Sarcopenic obesity and weight loss-induced muscle mass loss

Abstract

Purpose of review

Sarcopenic obesity is a clinical condition characterized by the coexistence of excess adiposity and impaired muscle function, associated with heightened cardiometabolic risk and frailty. The emergence of new incretin-based obesity management medications (OMMs), which allow unprecedented weight loss, has raised concerns regarding weight loss-induced fat-free mass (FFM) reduction, including skeletal muscle mass (SMM). This review examines recent findings on the prevalence, diagnosis, and implications of sarcopenic obesity, explores the effects of weight-loss interventions on body composition and their impact on health, and discusses strategies to preserve muscle mass.

Recent findings

Weight loss induced by incretin-based OMMs results in a variable but significant reduction in FFM. The extent to which this loss affects SMM and function remains uncertain. Nutritional strategies, particularly adequate protein intake, and structured exercise interventions, especially resistance training, play a key role in mitigating FFM loss. Digital health interventions and telemedicine-based exercise programs offer promising approaches for maintaining muscle health during weight loss.

Summary

The clinical significance of FFM loss during weight reduction remains debated. Future research should refine sarcopenic obesity diagnostic criteria, assess the long-term impact of FFM/SMM reduction during intentional weight loss, and evaluate interventions that optimize body composition while preserving functional health.

INTRODUCTION

Recent advances in obesity pharmacotherapy have transformed obesity management, with incretin-based obesity management medications (OMMs) achieving weight loss magnitudes that approach those of bariatric surgery [1]. However, emerging evidence suggests that this pharmacologically induced weight loss, similar to bariatric surgery-induced weight loss [2], is often accompanied by reductions in fat-free mass (FFM), including skeletal muscle, raising concerns about its potential implications for frailty and sarcopenic obesity [3,4]. While weight loss has well documented metabolic benefits, the degree to which skeletal muscle mass (SMM) is affected is not known, and whether this represents an adaptive response, where muscle function and metabolic health remain preserved, or a clinically relevant, maladaptive process that could contribute to sarcopenic obesity and functional decline remains unclear [3,5^▪,6^▪]. This review aims to provide an updated perspective on the intersection of pharmacologically induced weight loss, sarcopenic obesity, and muscle health. Specifically, it explores issues in the definition and diagnosis of sarcopenic obesity, summarizes recent epidemiological findings, examines the effects of weight loss interventions, including incretin-based OMMs on body composition, and explores the potential risks associated with weight loss-induced SMM loss. Finally, we discuss strategies to improve body composition during weight loss, including nutritional, exercise-based, and pharmacological interventions. 

Box 1.

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DEFINITIONS AND EPIDEMIOLOGY

Sarcopenia is now recognized as a generalized skeletal muscle disease, defined by both low muscle mass and reduced muscle strength [7]. The diagnosis of sarcopenia relies on the combined assessment of muscle mass and strength [8]. While initial definitions emphasized low muscle mass as the key feature of sarcopenia, accumulating evidence supports a more comprehensive approach that prioritizes muscle strength as a critical indicator of functional impairment, with impaired physical performance considered an outcome rather than a defining feature of sarcopenia. This evolving perspective aligns with research demonstrating that muscle weakness, rather than muscle mass alone, is more strongly predictive of adverse health outcomes [7,8].

