Evaluating the molecular drivers of physical inactivity and muscle atrophy as initiating factors in cognitive impairment
Authors:   , Kerr Nathan Ryan 
Published: October 2023

[EMBARGOED UNTIL 8/1/2024] Physical activity has played an essential role in the evolution of humans and the development of the human brain. Therefore, it comes as no surprise that the modern-day pandemic levels of sedentarism and physical inactivity would have numerous negative effects on the body, with physical inactivity being recognized as a major contributor to at least 40 chronic diseases. At the forefront of the 40 chronic diseases associated with physical inactivity is Alzheimer's Disease (AD). The primary focus of this dissertation was to first address what factors contribute to the lack of desire to be physically active, then to investigate the molecular changes that occur in the hippocampus in response to a genetic model of physical inactivity and an immobilization model as it relates to AD risk and pathogenesis. Despite evidence demonstrating that physical inactivity increases the risk of developing AD by 40 percent and that inactivity levels are approaching 97 percent in for U.S. adults, the underlying mechanisms for how this occurs remains largely unknown and understudied. First, I investigated the role of stress as a deterrent in maintaining physical activity levels, providing a potential explanation for the pathways involved in the brain that regulate whether one finds physical activity rewarding or not. This study revealed that a genetic model of physical inactivity displayed increased adrenal weights and corticosterone levels in response to acute running wheel access. This was associated with changes in dynorphin signaling through the kappa-opioid receptor pathway in the basolateral amygdala, all of which returned to normal following long-term running-wheel access. This suggests that acute physical activity can activate stress and aversive signaling in the brain acting to discourage the continuance of physical activity. The remaining portions of this dissertation focused on the contributions of physical inactivity and muscle atrophy to cognitive dysfunction and identification of the molecules involved in this process. In our genetic model for physical inactivity, we found that female rats performed poorly in cognitive behavioral testing, had deficits in hippocampal mitochondrial respiration, Long Term Potentiation (LTP) induction via decreased Glutamate AMPA Receptor 1 (GluA1) protein levels, and neurogenesis. Our genetic model for high physical activity on the other hand had enhanced performance in cognitive behavioral testing, increased hippocampal volumes, and increased markers for brain glucose metabolism. The hindlimb immobilization (HLI) experiments found that inducing muscle atrophy through inactivity in female rats caused significant increases in hippocampal mitochondrial H2O2 emissions, signs of hippocampal insulin resistance via decreased insulin receptor surface expression, and increased amyloidogenic processing of APP through BACE1 leading to increased levels of the APP cleavage product APP Intracellular Domain (AICD). Brain Derived Neurotrophic Factor (BDNF) IX levels were also significantly reduced along with significant reductions in GluA1:pGluA1 ratios. These changes mimic many of the early signs of AD pathogenesis and were associated with elevated markers for iron in the atrophied soleus and hippocampus, providing a potential mechanism for how inactivity-induced muscle atrophy could contribute to AD onset. Altogether, these studies provide novel molecular targets in the study of physical inactivity and muscle atrophy as risk factors for AD. This emphasizes the importance and dire need to study physical inactivity as a contributor to chronic disease, especially in regard to neurodegenerative diseases like AD.