Emerging Role of Myostatin Inhibitors in the Management of Glucagon-Like Peptide-1-Associated Sarcopenia and Metabolic Disorders

Abstract

Glucagon-like peptide-1 (GLP-1) analogs, originally developed as antidiabetic agents, have emerged as groundbreaking drugs for treating obesity, following reports of their remarkable weight-reducing effects. With growing recognition of obesity as a disease in modern society and a sharp rise in its prevalence, pharmacological interventions are now being actively pursued. However, due to their mechanism of action, primarily appetite suppression, GLP-1 analogs have been associated with various adverse effects. Most notably, muscle loss — which may be related to reduced nutritional intake — has become an important issue in the long-term management of patients undergoing GLP-1 therapy. This has drawn attention to myostatin (MSTN) inhibitors for their ability to significantly increase muscle mass. These agents are now being explored not only as a strategy to offset the side effects of GLP-1 analogs, but also as direct therapeutics for a range of metabolic disorders, including obesity and diabetes. In this review, we discuss the emerging therapeutic potential of MSTN inhibitors and examine current clinical trials investigating their use alone or in combination with GLP-1 analogs in metabolic disorders.

GRAPHICAL ABSTRACT

INTRODUCTION

Metabolic syndrome is a cluster of conditions commonly associated with aging, such as insulin resistance and abdominal obesity, which can lead to complications including cardiovascular disease, hypertension, and type 2 diabetes.[1] This pathological condition is now considered an epidemic due to its rising global prevalence across all age groups, from children to adults.[2] A key challenge in managing metabolic syndrome is the absence of a single drug that can treat the disease due to its multifactorial nature.[3] As a result, most available medications for metabolic syndrome can only target one or more of its components but cannot fully eradicate the syndrome.

In addition to its multifactorial pathophysiology, the increasing incidence of metabolic syndrome is attributed to a combination of modifiable and non-modifiable factors. Lifestyle factors, such as physical inactivity and unhealthy diets, are major contributors, while genetic susceptibility also plays a significant role in disease onset.[4] Moreover, several commonly prescribed medications, including beta blockers, niacin, thiazolidinedione, protease inhibitors, antipsychotics, antidepressants, and immunosuppressive agents, have been shown to induce or exacerbate metabolic syndrome, further complicating disease management.[5] As a result, there is an urgent need for effective therapeutic interventions to manage or ultimately cure this condition. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist developed by Novo Nordisk, has been formulated as Wegovy for obesity treatment and as Ozempic for the management of type 2 diabetes mellitus, utilizing GLP-1 signaling to improve glucose metabolism and promote weight loss.[6] Semaglutide-based drugs are among the most effective weight-loss therapies currently available and are gaining widespread popularity for the treatment of obesity. However, treatment-related muscle loss and weight regain after discontinuation have been reported, highlighting the need for further research to elucidate the potential adverse effects associated with long-term use.[7]

Sarcopenia is defined as the loss of skeletal muscle mass and function, most commonly observed in older adults.[8] In contrast, obesity is diagnosed in individuals with a body mass index of 30 kg/m² or higher and can occur across all age groups. It has become one of the most rapidly growing global epidemics over the past three decades, with a prevalence of 27.5% in adults and 47.1% in children.[9] Although sarcopenia and obesity share both overlapping and distinct characteristics, a growing concern is the emergence of sarcopenic obesity, a condition that requires a different therapeutic approach from either disease alone. This is because the pathological interactions between sarcopenia and obesity are often overlooked when they are treated separately, and individuals affected by both conditions are at higher risk of developing metabolic dysfunction.[10] To mitigate the loss of skeletal muscle mass and function associated with sarcopenia, various therapeutic targets are being investigated, including activation of sphingosine-1-phosphate, AMPK, and glutathione, as well as inhibition of myostatin (MSTN) and nuclear factor-κβ, with MSTN emerging as a particularly promising target. [11] Although the role of MSTN in regulating muscle mass is well established, this review extends the discussion to include its impact on fat metabolism. Specifically, we aim to address the following: (1) the role of MSTN in regulating both muscle and adipose tissue; (2) therapeutic targeting of MSTN to promote muscle growth and fat loss; (3) the potential of MSTN blockade to mitigate adverse effects associated with GLP-1-based therapies; (4) clinical trials evaluating MSTN inhibition for the treatment of metabolic disorders; and (5) finally, the current challenges and future directions in the therapeutic application of MSTN inhibitors.

