Investigation of Sarcopenia in a Murine Model: Symptoms of Age-Related Neuromuscular Decline and Resistance Training Intervention

Abstract

The world population demographic is rapidly aging. With advancing age comes the onset of age-related diseases and syndromes such as sarcopenia, the age-associated loss of muscle mass and strength. Sarcopenia leads to a multitude of adverse outcomes including a reduced quality of life, increased mortality, functional disability, and eventual loss of independence. Currently no cure for sarcopenia exists and its etiology is still largely undefined. Thus, there is a need for animal models for preclinical investigation of novel interventions. The overall purpose was to first investigate, characterize, and describe the neuromuscular healthspan of the C57BL/6 mouse, a common animal model of aging, and then to subsequently create a treatment model for sarcopenia by producing and validating a voluntary resistance training protocol for mice. The first research chapters (2 and 3) investigate and define the neuromuscular healthspan and the age-related decline of contractile parameters in the mouse. Chapter 2 outlines the neuromuscular healthspan scoring system, a composite score consisting of two functional measures combined with in vitro maximum isometric force of the extensor digitorum longus (EDL). This composite outcome measurement increased the power to detect change beyond the capacity of the individual component measures alone. Chapter 3 examines unique aspects of contractile velocity and power production in the soleus and EDL, revealing that age has a greater effect on concentric contraction performed at higher percentages of maximum force. Because the only consensus treatment for sarcopenia is resistance exercise, in Chapter 4 a mouse model of voluntary resistance training was designed and validated. The protocol was designed using human principles of weight training and was assessed with a comprehensive battery of outcome measurements. The outcomes were selected to test whether the mice had the same type of adaptations as would be observed in humans undergoing a similar training intervention. In Chapter 5, the resistance training protocol was applied to a cohort of aged mice to test if signs of anabolic resistance would be detected. Overall, the thesis tells the story of age-related neuromuscular dysfunction that can be partially rescued though exercise and creates a novel preclinical animal model of voluntary resistance training.