Sarcopenic obesity is a complex condition characterized by the coexistence of sarcopenia and excess adiposity, leading to heightened health risks. Sarcopenic obesity is particularly prevalent in older adults [9], and is associated with functional decline, reduced mobility, and an increased risk of disability, contributing to a heightened burden of frailty [10,11]. A growing body of evidence also links sarcopenic obesity to adverse cardiometabolic outcomes, including insulin resistance, dyslipidemia, and coronary artery disease, amplifying the risk of cardiovascular morbidity and mortality [12], and all-cause mortality [13]. The recognition of sarcopenic obesity as a separate clinical entity has grown following the establishment of international standard definitions, particularly by the European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) [14]. This classification underscores the need for an integrated assessment of muscle mass/function and fat accumulation (Fig. 1). Since the publication of this consensus statement in 2022 [15], several studies have sought to estimate the prevalence of sarcopenic obesity in different populations using the ESPEN/EASO criteria, which were consistently applied across all studies cited below. Sarcopenic obesity is present in approximately 9% of community-dwelling older adults aged at least 65 years, with similar prevalence rates reported in specific cohorts, such as Australian men aged at least 70 years [14,16]. A study conducted in Korea found that 8.7% of men and 10.4% of women aged at least 70 years met the diagnostic criteria for sarcopenic obesity [17]. The prevalence appears to be markedly higher in individuals with severe obesity, with estimates reaching 25.5% in those with a BMI of at least 35 kg/m² aged at least 60 years [18]. In contrast, in adults aged at least 50 years with a BMI of at least 27 kg/m², the prevalence was as low as 1.2% [13]. Most epidemiological studies on sarcopenic obesity have focused on older adults because sarcopenia is traditionally considered an age-related condition. There is a notable lack of data on the prevalence of sarcopenic obesity in younger individuals, a population that is becoming increasingly relevant, especially given that those receiving incretin-based OMMs are, on average, younger than 50 years [19,20].

FIGURE 1.

Screening, diagnosis, and staging of SO is a sequential process [15]. Screening requires the presence of elevated BMI or waist circumference (ethnicity-specific cut-offs) AND indicators of sarcopenia, such as clinical symptoms, risk factors, or validated questionnaires. Diagnosis is confirmed only if both impaired muscle function and increased fat mass + reduced muscle mass are present. Only if muscle function is impaired, DXA (preferred) or BIA (alternative) is used to evaluate body composition. Staging is performed once SO is diagnosed. ALM/W, appendicular lean mass adjusted to body weight; BIA, bioelectrical impedance analysis; BMI, body mass index; DXA, dual X-ray absorptiometry; FM, fat mass; SMM/W, total skeletal muscle mass adjusted by weight; SO, sarcopenic obesity; WC, waist circumference. Created in BioRender. Conte, C. (2025) https://BioRender.com/j35q358.

BODY COMPOSITION AND MUSCLE STRENGTH: DO WE REALLY KNOW WHAT WE ARE TALKING ABOUT?

The study of body composition and muscle strength has long been complicated by inconsistent terminology and methodological differences, leading to considerable confusion in both the clinical and research settings. Key terms such as FFM, lean soft tissue, and SMM are frequently used interchangeably despite representing distinct entities. Historically, body composition research was built on two-component models that categorized the body into fat mass and FFM [21]. The latter comprises not only SMM but also skin, organs, bones, and extracellular fluid. Although commonly used, this description lacks precision, as FFM is a molecular entity, whereas tissues and organs are anatomically defined structures that may contain both fat and fat-free molecules (Fig. 2). Modern perspectives advocate for the use of the chemically accurate term “FFM” to describe all nonfat molecules in the body, regardless of where they occur, and prefer the term “lean soft tissue” over “lean body mass” when referring to FFM excluding bone mineral content [22]. While both FFM and lean soft tissue can be measured by bioelectrical impedance analysis (BIA), dual-energy X-ray absorptiometry (DXA), and 3D optical imaging, SMM can only be quantified by techniques such as computed tomography or MRI, or estimated using validated equations based on these techniques. However, no universally accepted standard for SMM quantification exists [23]. Importantly, as the proportion of FFM derived from skeletal muscle is highly variable, changes in FFM/lean soft tissue mass may not always reflect changes in SMM [6^▪].

FIGURE 2.