MSTN: A KEY REGULATOR OF MUSCLE AND FAT

MSTN, also known as growth/differentiation factor-8 (GDF-8), is a member of the transforming growth factor-β (TGF-β) superfamily that negatively regulates skeletal muscle mass.[12] Its regulatory role in muscle was first discovered through the observation of a doubled muscle phenotype in homozygous Mstn knockout (Mstn^−/−) mice, with the increased muscle mass resulting from both hyperplasia and hypertrophy of muscle cells.[12,13] This phenotype is thought to arise because MSTN represses myoblast proliferation and differentiation.[12,14,15] Such a role of MSTN in muscle is well conserved across species, as a doubled muscle phenotype has been observed not only in Mstn^−/− mice, but also in humans,[16] dogs,[17] sheep,[18] and cattle,[19] with naturally occurring mutations in the MSTN gene. Also noteworthy is the stage-specific expression of MSTN. During embryonic development, MSTN is exclusively expressed in the myotome compartment of the somites. After maturation, MSTN is expressed in various tissues,[12,20,21] with the highest levels in skeletal muscle and lower levels in visceral and subcutaneous fat,[21] as well as cardiac muscle.[20]

MSTN has also been reported to negatively regulate adipocyte differentiation and lipid accumulation by suppressing the expression of key transcription factors such as peroxisome proliferator-activated receptor γ (PPAR-γ) and CCAAT/enhancer binding protein-α.[22] However, Mstn^−/− mice exhibit significantly reduced fat accumulation under normal aging conditions despite a lower metabolic rate, [23] whereas a genetically obese mouse model shows elevated MSTN mRNA levels compared to wild-type mice, suggesting a positive correlation between MSTN expression and fat mass.[21] These findings have paved the way for MSTN to become a therapeutic target not only for muscle atrophy, but also for diabetes and obesity.

TARGETING MSTN FOR MUSCLE GROWTH, FAT REDUCTION, AND METABOLIC IMPROVEMENT

Following the identification of MSTN as a negative regulator of muscle mass, various attempts have been made to inhibit its function to promote the growth of pathologically degenerated muscle. In studies using the Duchenne muscular dystrophy mouse model (mdx), both the genetic crossing of mdx mice with Mstn^−/− mice and the administration of the MSTN-neutralizing antibody mRK35 led to similar outcomes, specifically increased muscle mass and improved grip strength.[24,25] However, another mouse study reported that Mstn^−/− mice, despite having increased muscle mass, did not exhibit a corresponding increase in muscle strength.[26] Although there are conflicting results regarding the ability of MSTN inhibition to improve muscle functions, such as muscle strength, most studies consistently show that inhibition of MSTN results in a significant increase in muscle mass.

In addition to muscle hypertrophy, Mstn^−/− mice show reduced fat accumulation, which becomes more evident with aging.[23] These mice exhibit lower levels of leptin but increased leptin sensitivity, likely contributing to reduced adiposity. Increased muscle mass may also enhance energy expenditure and redirect energy use toward muscle rather than fat storage.[22] In humans, elevated MSTN levels have been associated with obesity.[27] In mice, MSTN inhibition reduces white fat accumulation, improves lipid metabolism in diabetic models, and promotes browning of white fat.[28] As low muscle mass is a risk factor for insulin resistance and obesity,[29] increasing muscle via MSTN blockade may enhance insulin sensitivity, partly through irisin-driven crosstalk between muscle and fat.[30] Irisin is an exercise-induced adipomyokine, generated by cleavage of the transmembrane protein fibronectin type III domain-containing protein 5 predominantly in skeletal muscle and, to a lesser extent, in adipose tissue. It promotes adipose tissue browning and thermogenesis by upregulating type 2 iodothyronine deiodinase and uncoupling protein 1.[31] In aged mice, MSTN-neutralizing antibodies enhanced both muscle mass and insulin sensitivity. [32]

