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.
Visão geral do estudo
Status
Condições
Intervenção / Tratamento
Descrição detalhada
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 estudo
Inscrição (Real)
Estágio
- Fase 2
Contactos e Locais
Locais de estudo
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Copenhagen, Dinamarca, 2100
- University of Copenhagen, August Krogh Section for Human & Molecular Physiology
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Gêneros Elegíveis para o Estudo
Descrição
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
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Ciência básica
- Alocação: N / D
- Modelo Intervencional: Atribuição de grupo único
- Mascaramento: Nenhum (rótulo aberto)
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
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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). |
O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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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
Prazo: 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 resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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Phosphorylation of rpS6, mTOR, and Akt in type I and type II muscle fibers
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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
Prazo: 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)
Prazo: 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
Prazo: 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
Prazo: 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)
Prazo: 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
Prazo: 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
Datas de registro do estudo
Datas Principais do Estudo
Início do estudo (Real)
Conclusão Primária (Estimado)
Conclusão do estudo (Estimado)
Datas de inscrição no estudo
Enviado pela primeira vez
Enviado pela primeira vez que atendeu aos critérios de CQ
Primeira postagem (Real)
Atualizações de registro de estudo
Última Atualização Postada (Real)
Última atualização enviada que atendeu aos critérios de controle de qualidade
Última verificação
Mais Informações
Termos relacionados a este estudo
Palavras-chave
Termos MeSH relevantes adicionais
- Doenças do Sistema Endócrino
- Distúrbios Nutricionais
- Doenças Metabólicas
- Supernutrição
- Peso corporal
- Distúrbios do Metabolismo da Glicose
- Diabetes Mellitus
- Condições Patológicas, Sinais e Sintomas
- Doenças Nutricionais e Metabólicas
- Sinais e sintomas
- Excesso de peso
- Obesidade
- Diabetes Mellitus, Tipo 2
Outros números de identificação do estudo
- ATR
- H-25045258 (Outro identificador: Danish Ethics Board)
Plano para dados de participantes individuais (IPD)
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