, morbidity, functional impairments, and lifelong disability. Physical rehabilitation is the most effective therapeutic approach to recover skeletal muscle; however, exercise is not always feasible nor sufficient for certain populations due to functional limitations. Currently, there are no pharmacological or nutritional interventions to effectively recover muscle following disuse, thus there is a need to create novel therapeutics to treat or prevent disability. Extracellular vesicles (EVs) are nanosized, membrane-bound vesicles released from cells in response to a variety of physiological stressors, including mechanical stress, hypoxia, and reactive oxygen species. EVs contain cytoplasmic molecular cargo including proteins, nucleic acids, and lipids. Studies have demonstrated that acute bouts of endurance or resistance exercise can modify the cargo in EVs, suggesting that EVs provide a means for exercise adaptation. Despite these intriguing findings, the extent to which EVs carry and transfer the therapeutic benefits of exercise remains unknown. Thus, the goal of this dissertation is to characterize the content of systemic EVs after exercise, and to determine their therapeutic potential to recover skeletal muscle after disuse. In Chapter 2, EVs were isolated from blood of sedentary (SedV) or endurance exercise trained (ExerV) young adult mice. EVs were then transplanted into healthy, sedentary mice or into the tibialis anterior muscle (TA) in young adult mice after two weeks of immobilization. Transplantation of EVs improved the vascularization of mice following disuse. Proteomic evaluation of ExerVs revealed an upregulation of antioxidants. In Chapter 3, EVs were isolated from humans before and after a 6-week progressive multicomponent exercise training. EVs were then transplanted into mice during hindlimb unloading. Administration of ExerVs during hindlimb unloading did not maintain skeletal muscle mass or capillary content but assisted in the remodeling of collagen. The remodeling of collagen allowed for an enhanced recovery of skeletal muscle upon remobilization following hindlimb unloading. Overall, the findings presented in this dissertation demonstrate that ExerVs may possess the capacity to preserve skeletal muscle plasticity during disuse that allows for an enhanced recovery of skeletal muscle during remobilization. These results represent an important step in the design of a novel therapeutic to enhance muscle recovery following periods of disuse.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Kinesiology

Grantor

University of Illinois Urbana-Champaign

Year dc:date

2025

Author dc:creator

• Fliflet, Alexander Michael

Contributors dc:contributor

• Boppart, Marni D.
• Boppart, Marni D
• Burd, Nicholas
• Chen, Jie
• Miller, Benjamin

• Extracellular Vesicle
• Ev
• Therapy
• Disuse
• Atrophy
• Exercise

Statement dc:rights

• Copyright 2025 Alexander Fliflet

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/129931

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F129931