Files
Abstract
Volumetric muscle loss (VML) is an irrecoverable skeletal muscle injury that leads to permanent functional deficits and long-term disability. It affects both military and civilian populations, with blast exposure being a primary cause in the military, while accidents and tumor ablation contribute to cases in civilians. Despite its prevalence, there is no clinical standard of care for VML rehabilitation and treatment. While extensive efforts have been made to comprehend the pathophysiology of VML, the metabolic impact of a Western diet (WD) on VML-injured muscle remains unclear. Additionally, evidence for mitochondrial ROS-associated oxidative stress following VML is circumstantial, primarily characterized by hyperpolarized mitochondrial membrane potential (Δψm) and lower respiratory capacity (JO₂). Furthermore, most VML studies rely on male animal models, leaving a critical gap in understanding sex-specific responses to injury and recovery. This dissertation addresses these knowledge gaps through three studies. Study 1 examined the impact of WD on muscle metabolism post-VML in both sexes. In males, WD worsened carbohydrate-supported mitochondrial respiration, impairing pyruvate dehydrogenase (PDH) enzyme kinetics and complexes I and II, while no significant effects were observed in females. Study 2 explored the relationship between VML and mitochondrial ROS in male mice and assessed the effects of the mitochondrial-targeted antioxidant SS-31. While SS-31 improved mitochondrial function and fixed ROS, it had limited effects on muscle contractility, suggesting that oxidative stress alone is not the primary driver of impaired muscle adaptation. The combination of SS-31 with rehabilitation modestly improved metabolic outcomes but did not restore muscle function, emphasizing the need for multifaceted therapeutic approaches. Study 3 investigated the role of 17β-estradiol (E2) in muscle metabolism and redox balance in E2-deficient mice post-VML injury. Ovariectomy exacerbated mitochondrial dysfunction, increased ROS emission, and impaired antioxidant capacity after VML injury, while E2 replacement improved mitochondrial bioenergetic efficiency and antioxidant defense. Together, these studies enhance our understanding of VML pathophysiology in a sex-dependent manner, highlight the metabolic consequences of WD, and underscore the role of ovarian hormones. The findings provide a foundation for developing targeted therapeutic strategies to optimize muscle metabolic function and redox homeostasis post-VML injury.