Weight-loss drugs like semaglutide may melt fat, but at the cost of muscle mass. A new review reveals how to protect your strength while reaping the benefits.
Study: Glucagon-like peptide-1 receptor agonists and muscle mass effects. Image Credit: rasamma / Shutterstock
A recent study published in the journal Pharmacological Research reviewed evidence on the effects of glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) on skeletal muscle (SM) mass, quality, and function.
SM accounts for about 40% of body mass in healthy adults. This proportion alters with aging and in disease states. While age-related changes are characterized by a slow, progressive loss of muscle mass, this decline could lead to sarcopenia, frailty syndrome, and cachexia in more severe cases. Obesity has an even greater impact on SM function and composition.
SM accounts for up to 70% of glucose uptake in the postprandial state and is considered a vital regulator of energy and metabolism. Normal insulin sensitivity (IS) is crucial for maintaining this energy balance. Additionally, insulin has anabolic effects on muscle by inhibiting proteolysis and promoting protein synthesis. Insulin resistance (IR), commonly associated with obesity, disrupts these processes.
Conventional anti-obesity medications are limited to short-term use and have adverse effects, which have contributed to the rise of GLP-1 RAs, e.g., liraglutide, semaglutide, dulaglutide. GLP-1 RAs offer multiple beneficial effects and have a favorable safety profile. However, concerns exist regarding the impact of GLP-1 RAs on lean mass, particularly with respect to true skeletal muscle mass. In the present study, researchers reviewed the effects of GLP-1 RAs on SM mass, quality, and function.
GLP-1 RAs: effects and indications
GLP-1 RAs are primarily used for the treatment of chronic weight management and type 2 diabetes (T2D). GLP-1 RAs bind to the G protein-coupled GLP-1 receptor, whose activation results in insulin synthesis and release by pancreatic beta cells. Additionally, GLP-1 RAs inhibit gallbladder and gastric emptying, as well as intestinal motility, thereby reducing energy intake.
In the central nervous system, GLP-1 RAs regulate response to food cues and decrease food intake. GLP-1 RAs reduce adipose tissue mass in subcutaneous and visceral depots and increase circulating adiponectin levels. Consequently, GLP-1 RAs reduce blood glucose and glycated hemoglobin levels, facilitating weight loss and improving blood pressure and lipid profile in T2D patients.
SM biology and obesity-related changes
SM produces myokines that influence metabolic and immune processes through endocrine, paracrine, and autocrine effects. Interleukin-6 (IL-6) is a myokine produced in response to physical activity. It facilitates muscle glucose uptake and also exerts systemic effects. Preclinical studies report that IL-6 may promote GLP-1 release from intestinal L-cells. However, the role of IL-6 in human GLP-1 regulation is debated.
Irisin is another myokine produced in response to exercise, and regulates energy metabolism. While the physiological relevance of irisin in humans is under investigation, growing preclinical evidence suggests its role in lipid metabolism, browning of white adipose tissue, and glucose uptake. Obesity leads to significant SM changes; it impairs SM microcirculation, lipid oxidation, mitochondrial activity, and glucose metabolism, which might aggravate metabolic dysfunction and IR.
In obesity, the proportion of type I muscle fibers decreases while that of type IIx muscle fibers increases. This is associated with reduced capacity to utilize fatty acids and glucose, and this impairment promotes lipid accumulation within muscle, aggravating IR and muscle dysfunction. Sarcopenic obesity, which combines obesity and sarcopenia, is concerning and is associated with reduced quality of life and elevated risk of falls, cardiovascular disease, and mortality.
Effects of weight loss on body composition and muscle mass
Physiological weight loss can help decrease metabolic risk factors and is effective in managing several diseases. Weight reduction can improve IR, muscle energy balance, and muscle microcirculation by restoring glucose metabolism and oxidative phosphorylation and improving mitochondrial function. However, high rates of weight loss carry substantial risks of muscle loss. GLP-1 RA use is associated with a significant loss of lean body mass, including skeletal muscle mass.
The loss of muscle mass is particularly relevant for patients with metabolic diseases and older people, for whom muscle mass loss expedites sarcopenia development. Experimental studies have uncovered numerous benefits of GLP-1 RAs on SM. GLP-1 RAs have been shown to be effective in treating muscle-wasting diseases in animal models. For instance, liraglutide has been effective in restoring myofibrillar architecture in muscle atrophy models.
Dulaglutide and exendin-4 have shown positive effects on SM atrophy by suppressing muscle atrophy factors and myostatin and enhancing myogenic factors. In obese mice, semaglutide was found to reduce intramuscular fat accumulation and body weight, stimulate protein synthesis in muscle, and promote an increase in the relative proportion of SM. Clinical data also indicate beneficial molecular effects of GLP-1 RAs, despite their potential to reduce muscle mass.
It has been hypothesized that GLP-1 RA effects may be adaptive, and improved IS may contribute to enhanced muscle function. GLP-1 RA treatment has been reported to increase irisin levels in patients with obesity and T2D. A recent study reported a decrease in muscle fat content with liraglutide in obese or overweight adults without diabetes. Additionally, weight loss with semaglutide was associated with improvements in cardiovascular risk factors and physical fitness.
Strategies to mitigate muscle loss
Given concerns about muscle mass reduction with GLP-1 RAs, the reviewed paper emphasizes strategies to preserve or restore muscle health. Resistance training and higher dietary protein intake are strongly recommended to counteract sarcopenic effects. These interventions have shown promise in maintaining muscle mass and function during pharmacologically induced weight loss.
Moreover, emerging therapeutic agents are under investigation. Bimagrumab, a monoclonal antibody targeting activin type II receptors, has shown potential to increase lean mass while reducing fat mass. Tirzepatide, a dual GIP/GLP-1 receptor agonist, may also offer more favorable muscle preservation profiles, although further studies are needed.
The authors emphasize the importance of standardized assessments in clinical trials, including objective measures of muscle strength (e.g., grip strength) and physical function (e.g., gait speed), as well as the use of advanced imaging techniques beyond DXA and BIA (e.g., MRI or CT) to evaluate muscle quality and composition.
Concluding remarks
Together, the role of GLP-1 RAs has expanded beyond glycemic control in T2D, becoming a cornerstone in obesity management. However, increasing data suggest that the pronounced weight loss with GLP-1 RAs may be accompanied by a decrease in SM mass. This may increase the risk of sarcopenic obesity, particularly in older individuals.
Integrating exercise, adequate protein intake, and potentially adjunctive pharmacotherapies is essential to mitigate this risk. As the clinical use of GLP-1 RAs continues to grow, it is necessary to better understand their long-term effects and optimize their use to preserve the muscle health, functional status, and quality of life of patients.