Schematic representation of the difference between measurements at the molecular and anatomical body composition levels. FFM and FM consist of all nonfat (water, protein, mineral, residual component) and fat molecules in the body, respectively, regardless of their location. Skeletal muscle and adipose tissue are anatomically defined. Skeletal muscle predominantly includes fat-free molecules (water, protein, minerals, glycogen, etc.), but also a small amount of lipids. Adipose tissue predominantly includes fatty molecules, but it also includes a small amount of fat-free molecules (water, protein). Data and data representation are for illustrative purposes, and are from [6^▪]. 3DO, three-dimensional optical imaging; ADP, air displacement plethysmography; BIA, bioelectrical impedance analysis; BIS, bioimpedance spectroscopy; CT, computed tomography; DXA, dual-energy x-ray absorptiometry; FM, fat mass; FFM, fat-free mass; SKF, skinfold thickness; US, ultrasonography; UWW, underwater weighing. Created in BioRender. Conte, C. (2025) https://BioRender.com/m78t115.

In addition to muscle mass, strength assessments also exhibit methodological inconsistencies. The European Working Group on Sarcopenia in Older People (EWGSOP2) and ESPEN/EASO recommend handgrip strength or chair stand tests as measures of muscle function (Fig. 1) [15,24], yet these assessments are not interchangeable. While handgrip strength is widely used as a simple and reliable proxy for overall strength, lower-limb strength, as assessed by chair stands, often serves as a better predictor of mobility impairments and functional decline [25,26]. Recent studies indicate that adiposity differentially influences these measures, with excess fat mass disproportionately impairing lower-limb strength. This leads to discrepancies in sarcopenia prevalence depending on which test is used [27^▪].

In addition to proper nomenclature, the concept of muscle quality is essential for assessing muscle health. Muscle quality denotes the capacity of muscle to produce force in relation to its size, influenced by factors like fat infiltration (myosteatosis), fiber composition, and neuromuscular activation. Evaluating muscle quality offers a more thorough insight into muscle function, particularly in conditions such as sarcopenia and obesity, where muscle mass alone may inadequately represent functional capacity [28]. Skeletal muscle also plays a central role in metabolic homeostasis, serving as the primary site for glucose disposal and glycogen storage during feeding and in response to insulin stimulation, and functions as an endocrine organ that releases bioactive molecules, including myokines and exerkines that influence systemic metabolism [29]. In sarcopenic obesity, alterations in skeletal muscle extend beyond mass reductions, with increased intramuscular fat infiltration and mitochondrial dysfunction contributing to a decline in muscle quality. These metabolic changes are associated with impaired insulin sensitivity and reduced muscle oxidative capacity, which exacerbate the risk of cardiometabolic disorders [30]. The interplay between skeletal muscle and systemic metabolic regulation highlights the need to consider not only muscle mass, but also its functional and biochemical properties when evaluating the impact of weight loss, aging, and pharmacological interventions on metabolic health.

The complexity of assessing body composition, muscle strength, and other muscle features underscores the need for standardized definitions and methodologies in this field.

IMPACT OF GLP-1 RECEPTOR AGONISTS ON BODY COMPOSITION

The most recently marketed incretin-based OMMs, such as semaglutide and tirzepatide, offer weight loss magnitudes approaching those achieved with bariatric surgery [31]. Studies indicate that weight reduction using incretin-based medications is associated with a variable but considerable loss of FFM, raising concerns regarding muscle health. The proportion of weight lost as FFM ranges from approximately 20% to approximately 40% of total weight loss, with the majority of studies reporting FFM loss exceeding 25% [32,33^▪,34,35], which is consistent with expected physiological responses to weight reduction rather than an unintended adverse effect. During calorie restriction, FFM loss typically accounts for 20–30% of total weight loss, with SMM making up only a fraction of this loss [6^▪]. A recent meta-analysis showed that incretin-based medications led to significant reductions in fat mass, while the modest decline in FFM – similar in individuals with and without diabetes – did not result in a significant change in the proportion of FFM compared to nonusers [33^▪].

