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

ABSTRACT Background 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. Methods 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. Results Eight studies were eligible for analysis; no human studies were identified. All of the included studies used GLP‐1 RAs (single agonists) as intervention. The emerging evidence suggests that GLP‐1 RAs increase mitochondrial area, number and morphology (i.e., reduces swelling). Data are conflicting on the effect of GLP‐1 RAs upon mitochondrial mass, respiration and the expression of uncoupling proteins and PGC‐1α. Data also demonstrate muscle specific (i.e., soleus vs. extensor digitorum longus) responses to GLP‐1 RAs. Conclusion GLP‐1 RAs appear to have a positive effect upon mitochondria area, number and morphology, but effects upon other aspects of mitochondrial health remain inconclusive. Data are very limited and solely presented in animal and in vitro models. Future studies should be conducted in human populations in order to begin to understand the effect of GLP‐1 RAs and GLP‐1‐based therapies on human skeletal muscle mitochondria.