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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Overweight and Obesity
• Intervention / Treatment: Drug: ATR-258

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.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Morten Hostrup, PhD, MD; Phone Number: +45 24474785; Email: mhostrup@nexs.ku.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • University of Copenhagen, August Krogh Section for Human & Molecular Physiology
    • Contact: Morten Hostrup; Email: mhostrup@nexs.ku.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ATR-258; Daily oral ATR-258	Drug: ATR-258; Daily oral ATR-258 for 8 weeks with repeated experimental assessment days (Days 1, 15, 29, 56).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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.

Secondary Outcome Measures

Outcome Measure	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	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.

Collaborators and Investigators

• Sponsor: Morten Hostrup, PhD
• Collaborators: University of Copenhagen; Stockholm University; Atrogi AB

Study record dates

Study Major Dates

• Study Start (Estimated): February 20, 2026
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: January 30, 2026
• First Submitted That Met QC Criteria: February 16, 2026
• First Posted (Actual): February 19, 2026

Study Record Updates

• Last Update Posted (Actual): February 19, 2026
• Last Update Submitted That Met QC Criteria: February 16, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: muscle; adrenergic; beta2; atr-258; biased signaling
• Additional Relevant MeSH Terms: Endocrine System Diseases; Nutrition Disorders; Metabolic Diseases; Overnutrition; Body Weight; Glucose Metabolism Disorders; Diabetes Mellitus; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Overweight; Obesity; Diabetes Mellitus, Type 2
• Other Study ID Numbers: ATR; H-25045258 (Other Identifier: Danish Ethics Board)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No