Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| H-25045258 | Other Identifier | Danish Ethics Board |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| Atrogi AB | INDUSTRY |
| University of Copenhagen | OTHER |
| Stockholm University | OTHER |
Not provided
Not provided
Not provided
Not provided
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| ATR-258 | Experimental | Daily oral ATR-258 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| ATR-258 | Drug | Daily oral ATR-258 for 8 weeks with repeated experimental assessment days (Days 1, 15, 29, 56). |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Before and 4 hours after ATR-258 ingestion on day 1, 29, and 56. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | Measured by DXA scan |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Morten Hostrup, PhD, MD | Contact | +45 24474785 | mhostrup@nexs.ku.dk |
Not provided
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Copenhagen, August Krogh Section for Human & Molecular Physiology | Copenhagen | 2100 | Denmark |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D050177 | Overweight |
| D009765 | Obesity |
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
| D001835 | Body Weight |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| 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. | 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 | Day 1, 29 and, 56. |
| Muscle fiber cross-sectional area (type I and type II) | Measured by histochemical analysis | 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 | Pre and post 12 weeks of daily ATR-258 ingestion. Post visit conducted 3-5 days after last day of ATR-258 ingestion. |
| β2-adrenergic receptor content in type I and type II muscle fibers | Measured by western blotting | On day 1, 29 and 56 |
| Maximal muscle force development | Isometric. Measured seated with leg in 90 degree angle and attached to strain gauge. | 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 | 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. | Before and 1, 2, 4 and 8 hours after ATR-258 ingestion on day 1, 15, 29, and 56. |
| D012816 |
| Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D004700 | Endocrine System Diseases |