It is crucial to highlight that not all FFM/lean soft tissue loss is attributable to SMM loss, and some reductions may reflect a decline in extracellular fluid or organ size rather than SMM losses. For example, despite significant (although modest) reductions in DXA-derived total body and appendicular lean soft tissue following a weight loss intervention in older adults, whole-body muscle mass, as measured by the D₃-creatine dilution method that directly measures whole body SMM via stable isotope tracer technology, remained unchanged [36]. Furthermore, obligatory fat-related FFM loss occurs naturally as a consequence of fat depletion, since adipose tissue contains structural and extracellular components that are chemically classified as FFM. As fat is lost, a proportional amount of FFM is also reduced [6^▪]. The extent of FFM/SMM reduction is influenced by several factors, such as age, sex, baseline adiposity, dietary intake, and physical activity. Very few studies have actually measured changes in SMM during weight loss. Recent analyses have highlighted sex differences in response to pharmacotherapy for obesity. In a large cohort study, Yang et al.[37] found that women treated with GLP-1 receptor agonists lost more weight than males, with differences becoming more pronounced at greater weight loss levels. Potential mechanisms underlying this difference include greater drug exposure, higher likelihood of gastrointestinal unwanted effects, and greater treatment adherence in women [37]. Most clinical trials do not report body composition changes separately by sex, limiting insight into sex-specific effects on FFM and SMM. Available evidence suggests that males tend to lose a greater absolute and relative proportion of FFM/SMM than females during weight loss interventions [38,39]. Using whole-body MRI, Heymsfield et al. [39] found that, on average, nonelderly men and women with overweight or obesity lose 2–2.5 and 1–1.5 kg of skeletal muscle, respectively, for each 10-kg diet-induced weight loss. Sex differences may be partly explained by baseline body composition; men generally have higher SMM, while women have greater fat mass. Individuals with greater initial fat mass may experience a smaller proportion of FFM loss as they can rely more on fat stores for energy during caloric restriction, sparing protein-rich tissues like muscle [40]. Hormonal factors may also play a role, but many aspects of the relationship between sex hormones and muscle mass, strength, and function remain incompletely understood. Caloric restriction affects sex hormone levels, with testosterone increasing in men and both estrogen and testosterone declining in women [41,42], yet the impact of these changes on SMM is unclear. Additional factors such as fibroblast growth factor 21 (FGF21) may also contribute to sex-specific adaptations in metabolism and muscle regulation during weight loss [43].

A critical question surrounding weight loss with GLP-1 RAs is whether reductions in FFM translate into loss of muscle strength and physical function. Studies evaluating diet and bariatric surgery-induced weight loss have provided valuable insights. Diet-induced weight loss has been associated with modest declines in isokinetic knee extensor strength, while handgrip strength shows more variability [44]. Systematic reviews have shown that bariatric surgery leads to reductions in absolute muscle strength, particularly in the lower limbs, and grip strength, with losses proportional to overall weight reduction [45^▪▪]. Nevertheless, when muscle strength is adjusted for body weight or lean mass, no significant changes or even improvements can be observed [45^▪▪], even in individuals with lower muscle mass and strength prior to surgery [46].

In trials of incretin-based OMMs, patient-reported outcomes related to physical function suggest improvements rather than deterioration. In the SURMOUNT-1 trial, participants receiving tirzepatide reported enhanced physical function and improved quality of life, as assessed by validated questionnaires [47^▪]. Similarly, in the STEP 9 trial, individuals with obesity and knee osteoarthritis treated with semaglutide experienced approximately 14% weight loss and demonstrated better functional capacity at study end [48]. Both drugs improved physical function (as assessed by 6-min walking distance) in people with obesity and heart failure with preserved ejection fraction (HFpEF) [49,50]. Improvements in all domains of the Kansas City Cardiomyopathy Questionnaire, including the Physical Limitations Score, were proportional to weight loss in the STEP HFpEF trial of semaglutide [51]. Thus, despite reductions in FFM associated with weight loss, physical function may remain stable or even improve, even in complex patients. Only a small proportion of trials on incretin-based OMMs reported body composition and functional outcomes [52]. There is an urgent need for accurate and objective assessments of muscle mass and strength in future trials to clarify the clinical relevance of FFM reduction with Incretin-based OMMs.

