This study is evaluating whether a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, tirzepatide, can affect the function, structure and metabolism of skeletal muscles in adults with obesity. Participants, premenopausal females with obesity, will receive either tirzepatide or placebo over 24 weeks. Researchers will assess body weight, body composition, muscle strength and functional performance, neuromuscular function and will perform muscle biopsies before and after treatment to study molecular and histological changes following treatment. The goal of this study is to investigate the effects of tirzepatide on skeletal muscle function, quantity, quality and metabolism in adults with obesity as well as clarify the molecular and structural adaptations in skeletal muscle during tirzepatide-induced weight loss, addressing an important gap in understanding the impact of incretin-based therapies on muscle health.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
30
Tirzepatide is a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist. It will be administered via subcutaneous injection once weekly in a dose-titration scheme: starting at 2.5 mg and increased every 4 weeks by 2.5 mg up to a maximum of 15 mg, based on tolerability.
Placebo (saline solution) will be administered via subcutaneous injection once weekly with dose escalation following the same schedule (2.5 mg equivalent increments every 4 weeks) to preserve blinding integrity.
Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana
Ljubljana, Slovenia
RECRUITINGChange in Body Mass and Composition
Measured primarily as changes in body weight and body composition measured by dual-energy X-ray absorptiometry (DXA).
Time frame: Baseline to Week 24
Change in Quadriceps Muscle Strength
Change in maximal knee extensor torque normalized to body mass (Nm/kg) will be evaluated using an isokinetic dynamometer.
Time frame: Baseline to Week 24
Change in MRI-derived Skeletal Muscle Composition and Myosteatosis
Muscle volume and muscle fat fraction will be quantified using magnetic resonance imaging (MRI).
Time frame: Baseline to Week 24
Change in Molecular Markers in Vastus Lateralis Muscle: Gene-level Differential Expression
Transcriptome-wide RNA-sequencing will be performed on vastus lateralis muscle biopsies from all participants (depending on sample quality and RNA integrity) before and after the intervention to identify differentially expressed genes associated with tirzepatide treatment. Differential gene expression will be reported as log2 fold change (log2FC) between post and pre-intervention, derived from normalized RNA-sequencing read counts. Statistical significance will be summarized using false discovery rate (FDR)-adjusted p-values.
Time frame: Baseline to Week 24
Change in Molecular Markers in Vastus Lateralis Muscle: Pathway-level Enrichment Analysis
Pathway-level changes will be reported using normalized enrichment scores (NES) derived from gene set enrichment analysis (GSEA), together with false discovery rate (FDR)-adjusted q-values for biological processes including mitochondrial function, lipid metabolism, insulin signaling, inflammation, muscle atrophy, and myogenesis.
Time frame: Baseline to Week 24
Change in Intramyocellular Lipid Content (IMCL) in Vastus Lateralis Muscle
Assessed by Oil Red O staining using a standard protocol. IMCL will be quantified as the proportion of Oil Red O-positive area per fibre and averaged across available fibres per section per time point. Microscopy imaging and analysis settings will be kept consistent across time points, and assessors will be blinded to group/time.
Time frame: Baseline to Week 24
Change in the Muscle Fiber Diameter of Type I and Type II Fibers
Muscle fiber diameter will be measured on the biopsy section using routine light microscopy. Fiber typing (type 1 vs type 2) will be performed by standard immunohistochemistry for myosin heavy chain isoforms. The metric is mean minimal Feret diameter in micrometers, averaged across available fibers of same type.
Time frame: Baseline to Week 24
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