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NCT Number: NCT07421024

Biased GRK Signaling Via β2-Adrenergic Receptors in Human Skeletal Muscle

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.

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Key information

Conditions

Overweight and Obesity Body Weight Diabetes Mellitus Diabetes Mellitus, Type 2 Endocrine System Diseases Glucose Metabolism Disorders Metabolic Diseases Nutrition Disorders Nutritional and Metabolic Diseases Obesity Overnutrition Overweight Pathological Conditions, Signs and Symptoms Signs and Symptoms

Age range

21 year–45 year

Sex eligibility

Male

Study type

Interventional

Phase

Phase 2

Primary location

University of Copenhagen, August Krogh Section for Human & Molecular Physiology

Copenhagen, 2100, Denmark

Location contact

Morten Hostrup

CONTACT

[email protected]

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

ATR-258

Drug

Daily oral ATR-258 for 8 weeks with repeated experimental assessment days (Days 1, 15, 29, 56).

Primary outcomes

  1. 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.

    Assessed in vastus lateralis biopsies at rest

Secondary outcomes

  1. 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.

  2. Lean mass

    Time frame: Day 1, 29, and 56

    Measured by DXA scan

  3. 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.

    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.

  4. Phosphorylation of rpS6, mTOR, and Akt in type I and type II muscle fibers

    Time frame: Day 1, 29 and, 56.

    In response to ATR-258 ingestion

  5. Muscle fiber cross-sectional area (type I and type II)

    Time frame: Day 1, 29, and 56

    Measured by histochemical analysis

  6. 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.

    Participants will perform a one-legged knee-extensor exercise protocol to exhaustion before and after the full intervention to assess muscle endurance

  7. β2-adrenergic receptor content in type I and type II muscle fibers

    Time frame: On day 1, 29 and 56

    Measured by western blotting

  8. 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.

    Isometric. Measured seated with leg in 90 degree angle and attached to strain gauge.

  9. 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.

    Measured by indirect calorimetry

  10. 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.

    Measured by Doppler.

Study contacts

Contact information is provided by the study sponsor or research team.

Morten Hostrup, PhD, MD

CONTACT

[email protected]

+45 24474785

Sponsors and collaborators

Lead sponsor

Morten Hostrup, PhD

Other

Collaborators

  • Atrogi AB
  • Stockholm University
  • University of Copenhagen

Registry information

Official study 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

Acronym: ATR

Important dates

Study start
2026
Primary completion
2026
Study completion
2026
First posted
Feb 19, 2026
Registry last updated
Feb 19, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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