Beyond mass and strength, muscle quality has gained attention as a critical determinant of functional capacity. Weight loss has been shown to reduce intramuscular lipid content and improve insulin sensitivity, a key marker of metabolic SMM function [53]. Similarly, weight loss induced by incretin-based OMMs may lead to favorable changes in muscle composition, potentially offsetting some of the concerns related to FFM reduction. For example, treatment with liraglutide was associated with a reduction in thigh muscle fat infiltration compared to placebo, suggesting an improvement in muscle composition during weight loss [54^▪▪]. Furthermore, preclinical evidence suggests that incretin-based OMMs have a positive effect upon certain indices of skeletal muscle mitochondrial health [55].

POTENTIAL RISKS ASSOCIATED WITH WEIGHT LOSS-INDUCED MUSCLE MASS LOSS

Unintentional weight loss and reductions in SMM have long been recognized as risk factors for increased morbidity and mortality in older adults. Longitudinal studies have demonstrated that age-related declines in muscle mass and function contribute to disability and reduced survival [4], as well as increased fracture risk [56]. Skeletal muscle plays a key role in bone health through both mechanical and biochemical pathways. Muscle contractions exert mechanical loading on bones, which stimulates bone remodeling and osteogenesis, enhancing bone strength and integrity [57–59]. Additionally, muscle-derived myokines such as irisin, IL-6, and IGF-1 contribute to anabolic signaling in bone tissue [58,60]. Registry studies show that loss of lean mass and reductions in bone mineral density (BMD) independently increase fracture risk; for instance, Giangregorio et al.[56] reported that loss of appendicular or total LBM is an independent predictor of major osteoporotic fractures, even in individuals on osteoporosis therapy. Calorie restriction-induced weight loss may lead to reductions in both SMM and BMD, which might synergistically increase fracture risk. While fracture risk after bariatric surgery appears to be procedure-dependent, with greater risk after malabsorptive procedures [61], data on fracture risk following nonsurgical weight loss, including incretin-based OMMs, are limited. Preclinical studies suggest a neutral effect of semaglutide and tirzepatide on bone in diabetic and obese mice [62,63], and meta-analyses in humans indicate no consistent adverse impact on BMD, although bone resorption markers may increase [64].

The degree of FFM reduction observed with incretin-based OMMs (up to ∼10% from baseline FFM or ∼6 kg) has been compared to age-related FFM decline and even cancer-related sarcopenia [65]. However, it is important to distinguish involuntary weight loss due to aging, underlying disease or frailty from intentional weight loss aimed at improving health in people living with obesity. The mechanisms of muscle loss in obesity treatment differ from sarcopenia of aging. Age-related sarcopenia is driven by chronic inflammation, hormonal changes, and mitochondrial dysfunction [66,67]. In addition to these mechanisms, in SO, excess adiposity sustains a proinflammatory state and leads to intramuscular fat deposition, which contributes to anabolic resistance and activates pro-inflammatory pathways, disrupting muscle remodeling and regeneration [66,68]. Aging and disease-related sarcopenia, as well as sarcopenic obesity, are associated with detrimental health outcomes [66–68]. Contrary to unintentional weight loss, intentional weight reduction achieved through pharmacotherapy, bariatric surgery or lifestyle interventions leads to a reduction in lean mass due to caloric restriction and metabolic changes that appear to be adaptive [5^▪], with health benefits that are proportional to the amount of weight lost [69,70]. A comparison of calorie restriction, aerobic exercise, both, and age-related changes in muscle strength and lean mass, both measured at the thigh level, highlights that age-related declines in muscle strength occur approximately three times faster than losses in muscle mass (Fig. 3) [71,72]. In contrast, calorie restriction alone leads to reductions in lean mass equivalent to about 4 years of aging, yet muscle strength improves. Incorporating aerobic exercise mitigates lean mass loss and further enhances strength gains. Furthermore, emerging evidence suggests that even massive weight loss achieved with bariatric surgery does not result in worsening of measures of sarcopenic obesity. It can, instead, lead to sarcopenic obesity remission in a significant proportion of patients [73,74^▪▪].

