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
Trial Snapshot
- Phase
- Phase 2
- Status
- Active, not recruiting
- Sponsor
- Enrollment
- 13
- Locations
- 1
- Primary Endpoint
- Intensity of β2-AR downstream signaling pathways (GRK, cAMP/PKA, and β-arrestin) in type I and type II muscle fibers
Study Overview
Brief Summary
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 along with functional read-outs, tissue distribution, cardiovascular response and tolerability.
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 lower extremity muscle function/power 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 Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Basic Science
- Masking
- None
Eligibility Criteria
- Ages
- 21 Years to 45 Years (Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- Yes
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
Arms & Interventions
ATR-258
Daily oral ATR-258
Intervention: ATR-258 (Drug)
Outcomes
Primary Outcomes
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
- Lean/fat mass(Day 1, 15, 29, and 56)
- Peripheral glucose clearance including OGTT-derived outcomes(Pre and post 8 weeks of daily ATR-258 ingestion. Post visit conducted 2-5 days after last day of ATR-258 ingestion.)
- Muscle function(Pre and post 8 weeks of daily ATR-258 ingestion. Post visit conducted 2-5 days after last day of ATR-258 ingestion.)
- Maximal electrically-stimulated muscle force development and relaxation(Pre and post 8 weeks of daily ATR-258 ingestion. Post visit conducted 2-5 days after last day of ATR-258 ingestion.)
- Continous ECG and heart rate(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(Day 1, 29 and, 56.)
- Muscle fiber cross-sectional area (type I and type II)(Day 1, 29, and 56)
- β2-adrenergic receptor content in type I and type II muscle fibers(On day 1, 29 and 56)
- Resting metabolic rate (incl. carbohydrate and fat oxidation)(Before and 1, 2, 4 and 8 hours after ATR-258 ingestion on day 1, 15, 29, and 56.)
- Femoral arterial blood flow(Before and 1, 2, 4 and 8 hours after ATR-258 ingestion on day 1, 15, 29, and 56.)
Investigators
Morten Hostrup, PhD
Senior Researcher, Professor, MD
University of Copenhagen