Effects of Glucocortioids in Human Skeletal Muscle, Adipose Tissue and Skin

Study Overview
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Brief Summary
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BACKGROUND: A notorious and dreaded adverse effect of glucocorticoids (GC) is redistribution of muscle and fat mass towards muscle wasting and visceral obesity. Fibroadipogenic progenitors (FAPs) are hypothesized to mediate this process. AIM: Utilizing human data, the investigators study the effects of GC exposure on skeletal muscle structure and function, adipose tissue and skin in healthy older subjects. METHODS: FAPs will be analyzed in biopsies from skeletal muscles, adipose tissue and skin and further characterized using scRNA-sequencing and Fluorescence-Activated Cell Sorting. Body composition including muscle mass (DXA scan), muscle strength, spontaneous physical activity and glucose homeostasis are recorded. PERSPECTIVES: The investigators combine translational research with multidisciplinary and international collaboration to elucidate the pathophysiology of GC excess, which is of significant clinical interest since 3% of the Danish population receive GC treatment.

Detailed Description
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Design: randomized, double blind, placebo-controlled trial. The aim is to study the effect of short-term GC exposure on skeletal muscle, skin , adipose tissue in 12 healthy adults above the age of 50 years. This age group is close to that of patients receiving short-term, high dose anti-inflammatory prednisolone treatment and thus provides a bridge between a clinically observered problem. The participants will be randomized to receive either prednisolone (37,5mg/d) or placebo treatment for five consecutive days. In addition to muscle, skin, and adipose tissue biopsies and body composition measurement (DXA), each participant will undergo the following measurements before and after the intervention: spontaneous physical activity (actigraphy), ambulatory 24-hour blood pressure, continuous glucose monitoring (CGM), pulse wave velocity (PWV), and muscle strength. Each participant is studied before and after the 5-day treatment period. Outcomes: FAPs expression in skeletal muscle and adipose tissue: Fluorescence Activated Cell Sorting (FACS) mediated quantification, isolation and transcriptomic profiling at population and single-cell level of FAPs, and immunological cells Time-to-first division of isolation FAPs In vitro fibro- and adipogenic differentiation of FAPs Single cell transcriptome analysis (scRNA-seq) to profile cell types in a hypothesis-generating perspective. Functional outcomes: Muscle mass and strength (DXA scan and isometric quadriceps strength) and spontaneous physical activity (actigraphy) Metabolic outcomes: circadian blood glucose and blood pressure, and basal insulin sensitivity.

Official Title
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Effects of Glucocortioids in Human Skeletal Muscle, Adipose Tissue and Skin

Conditions
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Glucocorticoids Toxicity, Iatrogenic Effect

Intervention / Treatment
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* Other: Prednisolone
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written and oral consent prior to study beginning Age of or above 50 years Healthy (uncomplicated hypertension and hypercholesteroleamia is accepted) BMI of or below 35 Exclusion Criteria: Consumption of glucocorticoid pharmaceuticals (inhalation steroids, intra-articular or intra-muscular injections, steroid creme group IV-V used in the genital area). Allowed pharmaceuticals: ocular drops, nasal sprays/drops, steroid creme group I-III, steroid creme group IV-V used in non-genital areas Alcohol consumption of more than 21 units per week Consumption of strong CYP3A4 inhibitors/inducers Serious comorbidity (heart, liver, or kidney failure, as well as cooncurrent cancer/chemotherapy treatment) High daily activity level (more than 30min per day or more than 2 organized workouts per week)

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Placebo-controlled, randomized, crossover
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Start pred/End placebo<br>Both arms will receive both placebo and prednisone | Other: Prednisolone<br>* Predisolone is used as a tool to elicit a physiological response (toolbox trial) and not as a pharmaceutical agent/treatment.<br>Other: Placebo<br>* Placebo to predinisolon<br>|
| Other: Start placebo/End pred<br>Both arms will receive both placebo and prednisone | Other: Prednisolone<br>* Predisolone is used as a tool to elicit a physiological response (toolbox trial) and not as a pharmaceutical agent/treatment.<br>Other: Placebo<br>* Placebo to predinisolon<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FAPs expression in skeletal muscle, adipose tissue, and skin | Single cell transcriptome analysis (scRNA-seq) to profile cell types in a hypothesis-generating perspective. | 2 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dual X-ray scan (DXA) | Bodycomposition (grams) | 2 Years | 
| Metabolic outcomes - Circadian blood glucose | Blood monitoring using Dexcom censor (unit: mmol/L) | Years | 
| Dynamometer | Isometric muscle contraction (power) | 2 Years | 
| 24h blood pressure | Systolic and diastolic (mmHg) | 2 Years | 
| Basal insulin sensitivity. | Blood samples (pmol/L) | 2 Years | 
| Activity level | Spontanous activity level using a wrist ban monitor (ActiGraph) | 2 Years |