FIGURE 3.

Changes in lean mass and strength with aging (grey, annualized rates) and after ∼ 7% weight loss achieved with calorie restriction, aerobic exercise, or both in men and women with overweight (green). Leg lean mass was measured by DXA. Leg strength was measured by isokinetic knee extensor strength at 60°/s. Approximate relative changes were derived from group-level means or medians and are reported for illustrative purposes only. Data from [71] and [72].

To date, there is no evidence that intentional weight loss in people living with obesity, whether through medical or surgical interventions, leads to frailty or impaired physical function. There is, instead, evidence that obesity, abdominal obesity, and excess adiposity are associated with frailty [75,76], suggesting that reducing adiposity may reduce this risk. Nevertheless, it is possible that weight-loss-induced muscle loss has clinical implications in specific populations, particularly those with low SMM at baseline such as the elderly or people with sarcopenic obesity and comorbid conditions, including metabolic-dysfunction associated steatotic liver disease and steatohepatitis, which are very often associated with sarcopenic obesity [77]. A comprehensive clinical assessment is essential for proper diagnosis, staging, and management of obesity to optimize health outcomes and mitigate SMM loss risks [78–80]. A recent expert panel identified 50 key risk and protective factors for sarcopenic obesity, including lifestyle behaviors, clinical conditions, and biological determinants [81] that could be assessed in a weight management program.

Weight cycling, commonly referred to as “yo-yo dieting”, involves repeated cycles of weight loss, followed by weight regain. This phenomenon is particularly relevant in the context of OMM-induced weight loss, where high discontinuation rates often lead to weight regain, potentially necessitating reinitiation of therapy and subsequent weight loss cycles [82]. The long-term consequences of repeated fluctuations in body weight remain controversial, with some studies suggesting that weight cycling may have minimal effects on long-term body composition, metabolic rate, or lean body mass [83], and others raising concerns about its role in progressive metabolic deterioration, particularly when weight regain consists predominantly of adipose tissue rather than lean mass [84,85]. However, to the best of our knowledge, no studies have directly assessed the composition of weight regain following the discontinuation of incretin-based OMMs. Concerns about disproportionate fat regain, often referred to as “fat overshooting” or “catch-up fat”, originated from the Minnesota Starvation Experiment, which demonstrated that in lean individuals undergoing prolonged semistarvation, weight regain favored fat over lean tissue. Yet, this model may not be applicable to individuals with obesity [3,86]. For example, a meta-analysis of longitudinal studies in which weight loss (≥5%) and subsequent weight regain (≥2%) occurred found that the proportion of FFM regained after weight loss (21.6%) was comparable to or slightly higher than the proportion of FFM lost (19.6%) [87], providing no evidence for progressive deterioration of body composition with weight regain in people with obesity. Nonetheless, weight cycling has been linked to an increased risk of sarcopenia and frailty in older adults [85] and is deemed as one of the “lifestyle factors” associated with sarcopenic obesity [81], underscoring the importance of monitoring muscle mass and function in individuals undergoing repeated weight loss attempts.

STRATEGIES TO PRESERVE MUSCLE HEALTH

While intentional weight-loss-induced reductions in muscle mass are often an adaptive response, preserving FFM may provide additional metabolic and functional benefits, particularly in individuals at risk for sarcopenic obesity and frailty. Increasing protein consumption beyond the levels recommended for healthy individuals is a crucial approach for reducing FFM loss during weight loss. Prolonged, moderate caloric restriction predominantly induces muscle proteolysis rather than inhibiting muscle protein synthesis, highlighting the necessity for dietary approaches to “feed” the skeletal muscle [5^▪]. In fact, while protein ingestion may not significantly reduce proteolysis or stimulate muscle protein synthesis beyond a certain point, it may still contribute to a positive net protein balance during periods of energy deficit.

