This longitudinal mechanistic physiological study examines biased β2-adrenergic receptor (β2-AR) signaling in human skeletal muscle, with emphasis on G protein-coupled receptor kinase (GRK)-mediated pathways. Participants will receive daily oral dosing of the GRK-selective long-acting β2-agonist ATR-258 for 8 weeks. Muscle biopsies and physiological measurements will quantify GRK-, cAMP/PKA-, and β-arrestin-related signaling, fiber-type specificity, and potential receptor desensitization with repeated stimulation.
Healthy men with overweight/obesity will complete an 8-week intervention with daily oral ATR-258 (0.5-2.5 mg/day). On experimental days (Days 1, 15, 29, and 56), β2-AR signaling sensitivity will be assessed before and after stimulation (1-2, 4, and 8 hours) using blood biomarkers, hemodynamics, indirect calorimetry, and muscle function testing. Muscle biopsies (vastus lateralis) will be obtained at rest and 4 hours after stimulation on Days 1, 29, and 56 to quantify downstream signaling (GRK, cAMP/PKA, β-arrestin), phosphorylation of rpS6/mTOR/Akt, β2-AR content, and muscle fiber morphology.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
10
Daily oral ATR-258 for 8 weeks with repeated experimental assessment days (Days 1, 15, 29, 56).
University of Copenhagen, August Krogh Section for Human & Molecular Physiology
Copenhagen, Denmark
Intensity of β2-AR downstream signaling pathways (GRK, cAMP/PKA, and β-arrestin) in type I and type II muscle fibers
Assessed in vastus lateralis biopsies at rest
Time frame: Before and 4 hours after ATR-258 ingestion on day 1, 29, and 56.
Peripheral glucose clearance including OGTT-derived outcomes
Time frame: Pre and post 12 weeks of daily ATR-258 ingestion. Post visit conducted 3-5 days after last day of ATR-258 ingestion.
Lean mass
Measured by DXA scan
Time frame: Day 1, 29, and 56
Continous ECG and heart rate
Participants will wear a Holter-device for 4 x 5 days to continuously measure ECG and heart rate. The periods will be after the screening (baseline period), and after trial days on Day 1, 15, and 29.
Time frame: A 5-day baseline period, and day 1-5, day 15-20, and day 29-34 of ATR-258 administration.
Phosphorylation of rpS6, mTOR, and Akt in type I and type II muscle fibers
In response to ATR-258 ingestion
Time frame: Day 1, 29 and, 56.
Muscle fiber cross-sectional area (type I and type II)
Measured by histochemical analysis
Time frame: Day 1, 29, and 56
Muscle function (endurance)
Participants will perform a one-legged knee-extensor exercise protocol to exhaustion before and after the full intervention to assess muscle endurance
Time frame: Pre and post 12 weeks of daily ATR-258 ingestion. Post visit conducted 3-5 days after last day of ATR-258 ingestion.
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β2-adrenergic receptor content in type I and type II muscle fibers
Measured by western blotting
Time frame: On day 1, 29 and 56
Maximal muscle force development
Isometric. Measured seated with leg in 90 degree angle and attached to strain gauge.
Time frame: Pre and post 12 weeks of daily ATR-258 ingestion. Post visit conducted 3-5 days after last day of ATR-258 ingestion.
Resting metabolic rate (incl. carbohydrate and fat oxidation)
Measured by indirect calorimetry
Time frame: Before and 1, 2, 4 and 8 hours after ATR-258 ingestion on day 1, 15, 29, and 56.
Femoral arterial blood flow
Measured by Doppler.
Time frame: Before and 1, 2, 4 and 8 hours after ATR-258 ingestion on day 1, 15, 29, and 56.