GRK-Biased Activation Via β2-Adrenergic Receptors in Human Skeletal Muscle (GAIN)
G Protein-Coupled Receptor Kinase (GRK)-Biased Signaling Via β2-Adrenergic Receptors and Downstream Activation and Its Role for Protein Synthesis-Regulating Kinases, Function 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 up- and downstream signaling, fiber-type specificity, and potential receptor desensitization with repeated stimulation along with functional read-outs, tissue distribution, cardiovascular response and tolerability.
Studieoversikt
Status
Forhold
Intervensjon / Behandling
Detaljert beskrivelse
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.
Studietype
Registrering (Faktiske)
Fase
- Fase 2
Kontakter og plasseringer
Studiesteder
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Copenhagen, Danmark, 2100
- University of Copenhagen, August Krogh Section for Human & Molecular Physiology
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Deltakelseskriterier
Kvalifikasjonskriterier
Alder som er kvalifisert for studier
Tar imot friske frivillige
Kjønn som er kvalifisert for studier
Beskrivelse
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
Studieplan
Hvordan er studiet utformet?
Designdetaljer
- Primært formål: Grunnvitenskap
- Tildeling: N/A
- Intervensjonsmodell: Enkeltgruppeoppdrag
- Masking: Ingen (Open Label)
Våpen og intervensjoner
Deltakergruppe / Arm |
Intervensjon / Behandling |
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Eksperimentell: ATR-258
Daily oral ATR-258 |
Daily oral ATR-258 for 8 weeks with repeated experimental assessment days (Days 1, 15, 29, 56). |
Hva måler studien?
Primære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
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Intensity of β2-AR downstream signaling pathways (e.g. GRK, cAMP/PKA, β-arrestin, rpS6) in type I and type II muscle fibers
Tidsramme: Before and 4 hours after ATR-258 ingestion on day 1, 29, and 56.
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Assessed in vastus lateralis biopsies at rest |
Before and 4 hours after ATR-258 ingestion on day 1, 29, and 56.
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Sekundære resultatmål
Resultatmål |
Tiltaksbeskrivelse |
Tidsramme |
|---|---|---|
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Phosphorylation of rpS6, mTOR, and Akt in type I and type II muscle fibers
Tidsramme: Day 1, 29 and, 56.
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In response to ATR-258 ingestion |
Day 1, 29 and, 56.
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Lean/fat mass
Tidsramme: Day 1, 15, 29, and 56
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Measured by DXA scan |
Day 1, 15, 29, and 56
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Muscle function
Tidsramme: Pre and post 8 weeks of daily ATR-258 ingestion. Post visit conducted 2-5 days after last day of ATR-258 ingestion.
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Participants will perform lower extremity peak exercise and a one-legged knee-extensor exercise protocol to exhaustion before and after the full intervention to assess muscle power and endurance |
Pre and post 8 weeks of daily ATR-258 ingestion. Post visit conducted 2-5 days after last day of ATR-258 ingestion.
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Peripheral glucose clearance including OGTT-derived outcomes
Tidsramme: Pre and post 8 weeks of daily ATR-258 ingestion. Post visit conducted 2-5 days after last day of ATR-258 ingestion.
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Pre and post 8 weeks of daily ATR-258 ingestion. Post visit conducted 2-5 days after last day of ATR-258 ingestion.
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β2-adrenergic receptor content in type I and type II muscle fibers
Tidsramme: On day 1, 29 and 56
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Measured by western blotting |
On day 1, 29 and 56
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Resting metabolic rate (incl. carbohydrate and fat oxidation)
Tidsramme: Before and 1, 2, 4 and 8 hours after ATR-258 ingestion on day 1, 15, 29, and 56.
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Measured by indirect calorimetry |
Before and 1, 2, 4 and 8 hours after ATR-258 ingestion on day 1, 15, 29, and 56.
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Femoral arterial blood flow
Tidsramme: Before and 1, 2, 4 and 8 hours after ATR-258 ingestion on day 1, 15, 29, and 56.
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Measured by Doppler. |
Before and 1, 2, 4 and 8 hours after ATR-258 ingestion on day 1, 15, 29, and 56.
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Continous ECG and heart rate
Tidsramme: A 5-day baseline period, and day 1-5, day 15-20, and day 29-34 of ATR-258 administration.
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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.
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Muscle fiber cross-sectional area (type I and type II)
Tidsramme: Day 1, 29, and 56
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Measured by histochemical analysis |
Day 1, 29, and 56
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Maximal electrically-stimulated muscle force development and relaxation
Tidsramme: Pre and post 8 weeks of daily ATR-258 ingestion. Post visit conducted 2-5 days after last day of ATR-258 ingestion.
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Isometric quadriceps. Measured seated with leg in 90 degree angle and attached to strain gauge. |
Pre and post 8 weeks of daily ATR-258 ingestion. Post visit conducted 2-5 days after last day of ATR-258 ingestion.
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Samarbeidspartnere og etterforskere
Sponsor
Studierekorddatoer
Studer hoveddatoer
Studiestart (Faktiske)
Primær fullføring (Antatt)
Studiet fullført (Antatt)
Datoer for studieregistrering
Først innsendt
Først innsendt som oppfylte QC-kriteriene
Først lagt ut (Faktiske)
Oppdateringer av studieposter
Sist oppdatering lagt ut (Faktiske)
Siste oppdatering sendt inn som oppfylte QC-kriteriene
Sist bekreftet
Mer informasjon
Begreper knyttet til denne studien
Nøkkelord
Ytterligere relevante MeSH-vilkår
Andre studie-ID-numre
- ATR
- H-25045258 (Annen identifikator: Danish Ethics Board)
Plan for individuelle deltakerdata (IPD)
Planlegger du å dele individuelle deltakerdata (IPD)?
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