Recommended protein intake varies widely across guidelines, ranging from 0.8 g/kg body weight per day for healthy individuals to 1.2–1.5 g/kg for those over 65 years. In specific populations, recommendations increase further, with 60 g/day or up to 1.5 g/kg of ideal body weight advised following bariatric surgery and 1.0–1.5 g/kg of adjusted body weight for adults with type 2 diabetes and overweight or obesity [88]. Recent studies indicate that individuals with overweight or obesity who consume higher protein diets (1.3 g/kg per day) during weight loss retain more muscle mass compared to those without enhanced protein intake [89]. However, enhanced protein intake does not seem to preserve muscle strength and physical function [89]. While some evidence suggests that the anabolic response to protein ingestion may persist beyond traditionally accepted thresholds under specific experimental conditions [90], extensive prior research indicates that muscle protein synthesis responses typically plateau at approximately 20–30 g of high-quality protein per meal in younger adults [91–93]. These findings suggest that protein intake beyond this threshold may not further increase muscle protein synthesis in most real-world settings. The relationship between protein intake, weight loss, and metabolic outcomes in people with obesity is complex. Some studies suggest that high protein intake (1.2 g/kg per day) during weight loss may attenuate improvements in insulin sensitivity [94], and that protein supplementation may dampen the positive effects of exercise on glucose homeostasis [95], raising questions about the optimal amount of protein to optimize overall metabolic health during weight loss. Additional factors beyond absolute protein amount, including meal distribution, co-ingestion with other macronutrients, physical activity, and baseline nutritional status, may also influence the anabolic response to dietary protein and may contribute to the observed attenuation of muscle loss with higher protein intakes during weight loss. A systematic review and meta-analysis of randomized controlled trials is currently underway to evaluate the impact of nutritional supplements on FFM preservation during weight loss [96].

Low physical activity levels are a major risk factor for sarcopenia, whereas higher physical activity levels are associated with a reduced risk of sarcopenic obesity [68,81,97,98^▪]. Exercise interventions may play a crucial role in improving body composition and functional performance during weight loss, particularly for individuals with sarcopenic obesity or those undergoing weight loss interventions. In people living with sarcopenic obesity, exercise training improves body composition and physical function [98^▪]. Resistance training, specifically, is associated with significant improvements in grip strength, knee extension strength, and walking speed, while mixed training (combining resistance and aerobic exercise) may yield favorable changes in body composition and metabolic markers [97].

Exercise not only complements dietary weight loss but also enhances its metabolic benefits. Regular physical activity during weight loss interventions has been shown to amplify improvements in insulin sensitivity and metabolic function [99]. In elderly individuals with obesity, a 6-month multimodal weight-loss intervention combining diet and exercise reduced weight and fat mass while improving metabolic health, inflammation, and quality of life [100]. The intervention did not increase frailty, and some functional parameters even improved. However, these benefits diminished within months of discontinuation, emphasizing the need for long-term obesity management strategies to sustain positive outcomes. In individuals undergoing bariatric surgery, structured exercise programs have been effective in preventing excessive loss of SMM, improving muscle strength, and enhancing functional capacity [101]. Combining aerobic and resistance training in the postoperative period can help mitigate potential adverse effects of rapid weight loss on SMM and function. There is paucity of data on the combination of Incretin-based OMMs and exercise. Jensen et al.[102^▪▪] investigated weight loss maintenance following the discontinuation of liraglutide, supervised exercise, or their combination. After an initial 8-week low-calorie diet, participants with obesity were randomized to one of four groups for a year: exercise alone, liraglutide alone, a combination of both, or placebo, followed by a 1-year post-treatment phase without intervention. Those who had previously received the combined treatment maintained greater weight loss and lower body fat percentage compared to liraglutide alone, with weight regain being most pronounced in the liraglutide-only group. These findings suggest that integrating exercise with OMMs enhances long-term weight maintenance after treatment cessation. Despite the benefits of exercise interventions, challenges remain in optimizing management strategies for individuals with obesity. Metabolic disease and obesity have been shown to impair the anabolic response to resistance exercise and protein supplementation, potentially limiting muscle mass retention [103]. Combining exercise and nutrition might yield better results in people with sarcopenic obesity [104] (Fig. 4). Innovative approaches, such as telemedicine and digital platforms, offer a scalable and accessible alternative to traditional weight loss programs, with some studies suggesting they may be at least equally effective [105]. A 6-month technology-based program combining diet and physical therapy enabled older adults with obesity to lose weight, regardless of frailty status, without adverse effects on lean mass [106]. Remote exercise programs have also been effective in preserving muscle function. A digital home-based exercise platform improved muscle strength in older adults with sarcopenia, while telemedicine-based multicomponent interventions produced comparable benefits regardless of sarcopenia status [107].