MSTN BLOCKADE AS A STRATEGY TO COUNTERACT GLP-1-INDUCED MUSCLE LOSS

GLP-1 is a hormone secreted from intestinal L cells following food intake. It promotes insulin secretion, suppresses glucagon release, and regulates glucose homeostasis.[33] While GLP-1 has therapeutic potential for diabetes and obesity, its rapid degradation by dipeptidyl peptidase IV (DPP-IV) limits clinical use.[34] To overcome this, researchers turned their attention to exendin-4, a hormone found in the saliva of the Gila monster, a venomous lizard native to the southwestern United States. Despite consuming food equivalent to half of their body weight, these lizards can effectively regulate blood glucose levels due to the presence of exendin-4.[35] Exendin-4 shares structural similarity with GLP-1, binds to its receptor with comparable affinity, but has a longer half-life than GLP-1.[36] The discovery led to the development of exenatide, the first GLP-1 analog for type 2 diabetes,[37] followed by subsequent analogs with improved pharmacokinetics. Liraglutide, engineered with a lysine-to-arginine substitution at position 34 and the addition of a short-chain fatty acid, showed extended in vivo activity and proved effective in patients refractory to metformin.[38,39] However, both exenatide and liraglutide required daily injections due to short half-lives. This led to the development of semaglutide, which has a half-life of 6 to 7 days compared to 2 hr for exenatide and 11 to 13 hr for liraglutide.[40,41] The prolonged half-life of semaglutide was achieved by switching the alanine at position 8 with α-aminoisobutyric acid, making it DPP-IV resistant,[42] and a fatty acid chain that enhances albumin binding, protecting it from renal clearance and enzymatic degradation.[43] Semaglutide has demonstrated efficacy in lowering blood glucose and promoting weight loss in both obese mice and humans.[44–46]

GLP-1 analogs exert multiple beneficial effects in humans, including suppression of appetite,[47] reduction of fat mass,[45] and regulation of blood glucose levels.[48] However, limitations remain. Patients with comorbidities, such as depression, anxiety, or sedentary behavior, may experience reduced efficacy.[49] Moreover, over half of the lost weight is often regained after discontinuation.[50] Common side effects include gastrointestinal (GI) symptoms such as nausea, vomiting, and diarrhea,[51] while severe outcomes like pancreatitis or thyroid cancer have not shown significant increases.[52] Notably, weight loss does not always equate to improved health. For every 10 kg lost through caloric restriction, men and women lose ~2 to 2.5 kg and ~1 to 1.5 kg of skeletal muscle, respectively.[53] While GI symptoms and nutritional deficiencies are manageable, muscle atrophy remains difficult to reverse through diet and exercise alone. A recent study demonstrated that dual inhibition of MSTN and activin A effectively reversed GLP-1-induced muscle wasting,[54] highlighting MSTN as a promising target for mitigating muscle loss associated with GLP-1 therapy (Fig. 1).

Fig. 1.

Characterization of sarcopenic obesity and possible outcomes following administration of glucagon-like peptide-1 (GLP-1) agonists alone or in combination with myostatin inhibitors. Sarcopenic obesity is distinguished by excessive fat accumulation within and around skeletal muscle fibers, reduced lean mass, and is associated with insulin resistance, impaired glucose metabolism, and decreased skeletal muscle function. Administration of GLP-1 agonists decreases fat mass and improves glucose metabolism and insulin sensitivity, but muscle atrophy may occur due to associated nutritional deficiencies. In contrast, myostatin inhibitors co-administered with GLP-1 agonists can preserve muscle mass, thereby enhancing metabolic function and potentially enhancing skeletal muscle strength.

