Overweight and Obesity
Conditions
Keywords
beta2, muscle, atr-258, adrenergic, biased signaling
Brief summary
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.
Detailed description
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.
Interventions
DRUGATR-258
Daily oral ATR-258 for 8 weeks with repeated experimental assessment days (Days 1, 15, 29, 56).
Sponsors
Morten Hostrup, PhD
Atrogi AB
University of Copenhagen
Stockholm University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
21 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy men * Age 21-45 years * BMI 25-35 kg/m\^2 * Body fat percentage 25-40% * Lean Mass Index 14-22
Exclusion criteria
* Regular use of or allergy to β2-agonists * Serious adverse reactions to β2-agonists * Current smoker * Regular use of medication (except OTC allergy or analgesics) * Abnormal ECG before or after β2-AR stimulation * Hypertension * Reduced kidney function (eGFR \< 90 ml/min/1.73m\^2) * Cardiovascular, metabolic, gastrointestinal, renal, or pulmonary disease * Psychiatric or neurological disorders affecting compliance/safety reporting * Cancer history within the last 5 years * Substance abuse or alcohol intake \>14 units/week
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intensity of β2-AR downstream signaling pathways (GRK, cAMP/PKA, and β-arrestin) in type I and type II muscle fibers | Before and 4 hours after ATR-258 ingestion on day 1, 29, and 56. | Assessed in vastus lateralis biopsies at rest |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peripheral glucose clearance including OGTT-derived outcomes | 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 | Day 1, 29, and 56 | Measured by DXA scan |
| Continous ECG and heart rate | A 5-day baseline period, and day 1-5, day 15-20, and day 29-34 of ATR-258 administration. | 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. |
| Phosphorylation of rpS6, mTOR, and Akt in type I and type II muscle fibers | Day 1, 29 and, 56. | In response to ATR-258 ingestion |
| Muscle fiber cross-sectional area (type I and type II) | Day 1, 29, and 56 | Measured by histochemical analysis |
| Muscle function (endurance) | Pre and post 12 weeks of daily ATR-258 ingestion. Post visit conducted 3-5 days after last day of ATR-258 ingestion. | Participants will perform a one-legged knee-extensor exercise protocol to exhaustion before and after the full intervention to assess muscle endurance |
| β2-adrenergic receptor content in type I and type II muscle fibers | On day 1, 29 and 56 | Measured by western blotting |
| Maximal muscle force development | Pre and post 12 weeks of daily ATR-258 ingestion. Post visit conducted 3-5 days after last day of ATR-258 ingestion. | Isometric. Measured seated with leg in 90 degree angle and attached to strain gauge. |
| Resting metabolic rate (incl. carbohydrate and fat oxidation) | Before and 1, 2, 4 and 8 hours after ATR-258 ingestion on day 1, 15, 29, and 56. | Measured by indirect calorimetry |
| Femoral arterial blood flow | Before and 1, 2, 4 and 8 hours after ATR-258 ingestion on day 1, 15, 29, and 56. | Measured by Doppler. |
Countries
Denmark
Contacts
CONTACTMorten Hostrup, PhD, MD
Outcome results
None listed