Does Mirabegron Increase the Body Heat Generated by the Nervous System

Acute mirabegron administration has been shown to increase brown fat activity in humans. Long-term mirabegron administration upregulates brown fat, and appears to improve glucose regulation, and change skeletal muscle phenotype.

The Undersea Medicine Program at the Office of Naval Research has invited Indiana University, Rutgers and Colorado State University, to explore the potential of the medication, Mirabegron, to improve the cold tolerance of Navy personnel. Indiana University will submit the formal application for research funding. Research activities at Colorado State University will be supported by a sub-contact from Indiana University.

The project will address four hypotheses. One of these hypotheses will be investigated exclusively at Colorado State University during the second year of the project. The proposed activities at Colorado State University will be unique; the link to activities performed by Indiana University and Rutgers is thematic only.

Specialized Navy personnel are required to undertake duties while immersed in cold water for prolonged periods. These dives regularly require the use of external thermal protection (i.e., wet suits and dry suits). However, external thermal protection during prolonged cold-water diving is often times insufficient to maintain body temperature and thermal comfort, thereby potentially negatively impacting the safety and success of diving missions. Accordingly, developing an alternative strategy that can improve tolerance to cold-water immersion is of important interest to Navy divers and special forces. In this regard, the pharmaceutical, mirabegron, may hold considerable promise to mitigate the negative effects of cold-water immersion on cold-water tolerance by increasing thermogenesis (the generation of heat). Mirabegron (Myrbetriq®, extended-release tablet, Astellas Pharma), is a medication approved by the Food and Drug Administration for the treatment of overactive bladder. In 2020, it was the 160th most commonly prescribed medication in the United States, with more than three million prescriptions. The mechanism of action is stimulation of beta-3-adrenergic receptors (receptors that are usually stimulated by the sympathetic nervous system). Mirabegron is also known to stimulate brown fat, a metabolically active, heat-generating tissue. The overall goals of the project are to determine the efficacy of acute mirabegron administration to improve cold tolerance and determine if mirabegron can accentuate thermogenesis during sympathetic activation.

Eligibility Criteria:
Inclusion Criteria:

* age 18-40 years,
* regular participation in more than 150 minutes of moderate intensity exercise, every week, during the previous two years.

Exclusion Criteria:

* History of autonomic, cardio-pulmonary, and/or metabolic disease (including heart failure, hypertension, arrhythmia, vascular disease, and/or diabetes)
* contraindication for mirabegron ingestion, such as previously diagnosed liver and/or kidney dysfunction,
* use of medication that may unfavorably interact with mirabegron, including thioridazine (Mellaril™ and Mellaril-S™), flecainide (Tambocor®), propafenone (Rythmol®), digoxin (Lanoxin®) and solifenacin succinate (VESIcare®)
* pregnancy or breast feeding
* habitual use of tobacco/nicotine products (2 or more uses within the previous month)
* any type of bladder dysfunction, taking medication related to bladder issues, or a history of bladder issues.
* Sulfite Allergy '