Sex-based differences have been observed in the outcomes of both GLP-1 analog and MSTN inhibitor treatments. For GLP-1 analogs, meta-analyses have shown that women tend to experience greater weight loss than men, with a mean difference of approximately 1 kg, potentially due to sex-specific differences in GLP-1 receptor expression and hormonal interactions.[55] This more favorable response in women may also be attributable to interactions between estrogen and GLP-1, as demonstrated by preclinical studies in mice.[56,57] Regarding MSTN inhibition, sex-based variation has been reported in both circulating MSTN levels and physiological responses. In preclinical models, female mice showed greater increases in muscle mass in response to MSTN blockade, whereas male mice demonstrated more prominent reductions in fat mass.[58] However, clinical evidence for sex-based differences in patient outcomes remains limited, partly because most clinical studies have focused on assessing the safety of the drug in postmenopausal women or have primarily targeted elderly individuals with sarcopenia. Therefore, further studies are needed to clarify the effects of MSTN inhibitors across sexes.

TARGETING MSTN IN METABOLIC DISORDERS: THERAPEUTIC POTENTIAL AND CLINICAL PROSPECTS

As previously mentioned, higher serum MSTN levels have been observed in obese adults without other systemic diseases, and these individuals also exhibited reduced insulin sensitivity.[27] In addition, changes in the adiponectin levels, a key adipose-derived hormone that influences insulin sensitivity and glucose metabolism, have been reported to correlate with serum MSTN levels. [59–61] With increasing attention on the metabolic role of MSTN, a study demonstrated that inhibition of MSTN ameliorated type 1 diabetes in mice by improving insulin sensitivity and enhancing the expression of Glut1 and Glut4 glucose transporters in skeletal muscle.[62] This was found to be the same in humans as elevated circulating MSTN levels have also been found in patients with type 1 diabetes.[63] Collectively, these observations highlight the therapeutic potential of targeting MSTN for the treatment of metabolic disorders, including obesity and diabetes.

Like other members of the TGF-β superfamily, MSTN is secreted as an inactive latent complex composed of two Nterminal propeptides and a C-terminal disulfide-linked dimer, which remain noncovalently associated.[13,64,65] Upon cleavage of the propeptides by members of the bone morphogenetic protein (BMP)-1/tolloid-like metalloproteinase family, the active C-terminal dimer is released and can now bind to activin type II receptors A or B (ActRIIA/B), with a higher affinity for ActRIIB. This binding recruits and activates activin type I receptors, specifically activin receptor-like kinases (ALKs), ALK4 and ALK5, leading to the phosphorylation of SMAD2/3. The phosphorylated SMAD2/3 (pSMAD2/3) then forms a complex with SMAD4,[66] which translocates to the nucleus to regulate gene expression, thereby negatively regulating myoblast proliferation,[14] differentiation, and fusion.[67] MSTN signaling can be inhibited by (1) blocking the interaction between the active C-terminal dimer and ActRIIA/B, as seen with anti-MSTN antibodies such as MYO-029 and landogrozumab; (2) preventing activation of the latent complex, for example, with agents such as apitegromab and trevogrumab; or (3) directly inhibiting ActRIIA/B using agents such as bimagrumab (Fig. 2).

Fig. 2.

Schematic diagram showing the mechanisms of action of myostatin signalling inhibitors used in combination with glucagon-like peptide-1 (GLP-1) analogs to treat diabetes and obesity. Myostatin is produced as pro-myostatin, the most abundant form in muscle tissue. Upon cleavage by furin, pro-myostatin becomes a latent complex, the most abundant form in the blood, composed of two N-terminal propeptides (shown in blue) and a C-terminal (C-ter) disulfide-linked dimer (shown in yellow). When the propeptides are cleaved by bone morphogenetic protein (BMP)-1/tolloid (TLD)-like metalloproteinases, the C-ter dimer is released and binds to activin type II receptors A or B (ActRIIA/B). This binding recruits and activates activin receptor-like kinase 4/5 (ALK4/5), leading to SMAD2/3 phosphorylation and complex formation with SMAD4. The SMAD complex then translocates to the nucleus, where it regulates gene expression and thereby inhibits skeletal muscle growth. (1) Apitegromab targets pro-myostatin and latent myostatin complex, and its effects were evaluated in combination with semaglutide, a GLP-1 agonist, and tirzepatide, a dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonist, in the completed obesity trial NCT06445075. (2) Trevogrumab is an antibody that targets myostatin in its pro-, latent, and mature forms, and is being administered together with garetosmab, an antiactivin A antibody, and semaglutide in the ongoing obesity trial NCT06299098. (3) Bimagrumab blocks ActRIIA/B, thereby preventing myostatin binding, and has been tested as monotherapy in the completed diabetes and obesity trial NCT03005288 and is being evaluated in the obesity trial NCT05933499, as well as in combination with semaglutide in the obesity trial NCT05616013.

