Biased GRK Signaling Via β2-Adrenergic Receptors in Human Skeletal Muscle
For patients and families
In plain language
An automatic summary of structured registry data. It is an orientation aid, not a substitute for the official protocol or a physician assessment.
- What is being studied
- The protocol lists: ATR-258.
- Who it may be relevant to
- Registry conditions: Overweight and Obesity. Basic parameters: 21 years — 45 years · Male.
- What needs checking
- Age, condition and sex are only basic indicators. Prior treatment, laboratory values and other mandatory requirements appear in the eligibility criteria below.
- Where it takes place
- Denmark
- Next step
- Save the trial, show it to the treating physician, and confirm current recruitment with the study center. Costs, documents and travel →
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Official title
Biased G Protein-Coupled Receptor Kinase Signaling Via β2-Adrenergic Receptors and Downstream Activation of Protein Synthesis-Regulating Kinases and Receptor Desensitization in Human Skeletal Muscle
Overview
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
- Drug ATR-258
Daily oral ATR-258 for 8 weeks with repeated experimental assessment days (Days 1, 15, 29, 56).
Primary outcome measures
- Intensity of β2-AR downstream signaling pathways (GRK, cAMP/PKA, and β-arrestin) in type I and type II muscle fibers [Time frame: Before and 4 hours after ATR-258 ingestion on day 1, 29, and 56.]
Secondary outcome measures (10)
- 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 [Time frame: Day 1, 29, and 56]
- Continous ECG and heart rate [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 [Time frame: Day 1, 29 and, 56.]
- Muscle fiber cross-sectional area (type I and type II) [Time frame: Day 1, 29, and 56]
- Muscle function (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.]
- β2-adrenergic receptor content in type I and type II muscle fibers [Time frame: On day 1, 29 and 56]
- Maximal muscle force development [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) [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 [Time frame: Before and 1, 2, 4 and 8 hours after ATR-258 ingestion on day 1, 15, 29, and 56.]
Eligibility criteria
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
Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.
Healthy volunteers: Yes
Study design
- Allocation
- N/A
- Model
- Single group
- Masking
- Open label
- Primary purpose
- Basic science
Study locations
Denmark · 1 center
- University of Copenhagen, August Krogh Section for Human & Molecular Physiology — Copenhagen
Identifiers
NCT: NCT07421024 · ATR · H-25045258