Date of Graduation
12-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy in Health, Sport and Exercise Science (PhD)
Degree Level
Graduate
Department
Health, Human Performance and Recreation
Advisor/Mentor
Washington, Tyrone
Committee Member
Wolchok, Jeffery
Second Committee Member
Rosa-Caldwell
Third Committee Member
Greene, Nicholas
Keywords
Muscle biology; Muscle function; Regenerative rehabilitation; Regenerative repair; Volumetric muscle loss
Abstract
Volumetric muscle mass loss (VML) is the traumatic loss of approximately 20% of muscle mass, and results in significant loss of function. Studies seek to identify methods promoting recovery of muscle function, which consist of regenerative or rehabilitative therapies. Limited studies have explored biological sex differences in therapies promoting muscle regeneration in VML. Furthermore, no study has studied baseline sex differences in un-repaired VML. The purpose of this dissertation is to explore sex differences in the pathophysiology of VML, as well as in the muscle response to regenerative (minced muscle autografts (MMGs)) and rehabilitative (structured, low-intensity aerobic exercise) therapies following 12-weeks of recovery. Male and female Sprague Dawley rats (~12-weeks old) were randomly selected to receive VML left unrepaired, repaired with MMG, and with MMG coupled with 11-weeks of low intensity treadmill running (n=8/group/sex). All animals were subjected to functional testing at 2-, 4, and 12-week timepoints, along with in vivo morphological analysis with pQCT at 10-weeks. Injured and uninjured TAs were collected at 12-weeks and prepped for biochemical (polymerase-chain-reaction or western-blot) or histological analysis. In unrepaired VML (Sub-AIM1), males and females exhibited similar force reductions. Myogenesis and ECM-remodeling were specifically altered in females (i.e., suppression of myogenic factors and upregulation of ECM-remodeling), indicating dynamic regulation of these two processes. In sedentary groups with MMG (AIM 1), MMG resulted in greater force impairments in males, which may result from suppression of calcium regulation (Serca2) and heightened muscular denervation (NCAM1). Finally, in both sedentary and exercised animals (AIM 1 and AIM 2), neither therapy promoted force recovery by 12-weeks; however, females recovered from MMG-induced strength deficits, which are expected at early timepoints, while males did not, indicating females are more tolerable to MMG treatment. Exercise promoted heightened inflammation in males specifically, providing sex-specific insight to the molecular response to exercise (AIM 2). Together, findings presented in this dissertation provide novel and impactful insight to the pathophysiology of VML and the muscle response to therapeutic interventions between sex. Completion of these studies provides the groundwork to build more targeted and clinically relevant therapeutic interventions for VML.
Citation
Schrems, E. R. (2025). Evaluation of Biological Sex in the Pathophysiology of Recovery from Volumetric Muscle Loss with Integrated Regenerative and Rehabilitative Therapies. Graduate Theses and Dissertations Retrieved from https://scholarworks.uark.edu/etd/6026
