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.
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Descripción detallada
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.
Tipo de estudio
Inscripción (Actual)
Fase
- Fase 2
Contactos y Ubicaciones
Ubicaciones de estudio
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Copenhagen, Dinamarca, 2100
- University of Copenhagen, August Krogh Section for Human & Molecular Physiology
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
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
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Ciencia básica
- Asignación: N / A
- Modelo Intervencionista: Asignación de un solo grupo
- Enmascaramiento: Ninguno (etiqueta abierta)
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Experimental: ATR-258
Daily oral ATR-258 |
Daily oral ATR-258 for 8 weeks with repeated experimental assessment days (Days 1, 15, 29, 56). |
¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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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
Periodo de tiempo: 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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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Phosphorylation of rpS6, mTOR, and Akt in type I and type II muscle fibers
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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)
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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)
Periodo de tiempo: 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
Periodo de tiempo: 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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Colaboradores e Investigadores
Patrocinador
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Actual)
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Enfermedades del sistema endocrino
- Trastornos Nutricionales
- Enfermedades metabólicas
- Sobrenutrición
- Peso corporal
- Trastornos del metabolismo de la glucosa
- Diabetes mellitus
- Condiciones Patológicas, Signos y Síntomas
- Enfermedades Nutricionales y Metabólicas
- Signos y síntomas
- Exceso de peso
- Obesidad
- Diabetes Mellitus, Tipo 2
Otros números de identificación del estudio
- ATR
- H-25045258 (Otro identificador: Danish Ethics Board)
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
Información sobre medicamentos y dispositivos, documentos del estudio
Estudia un producto farmacéutico regulado por la FDA de EE. UU.
Estudia un producto de dispositivo regulado por la FDA de EE. UU.
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