MYO-029 is a recombinant human antibody with a strong affinity for MSTN, effectively blocking its activity. Originally developed as a treatment for muscular dystrophy, a study evaluating the safety of this MSTN inhibitor found no significant side effects, except for skin hypersensitivity reactions, such as rashes, particularly in cohorts receiving higher doses.[68] Landogrozumab (LY2495655) is another antibody that binds to and neutralizes MSTN. It was evaluated in a randomized phase 2 trial involving older individuals who had experienced a fall due to reduced muscle strength.[69] In contrast to MYO-029, which was found to be safe but insufficiently effective in producing a robust increase in muscle mass,[70] landogrozumab effectively increased lean body mass and improved overall physical performance in a geriatric population with diminished muscle strength.[69] However, due to the high similarity between MSTN and GDF11, many anti-MSTN antibodies have been reported to also bind to GDF11, raising concerns about potential side effects resulting from GDF11 inhibition. Notably, our recent studies demonstrated that GDF11 promotes bone formation, whereas MSTN inhibits it, indicating that agents like follistatin, which simultaneously inhibit both GDF11 and MSTN, may increase muscle mass through MSTN inhibition but weaken bone by suppressing GDF11. [71–73]

In the early stages of MSTN inhibitor development, the mature form of MSTN was primarily targeted. However, with growing evidence that the semi-latent form of MSTN also exhibits significant biological activity similar to the mature form,[74] antibody designs were refined to target not only the mature form, but also the latent form and the unprocessed pro-MSTN. Trevogrumab (REGN1033) is an antibody that binds to multiple forms of MSTN with high affinity and specificity, while avoiding closely related proteins such as GDF11 and activins, which also signal through activin type II receptors.[75] Another antibody that targets pro-MSTN and the latent form to inhibit the release of active MSTN is apitegromab (SRK-015).[76] The mature form of MSTN shares high similarity with other closely related TGF-β family members, including GDF11, and activin receptors can bind a variety of ligands.[72] Therefore, inhibitors that target only mature MSTN or activin receptors may lead to undesirable off-target effects, as highlighted earlier. In contrast, apitegromab and trevogrumab target pro-MSTN and the latent complex, which helps minimize such side effects.[75,76] An additional noteworthy finding from studies on these two antibodies is that they not only increased muscle mass but also reduced fat mass.[75,76] This supports the notion that comprehensive MSTN inhibition, from its inactive forms to the mature form, represents a promising strategy for treating muscle loss in conjunction with metabolic disorders (Fig. 2). Table 1 summarizes MSTN signaling inhibitors currently being tested for metabolic disorders, and these clinical trials highlight the emerging role of MSTN inhibitors as potent agents to counteract the loss of lean mass commonly observed with GLP-1 agonist therapy. It is also worth noting that Table 1 includes trials targeting various components of the MSTN signaling pathway, including inhibitors of ActRIIA/B and agents targeting specific forms of MSTN (e.g. pro-, latent, or mature MSTN). Although these agents act at different levels of the pathway, they all aim to block MSTN signaling and promote muscle mass, thereby addressing lean mass loss and associated metabolic dysregulation.

Table 1.

