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

Morten Hostrup, PhD

Status and phase: Not yet enrolling; Phase 2

Conditions: Overweight and Obesity

Treatments: Drug: ATR-258

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT07421024

H-25045258 (Other Identifier)

ATR

Details and patient eligibility

About

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.

Full 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.

Enrollment: 10 estimated patients

Sex: Male

Ages: 21 to 45 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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10 participants in 1 patient group

ATR-258

Experimental group

Description:

Daily oral ATR-258

Treatment:

Drug: ATR-258