The Effects of Glucagon‐Like Peptide‐1 Receptor Agonists on Mitochondrial Function Within Skeletal Muscle: A Systematic Review

Obesity is a chronic disease associated with increased risk of multiple metabolic and mental health-related comorbidities. Recent advances in obesity pharmacotherapy, particularly with glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), have the potential to transform obesity and type 2 diabetes mellitus (T2DM) care by promoting marked weight loss, improving glycaemic control and addressing multiple obesity-related comorbidities, with added cardio-renal benefits. Dual agonists combining GLP-1 with other enteropancreatic hormones such as glucose-dependent insulinotropic polypeptide (GIP) have also been developed in recent years, leading to greater weight loss than using GLP-1 RAs alone. However, up to 40% of the weight lost with GLP-1 RAs comes from lean body mass, raising concerns about potential adverse effects on skeletal muscle function. Mitochondrial dysfunction, characterized by reduced mitochondrial size and activity, is prevalent in individuals with obesity and T2DM and is a known contributor to muscle wasting in ageing and some chronic diseases. This systematic review investigates the impact of GLP-1-based therapies on skeletal muscle mitochondrial function in individuals with obesity and T2DM or in related animal and cell models.

A comprehensive search of MEDLINE, Scopus, CINAHL and clinicaltrials.gov was conducted. Inclusion criteria included randomized controlled trials, randomized crossover trials, cluster randomized control trials and basic science studies involving any GLP-1 RA or GLP-1/GIP dual agonist. Outcomes of interest were skeletal muscle respiratory function either in the form of measurements of mass, number, content, oxidative capacity/respiratory function, mitochondrial dynamics, mitochondrial biogenesis and mitophagy.