Current clinical trials of myostatin signaling pathway inhibitors, alone or in combination with glucagon-like peptide-1 agonists, in metabolic disorders

Conditions	Company	Interventions	Drug targets	Status	Year	NCT number
Obesity, type 2 diabetes mellitus	Novartis	Bimagrumab	- Bimagrumab: Human monoclonal antibody that blocks ActRII type A and B	Completed (phase 2)	- Start: 2017 - Primary completion: 2019 - Study completion: 2019	NCT03005288
Obesity	Eli Lilly and Company	Bimagrumab, semaglutide	- Bimagrumab: Human monoclonal antibody that blocks ActRII type A and B - Semaglutide: GLP-1 receptor agonist	Active, not recruiting (phase 2)	- Start: 2022 - Primary completion: 2024 - Study completion: 2025	NCT05616013
Obesity	Scholar Rock, Inc.	Apitegromab, semaglutide, tirzepatide	- Apitegromab: Human IgG4 monoclonal antibody that targets pro and latent forms of myostatin - Semaglutide: GLP-1 receptor agonist - Tirzepatide: GIP receptor and GLP-1 receptor agonist	Completed (phase 2)	- Start: 2024 - Primary completion: 2025 - Study completion: 2025	NCT06445075
Obesity	Regeneron Pharmaceuticals	Trevogrumab, garetosmab, semaglutide	- Trevogrumab: Human monoclonal antibody targeting myostatin (GDF-8) - Garetosmab: Human IgG4 monoclonal antibody that targets activin A - Semaglutide: GLP-1 receptor agonist	Recruiting (phase 2)	- Start: 2024 - Primary completion: 2026 - Estimated study completion: 2026	NCT06299098
Obesity	Massachusetts General Hospital	Bimagrumab	- Bimagrumab: Human monoclonal antibody that blocks ActRII type A and B	Not yet recruiting	- Start: 2025 - Primary completion: 2028 - Estimated study completion: 2028	NCT05933499

ActRII, activin type II receptor; GLP-1, glucagon-like peptide-1; GIP, glucose-dependent insulinotropic polypeptide; GDF-8, growth/differentiation factor-8.

A clinical trial conducted by Scholar Rock, Inc. investigated the synergistic effects of MSTN inhibitors and GLP-1 agonists by administering apitegromab in combination with semaglutide, a GLP-1 agonist, and tirzepatide, a dual agonist of GLP-1 and glucose-dependent insulinotropic polypeptide, in patients with obesity (NCT06445075). This trial demonstrated that combining apitegromab with tirzepatide preserved 54.9% more lean mass compared to tirzepatide alone, resulting in more favorable body composition changes, and validated the potential of MSTN inhibitors to support healthier weight loss in patients receiving GLP-1 therapies. Another clinical trial led by Regeneron is currently evaluating the synergistic effects of trevogrumab and garetosmab in combination with semaglutide in obese patients, with the goal of reducing fat mass while preserving lean mass (NCT06299098).

Bimagrumab is a human monoclonal antibody that was developed by Novartis and blocks activin type II receptors, specifically ActRIIA and ActRIIB, thereby inhibiting the binding of MSTN and related ligands, including such as activins and GDF11. It binds to ActRIIB with approximately 200-fold greater affinity than to ActRIIA and has been shown to induce skeletal muscle hypertrophy by 7% while preserving muscle function when administered in vivo.[77,78] This antibody was initially tested in muscle-related disorders such as inclusion body myositis [79] and sarcopenia.[78] Then, in 2017, its metabolic effects were explored by Novartis, demonstrating a 20.5% reduction in fat mass and a 3.6% increase in lean mass after 48 weeks of monthly administration with lifestyle intervention in obese patients with type 2 diabetes (NCT03005288).[80] This is currently being followed by an ongoing clinical trial sponsored by Eli Lilly and Company (NCT05616013), in which both bimagrumab and semaglutide are being tested in obese adults to evaluate their combined effects with GLP-1 agonists. In addition, Massachusetts General Hospital is conducting a clinical trial comparing 30 mg/kg of bimagrumab, higher than the 10 mg/kg used in most previous studies, combined with calcium and vitamin D supplementation, to placebo with semaglutide, and placebo alone. The goal is to assess the multifaceted effects of these interventions on muscle, fat, and bone (NCT05933499).

