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.
연구 개요
상세 설명
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.
연구 유형
등록 (실제)
단계
- 2 단계
연락처 및 위치
연구 장소
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Copenhagen, 덴마크, 2100
- University of Copenhagen, August Krogh Section for Human & Molecular Physiology
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참여기준
자격 기준
공부할 수 있는 나이
건강한 자원 봉사자를 받아들입니다
연구 대상 성별
설명
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
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 기초 과학
- 할당: 해당 없음
- 중재 모델: 단일 그룹 할당
- 마스킹: 없음(오픈 라벨)
무기와 개입
참가자 그룹 / 팔 |
개입 / 치료 |
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실험적: ATR-258
Daily oral ATR-258 |
Daily oral ATR-258 for 8 weeks with repeated experimental assessment days (Days 1, 15, 29, 56). |
연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
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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
기간: 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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2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
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Phosphorylation of rpS6, mTOR, and Akt in type I and type II muscle fibers
기간: 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
기간: 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
기간: 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
기간: 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
기간: 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)
기간: 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
기간: 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
기간: 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)
기간: 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
기간: 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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공동 작업자 및 조사자
연구 기록 날짜
연구 주요 날짜
연구 시작 (실제)
기본 완료 (추정된)
연구 완료 (추정된)
연구 등록 날짜
최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (실제)
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
추가 관련 MeSH 약관
기타 연구 ID 번호
- ATR
- H-25045258 (기타 식별자: Danish Ethics Board)
개별 참가자 데이터(IPD) 계획
개별 참가자 데이터(IPD)를 공유할 계획입니까?
약물 및 장치 정보, 연구 문서
미국 FDA 규제 의약품 연구
미국 FDA 규제 기기 제품 연구
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