Characterizing muscle metabolic alterations during the development of AN and following anabolic interventions

University Of Arkansas At Fayetteville, Fayetteville AR

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Abstract

Anorexia nervosa (AN) is one of the most pervasive and lethal psychiatric conditions in the United States and results in up to 20% musculoskeletal loss. Muscle is the largest metabolic organ in the body, correspondingly, alterations in muscle health will directly affect overall health. Treatment for AN is typically initiated after severe and sustained weight loss; at which point musculoskeletal deteriorations may be permanent, especially without specific muscle-building interventions. Therefore, identifying physiological alterations that occur prior to sustained weight loss is important for earlier detection and intervention in the treatment of AN. Resistance exercise is the only intervention known to elicit muscle hypertrophy, yet given the complex interplay of compulsive exercise during AN, exercise is often contraindicated. However, data from our laboratory has found sustained muscle loss following weight recovery in simulated models of AN, strongly implying muscle-building interventions are necessary to restore muscle mass in this population. Hitherto, the effect of resistance exercise following AN has never been characterized, making evidence-based interventional strategies to improve muscle health in this population impossible. In this proposal, we seek to solve both of these aforementioned unmet scientific needs, specifically identifying physiological alterations during the development of AN and determining the necessity of resistance exercise to restore muscle health following AN. We hypothesize that duration of AN is predictive of metabolic and functional alterations in skeletal muscle, and that resistance exercise is necessary to fully restore muscle function following weight restoration. To test the primary hypothesis, we will conduct a series of experiments leveraging our laboratory's rat model of AN. In Aim 1, we will simulate AN in rats for different durations of time and characterize metabolic and functional changes within skeletal muscle. In Aim 2, we will determine the necessity of resistance exercise to restore muscle health following AN. Rodents will undergo simulated AN and then be provided ad libitum food to simulate recovery. Following a designated recovery period, rats will be divided into sedentary and resistance-training interventions. Rats will undergo designated interventions for up to eight weeks; following these interventions, we will assess muscle metabolism and function. For all experiments, rats will be compared to age-matched healthy controls. Upon successful completion of this project, we will have thoroughly characterized the physiological landscape of metabolic and functional changes during the development of AN and after muscle-building interventions. This project will be foundational to understanding physiological implications of AN and has the potential to be paradigm shifting in the clinical management of AN. The Research Project Leader is an early-stage investigator with expertise in muscle and exercise physiology and optimally positioned to lead this research effort.