Mirabegron Ingestion Enhances Thermal Resiliency And Delays Shivering Onset During Progressive Cold-water Immersion

BACKGROUND: Mirabegron (MIRA) is a pharmaceutical that activates β3-adrenergic receptors on brown adipose tissue (BAT), stimulating heat production. Similarly, repeated cold-water immersions (CWI) delays shivering onset and increases BAT activation, enhancing thermal resiliency in future cold exposures. Whether MIRA-induced BAT activation offers thermogenic benefits during a progressive CWI is unknown. PURPOSE: To test the hypothesis that MIRA ingestion potentiates BAT activation, delays shivering onset, and increases immersion duration during a progressive CWI vs placebo (PLA). METHODS: 12 healthy adults (age: 25 ± 6 y; BMI: 26 ± 5 kg/m2, body fat: 27 ± 5%, 6 women) completed 2, double-blind, randomized study visits: ingestion of 100 mg of MIRA or PLA. 30 min after ingestion, participants rested in an empty immersion tank. Then, 35 °C water filled the tank up to the sternum, where participants were asked to remain for as long as possible. The temperature of the water was progressively cooled by 2.5oC every 15 min until reaching 10oC, where it was held constant for up to 240 min of total immersion time. BAT activity was estimated via supraclavicular skin temperature (Tsc; infrared thermography) and expressed relative to shoulder skin temperature. Shivering was assessed via mechanomyography (MMG) using 3 tri-axial accelerometers, O2 uptake (VO2; ml/kg/min) via indirect calorimetry, and the bedside shivering scale (BSS; 0 = no shivering, 3 = severe shivering). Segmental regression analysis identified the breakpoint where the dependent variable abruptly changed as a function of water temperature. Data are mean ± SD. RESULTS: Total duration of CWI was greater following MIRA ingestion vs PLA (127.1 ± 55 vs 142.2 ± 44.3 min; p = 0.050). Tsc was greater throughout CWI following MIRA ingestion vs PLA (1.4 ± 0.3oC vs 1.9 ± 0.4oC; p = 0.001). Breakpoint temperature for Tsc did not differ between trials (25.7 ± 3.1 vs 25.7 ± 3.4oC; p = 0.450) but were lower following MIRA ingestion vs. PLA for VO2 (22.4 ± 4.1 vs 20.3 ± 4.3oC; p = 0.017), MMG (24.1 ± 2.8 vs 22.7 ± 3.6oC; p = 0.038), and BSS (22.1 ± 2.5 vs 19.8 ± 3.9oC; p = 0.027). CONCLUSIONS: MIRA ingestion extended immersion time and increased Tsc, likely contributing to the delayed shivering onset vs PLA. Our findings suggest that MIRA enhances thermal resiliency during a progressive CWI. Supported by: Office of Naval Research N00014-21-1-2276.