FIGURE 4.

Schematic representation of the attenuation of weight loss-induced reduction in FFM by dietary protein and exercise. Data and data representation are for illustrative purposes. Created in BioRender. Conte, C. (2025) https://BioRender.com/b03c093.

As the field of obesity pharmacotherapy advances, increasing attention is being directed toward preserving muscle mass during weight loss. Several drugs are now being investigated in combination with incretin-based OMMs to mitigate SMM loss while promoting fat reduction. Among the most promising approaches are myostatin inhibitors targeting activin type II receptor (ActRII) signaling, as well as novel combination therapies that leverage multiple hormonal pathways to optimize body composition.

Bimagrumab is a mAb that blocks ActRIIA and ActRIIB signaling. In animal models, blockade of ActRIIA/IIB was associated with significant gains in muscle mass, bone formation, reduced fat accumulation [108], and enhanced fat loss while preserving lean mass during GLP-1RA-induced weight loss [109]. However, despite clear benefits in body composition, its impact on functional outcomes remains inconsistent [110]. Trevogrumab is another antimyostatin monoclonal antibody that is being explored [111]. Preliminary evidence suggests that myostatin inhibition by trevogrumab may synergize with incretin-based therapies to preserve muscle mass in individuals undergoing significant weight loss [112], though long-term clinical trials are needed to determine its efficacy, safety, and effects on muscle function. Azelaprag, an apelin receptor agonist, has been proposed as an adjunct to incretin-based therapies, enhancing weight loss while selectively preserving FFM. However, a Phase 2 clinical trial assessing azelaprag and tirzepatide in individuals aged at least 55 years (NCT06515418) was recently discontinued due to elevated liver transaminases, in the absence of clinically significant symptoms [113]. Finally, dual and triagonist therapies, such as GLP-1/glucagon co-agonists, are being explored for their potential to attenuate metabolic adaptation during weight loss while promoting fat oxidation [114]. However, the impact of glucagon co-agonism on protein metabolism remains unclear, and in some contexts, glucagon may enhance amino acid catabolism and contribute to lean mass loss [115].

These novel agents are still investigational, and their long-term impact on muscle mass, physical function, and metabolic function remains to be determined.

CONCLUSION

While pharmacologically induced weight loss offers significant metabolic benefits, its impact on skeletal muscle and functional health warrants further investigation. Current evidence suggests that reductions in FFM during weight loss may not necessarily translate into adverse clinical outcomes; however, high-risk populations may require tailored strategies to preserve muscle health. Addressing gaps in sarcopenic obesity diagnosis, refining assessment methodologies, and integrating multimodal interventions will be critical to optimizing long-term health outcomes and enhance quality of life of people with obesity undergoing weight loss therapy.

Acknowledgements

None.

Financial support and sponsorship

This work was supported by the Italian Ministry of Health, Ricerca Corrente IRCCS MultiMedica.

Conflicts of interest

C.C. received speaker's honoraria from Therascience SAM, NewPenta srl, and Novo Nordisk, and speaker's and consultancy fees from Eli Lilly, outside the submitted work. A.A. has received grant support and consultant fees from NovoNordisk, grant support from Fractyl Laboratories, and is a steering committee member of Oxford Medical Products, outside the submitted work. For the remaining authors none were declared.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

• ▪ of special interest

• ▪▪ of outstanding interest