The Effects of Glucagon-Like Peptide-1 Receptor Agonists on Mitochondrial Function Within Skeletal Muscle: A
Victoria J Old1, Melanie J Davies2, Dimitris Papamargaritis2
1Department of Cardiovascular Sciences, College of Life Sciences, University of Leicester, Leicester, UK.
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.
Insights
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show promise in improving skeletal muscle mitochondrial morphology in obesity and type 2 diabetes. However, their effects on overall mitochondrial health and function remain inconclusive, necessitating human studies.
Area of Science:
- Endocrinology and Metabolism
- Skeletal Muscle Physiology
- Mitochondrial Biology
Background:
- Obesity and type 2 diabetes mellitus (T2DM) increase the risk of comorbidities.
- Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) promote weight loss and improve glycemic control.
- GLP-1 RAs can lead to loss of lean body mass, raising concerns about skeletal muscle function.
Purpose of the Study:
- To systematically review the impact of GLP-1-based therapies on skeletal muscle mitochondrial function.
- To investigate effects in individuals with obesity and T2DM or related animal/cell models.
Main Methods:
- Comprehensive literature search of MEDLINE, Scopus, CINAHL, and clinicaltrials.gov.
- Inclusion of randomized controlled trials and basic science studies of GLP-1 RAs or GLP-1/GIP dual agonists.
- Focus on skeletal muscle respiratory function, including mass, number, content, oxidative capacity, dynamics, biogenesis, and mitophagy.
Main Results:
- Eight studies were included; no human studies were identified.
- GLP-1 RAs appear to increase mitochondrial area, number, and improve morphology.
- Data on mitochondrial mass, respiration, PGC-1α, and uncoupling proteins are conflicting and muscle-specific.
Conclusions:
- GLP-1 RAs may positively influence skeletal muscle mitochondrial area, number, and morphology.
- Effects on other aspects of mitochondrial health are inconclusive.
- Limited data from animal and in vitro models highlight the need for human studies on GLP-1-based therapies.
More Related Videos
08:01Measurement of Insulin- and Contraction-Stimulated Glucose Uptake in Isolated and Incubated Mature Skeletal Muscle from Mice
Published on: May 16, 2021
08:03Glucose Uptake Measurement and Response to Insulin Stimulation in In Vitro Cultured Human Primary Myotubes
Published on: June 25, 2017
Related Concept Videos
01:24Glucagon-like Receptor Agonists
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
01:16Hormones Regulating Blood Glucose
In addition to accelerating glucose uptake and utilization, insulin has...
01:25cAMP-dependent Protein Kinase Pathways
01:09GPCRs Regulate Adenylyl Cylase Activity
01:24Muscle Recovery and Fatigue
01:28Insulin: The Receptor and Signaling Pathways