Effects of Corticosteroid Administration on Tongue Musculature in Rats
Abstract
This project addresses the following Fiscal Year 2016 Peer Reviewed Medical Research Program Topic Area: Sleep Disorders. Obstructive sleep apnea (OSA) is one of the most widespread (yet underdiagnosed) chronic medical conditions in the United States, affecting ~41 million adults, with ~32 million experiencing moderate to severe disease. OSA occurs when an individual repetitively stops breathing for periods of time during sleep. This is caused by closure of the upper airway. The most important muscle that keeps the upper airway open is the tongue muscle. This muscle must remain tense during sleep; otherwise, if tension is lost or muscle is weakened, inhaling may cause the tongue to fall back and block the upper airway. People with asthma are more at risk for developing OSA than those without asthma. OSA, in turn, aggravates asthma and worsens its outcomes, closing in a vicious interacting cycle. Why asthma increases OSA risk is not understood, and interventions designed to prevent or mitigate the risk of OSA in asthma patients are lacking. The lack of such interventions is the critical problem this project addresses. Interestingly, inhaled corticosteroid (ICS) therapy, the standard and most commonly prescribed treatment for asthma, may play a role in the heightened risk for OSA. In fact, the most common adverse side effect of ICS is voice hoarseness due to dysfunction of speech generating muscles. Several studies have observed muscle weakness and altered muscle function in rats when chronically administered injectable corticosteroids. Moreover, a recent clinical study suggested an effect of ICS on upper airway floppiness during sleep and on wakefulness tongue function in a manner similar to that observed in people with OSA. Since ICS are the standard treatment for asthma, there is a critical need for strong scientific evidence to understand ICS? role in OSA pathogenesis. In the absence of such evidence, decisions concerning benefit/risk ratio using ICS may be biased, and potential breathing dysfunction in the upper airway, during sleep, and other important functions (such as swallowing and vocalization) could develop. Fluticasone propionate (FP) is the strongest among ICS medications in use today for treatment of asthma. Building on these observations, the objective of this study is to test the effects of ICS on tongue muscle function and structure in a controlled rat model of chronic oral ICS administration. It is hypothesized that the ICS treatment will increase tongue strength and fatigability as a result of changes in tongue muscle structure and cellular function. For this study, rats will be treated with FP by administering two puffs a day into the animal?s mouth from a metered dose inhaler (like the inhaled treatment of an asthma patient) every day for 4 weeks. Control rats will receive two puffs a day of placebo treatments (puffs from an inhaler with propellant gas but no active drug). At the end of the treatment, rats will be anesthetized and their tongue muscle nerves will be isolated and electrically stimulated to make the tongue contract. The maximum force and fatigability of the contractions will be measured, after which the rats will be euthanized and tongue muscle samples will be taken for analysis. Muscle fiber type (slow-twitch/fatigue-resistant versus fast-twitch/fatigue-prone) prevalence and size of individual fibers will be analyzed by microscopy, and enzyme activity related to protein degradation and glucose storage will be measured in these muscle samples. The innovation of this project arises from (1) its aim to fill in major clinical knowledge gaps such as the relationship between the standard, most common asthma treatment and OSA; (2) the use of thorough, objective methods to directly measure changes in tongue function and structural changes; and (3) the establishment of a novel animal model that can be used for further research regarding the effects of ICS on oropharyng
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710252
Entities
People
- Mihaela Teodorescu
Organizations
- United States Army
- University of Wisconsin–Madison