CURRENT CHALLENGES AND FUTURE DIRECTIONS

GLP-1 agonists have demonstrated remarkable efficacy in promoting weight loss; however, their use is often accompanied by reductions in lean mass and potential fat regain upon discontinuation. Since the discovery of MSTN, substantial progress has been made in understanding its role in regulating muscle, bone, and fat. To address the limitations of GLP-1 analogs, ongoing preclinical and clinical studies are evaluating the combined use of MSTN inhibitors and GLP-1 agonists. While early results are promising, further investigation is needed to resolve remaining safety and efficacy concerns. A major challenge in MSTN inhibition is the potential for off-target effects, as other TGF-β family ligands, such as GDF11, activins, and BMPs, share the same receptor.[81] Thus, blocking MSTN may unintentionally disrupt other critical signaling pathways. In particular, GDF11 is highly homologous to MSTN and can have opposing effects in tissues such as bone and muscle. [71–73] Targeting the pro- and latent forms of MSTN, as with apitegromab and trevogrumab, may offer a strategy to reduce off-target effects.

Other approaches to muscle anabolic therapeutics share similarities with MSTN inhibition but yield varied results. MSTN and activins both negatively regulate muscle growth, [13] prompting the development of inhibition strategies that also target activin A. Studies have shown that simultaneous blockade of both activin A and MSTN, both ligands of ActRIIA/B, produces greater increases in muscle mass than inhibiting either alone.[82] This finding is supported by clinical trials, where combined treatment with trevogrumab (anti-MSTN) and garetosmab (anti-activin A) increased total body muscle volume and reduced fat mass compared with placebo or either antibody alone.[83] Overall, activin A inhibitors are as promising as MSTN inhibitors, and their combination may yield superior outcomes.

Follistatin is a protein that binds to MSTN and activin, thereby preventing these ligands from interacting with their receptors, ActRIIA/B.[13] This property has been utilized in gene therapy to treat degenerative muscle diseases.[84] The application of this therapy is not limited to muscle-related diseases. In a study using high-fat diet mice treated with AAV-mediated follistatin gene therapy, follistatin overexpression demonstrated multifactorial effects, including increased muscle mass, improved metabolism, and browning of adipose tissue.[85]

Exercise mimetics offer an alternative for individuals unable to engage in physical activity but who require its physiological benefits. Recently, the exercise-induced microRNA miR-129-3p has been proposed as a promising candidate for exercise mimetics, as it maintains muscle integrity via the PARP1–SIRT1–PGC1α axis and ameliorates muscle atrophy and mitochondrial dysfunction.[86] Electrical pulse stimulation (EPS) has been used to mimic muscle contraction in myotubes and induce transcriptional changes comparable to in vivo exercise. The myokine amphiregulin, which activates endothelial growth factor receptor signaling to promote muscle repair, was upregulated in both EPS and in vivo exercise, further supporting its potential as an exercise mimetic.[87]

Recently, δ-like non-canonical Notch ligand 1 (DLK1) has been recently introduced as a novel modulator of MSTN signaling, offering a potential alternative mechanism. Although its selectivity is not necessarily superior to existing inhibitors, DLK1 competes with MSTN for binding to ActRIIB and promotes muscle regeneration through modulation of SMAD2/3 and Notch signaling pathways.[88] However, to date, no clinical trials have investigated DLK1 activation or overexpression as a strategy to promote muscle growth, although such studies may offer promising therapeutic opportunities for the management of metabolic disorders.

CONCLUSION

The obesity epidemic, driven by modern sedentary lifestyles and high-calorie diets, continues to challenge current treatment paradigms. While bariatric surgery has been the most effective traditional intervention for weight management, GLP-1 receptor agonists have brought a breakthrough in the treatment of obesity and diabetes.[89] Recent studies suggest that combining GLP-1 agonists with MSTN inhibitors may enhance therapeutic efficacy while mitigating muscle loss, a key side effect of GLP-1 therapy. This review has examined the potential of MSTN inhibition as a compensatory strategy to preserve lean mass, particularly in the context of GLP-1 therapy and sarcopenic obesity, as well as its emerging role in the management of broader metabolic diseases. We also summarized ongoing clinical trials evaluating MSTN inhibitors alone or in combination with GLP-1 agonists (Table 1). Although early results are promising, further research is needed to optimize dosing strategies and mitigate side effects from polypharmacy. Nevertheless, MSTN inhibition holds promise as a dual modulator of muscle and fat, offering a novel therapeutic avenue for metabolic disorders.