Dissertation
Sex, drugs, and physical activity: their role in the protection against and production of muscle pain
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2022
DOI: 10.25820/etd.006775
Abstract
Chronic pain is a significant health care issue affecting over 100 million Americans with musculoskeletal pain prevalent in 13-47% of the population. Musculoskeletal pain disproportionally impacts females in terms of higher prevalence and increased disease severity. One theory for the increased prevalence in females compared with males, is differing levels of sex hormones. Physical inactivity is also a risk factor for the development of musculoskeletal pain and exercise is commonly prescribed for the treatment of chronic pain conditions. While the role of sex hormones and physical activity on pain has been studied in the past, prior work has utilized mainly male animals which limits translatability to females as current pharmaceuticals for treating chronic pain are less effective and produce more side effects in women. Therefore, the overall goal of this work was to study sex, hormones, and physical activity’s role in the production and prevention of muscle pain with an emphasis on exploring sex differences.
Our activity-induced muscle pain model produces a sex dependent pain phenotype in which males develop unilateral pain and females develop bilateral pain. I first tested if the sex hormone testosterone mediates this pain phenotype. Reduction of testosterone in males prior to induction of the pain model resulted in bilateral pain similar to females. Increasing testosterone in females prior to induction of the pain model resulted in unilateral pain similar to males. Thus, testosterone, which binds and activates androgen receptors, appears to have had analgesic effects in male and female mice with regards to muscle pain. I next set out to test endogenous and exogenous approaches to activate androgen receptors for the treatment of muscle pain.
Resistance training is commonly prescribed in the clinical setting for the treatment of chronic pain; however, current animals models studying the beneficial effects of exercise have predominantly focused on aerobic based exercise (treadmill, wheel running). Also, a single resistance training bout has been shown to acutely increase testosterone in humans. Therefore, I tested if a resistance training model of exercise could be beneficial for muscle pain, and if so, if resistance training’s analgesic effects are mediated through activation of androgen receptors. Resistance training prior to induction of muscle pain blocked the development of muscle hyperalgesia in male and female mice. This was mediated through activation of androgen receptors as treatment with an androgen receptor antagonist (flutamide) during the exercise program blocked the beneficial effects of resistance training.
Selective androgen receptors modulators (SARM) were developed as a safer androgen receptor agonist as they bind androgen receptors responsible for the activation of anabolic signaling while minimizing activation of androgenic signaling. This drug was developed to reduce bone and muscle loss associated with cancer treatment but has never been tested in the context of pain. First, I demonstrated that daily administration of SARMs alleviated widespread muscle pain in both male and female mice. Next, to increase clinical utility, we developed a microparticle formulation which produced sustain release of SARM in vitro and in vivo for 4 weeks. Next, treatment with the SARM microparticle formulation resulted in alleviation of widespread muscle pain following just 2 administrations in both sexes. Lastly, I demonstrated that treatment with SARM microparticles produces pain relief through activation androgen receptors and was safe and non-toxic to male and female mice.
Finally, to uncover sex differences in muscle pain mechanisms, I utilized RNA sequencing and flow cytometry of the gastrocnemius muscle after induction of muscle pain. RNA sequencing revealed that males and females activate similar and different immune pathways in response to muscle pain. The biggest sex difference found was a female specific activation of antigen processing and presentation and MHC II signaling. Blockade of MHC II during induction of muscle pain attenuated the development of muscle hyperalgesia in females only. Flow cytometry revealed that following induction of muscle pain there is a large increase in the number of macrophages in both sexes. Finally, prior physical activity blunted the transcriptional activation of several immune pathways and altered the phenotype of macrophages toward an anti-inflammatory phenotype in response to muscle pain.
Details
- Title: Subtitle
- Sex, drugs, and physical activity: their role in the protection against and production of muscle pain
- Creators
- Joseph Bentley Lesnak
- Contributors
- Kathleen Sluka (Advisor)Laura Frey-Law (Committee Member)Vitor Lira (Committee Member)Andrew Russo (Committee Member)Yuriy Usachev (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Physical Rehabilitation Science
- Date degree season
- Autumn 2022
- DOI
- 10.25820/etd.006775
- Publisher
- University of Iowa
- Number of pages
- xv, 202 pages
- Copyright
- Copyright 2022 Joseph Bentley Lesnak
- Language
- English
- Description illustrations
- Illustrations, charts, graphs, tables
- Description bibliographic
- Includes bibliographical references (pages 176-201).
- Public Abstract (ETD)
Chronic pain conditions disproportionally impact females in terms of prevalence and severity of symptoms. Understanding why these sex differences exist could lead to more targeted and effective treatments for females with chronic pain. The overall goal of this work was to uncover mechanisms underlying the production of muscle pain and develop treatments aimed at these findings, with an emphasis on exploring sex differences.
First, I demonstrated that the sex hormone testosterone is analgesic in a mouse model of muscle pain as it protected against the development of widespread pain in both male and female mice. Taking that information, I developed two strategies aimed at targeting testosterone and its receptor, the androgen receptor, to produce pain protection and relief. First, I developed an animal model of resistance training which protected against the development of muscle pain in both male and female mice through activation of androgen receptors. Next, I developed and tested a selective androgen receptor modulator microparticle formulation which alleviated muscle pain in male and female mice.
To further explore sex differences in the development of muscle pain, I utilized RNA sequencing and flow cytometry to uncover sex specific mechanisms underlying the production of muscle pain. RNA sequencing revealed both sexes activate several immune pathways similarly, however females only activated a pathway responsible for the communication between the innate and adaptive immune system. Despite the changes at the transcript level, there were no differences between the sexes in terms of the presence of specific immune cell populations following muscle pain.
- Academic Unit
- Craniofacial Anomalies Research Center; Physical Therapy and Rehabilitation Science
- Record Identifier
- 9984362857502771
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