Metabolic dysfunction-associated steatotic liver disease: A story of muscle and mass

Abstract

Skeletal muscle alterations (SMA) are increasingly recognized as both contributors and consequences of metabolic dysfunction-associated steatotic liver disease (MASLD), affecting disease progression and outcomes. Sarcopenia is common in patients with MASLD, with a prevalence ranging from 20% to 40% depending on the population and diagnostic criteria used. In advanced stages, such as metabolic dysfunction-associated steatohepatitis and fibrosis, its prevalence is even higher. Sarcopenia exacerbates insulin resistance, systemic inflammation, and oxidative stress, all of which worsen MASLD. It is an independent risk factor for fibrosis progression and poor outcomes including mortality. Myosteatosis refers to the abnormal accumulation of fat within muscle tissue, leading to decreased muscle quality. Myosteatosis is prevalent (> 30%) in patients with MASLD, especially those with obesity or type 2 diabetes, although this can vary with the imaging techniques used. It reduces muscle strength and metabolic efficiency, further contributing to insulin resistance and is usually associated with advanced liver disease, cardiovascular complications, and lower levels of physical activity. Altered muscle metabolism, which includes mitochondrial dysfunction and impaired amino acid metabolism, has been reported in metabolic syndromes, including MASLD, although its actual prevalence is unknown. Altered muscle metabolism limits glucose uptake and oxidation, worsening hyperglycemia and lipotoxicity. Reduced muscle perfusion and oxygenation due to endothelial dysfunction and systemic metabolic alterations are common in MASLD associated with comorbidities, such as obesity, hypertension, and atherosclerosis. It decreases the muscle capacity for aerobic metabolism, leading to fatigue and reduced physical activity in patients with MASLD, aggravating metabolic dysfunction. Various SMA in MASLD worsen insulin resistance and hepatic fat accumulation, may accelerate progression to fibrosis and cirrhosis, and increase the risk of cardiovascular disease and mortality. Management strategies for SMA include resistance training, aerobic exercise, and nutritional support (e.g., high-protein diets, vitamin D, and omega-3 fatty acids), which are essential for mitigating skeletal muscle loss and improving outcomes. However, pharmacological agents that target the muscle and liver (such as glucagon-like peptide-1 receptor agonists) show promise but have not yet been approved for the treatment of MASLD.

Key Words: Metabolic dysfunction-associated steatotic liver disease; Skeletal muscle alterations; Sarcopenia; Skeletal muscle mass index; Myosteatosis; Dietary patterns; High-protein diet; Physical activity; Glucagon-like peptide-1 receptor agonists

Core Tip: Skeletal muscle alterations, such as sarcopenia, myosteatosis, and altered muscle metabolism, are highly prevalent in metabolic dysfunction-associated steatotic liver disease (MASLD) and are increasingly recognized as both contributors and consequences of MASLD, affecting disease progression and outcomes. Common treatment approaches for both conditions include nutritional interventions and physical activity/exercise aimed at increasing insulin sensitivity and reducing fat mass but maintaining muscle mass and function. Pharmacological agents that target the muscle and liver (such as glucagon-like peptide-1 receptor agonists) show promise, but have not yet been approved for the treatment of MASLD.

INTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, is characterized by the accumulation of fat in the liver (hepatic steatosis) in individuals with metabolic risk factors such as obesity, type 2 diabetes, metabolic syndrome, and minimal or no alcohol consumption[1,2]. According to the new nomenclature the term MASLD comprises different conditions, including isolated liver steatosis [metabolic dysfunction-associated steatotic liver (MASL)], metabolic dysfunction-associated steatohepatitis (MASH), as well as fibrosis and cirrhosis. Prevalence of MASL is increasing worldwide as well as of progressive form of the disease-MASH, which involves liver inflammation leading to fibrosis, cirrhosis, or hepatocellular carcinoma (HCC)[3,4]. Skeletal muscle alterations (SMA) are increasingly recognized as both contributors and consequences of MASLD, affecting disease progression and outcomes.

SARCOPENIA

Sarcopenia, characterized by the loss of skeletal muscle mass and function, is considered a common comorbidity in patients with MASLD, affecting both the progression of liver disease and overall health outcomes. Sarcopenia was described in 1988 by Rosenberg[5] as a loss of muscle mass related to ageing. However, recent guidelines separate primary sarcopenia, which is defined as age-related muscle decline in which no causes other than aging itself can be indicated, and secondary sarcopenia as the condition due to other detectable causes[6]. The latter is associated with MASLD. The prevalence of sarcopenia in patients with MASLD can be substantial and influenced by various factors, including age, sex, the severity of liver disease[7], and estimates suggest that between 25% and 70% of individuals with chronic liver disease exhibit signs of sarcopenia[8]. This prevalence is particularly pronounced in non-obese patients who may experience "hidden obesity", where muscle loss occurs despite normal body weight[9]. Recent meta-analyses showed that the prevalence of sarcopenia was higher in the MASLD group, with odds ratios (ORs) varied from 1.02 to 2.08, which is more prevalent in Asian patients and in males[7,10,11]. Results of the recent study evaluating the prevalence of SMA in 62 Spanish MASLD patients showed no significant sarcopenia and only a trend of decline in physical performance in patients with advanced stages of liver disease[12]. Despite the low number of patients, low prevalence of advanced hepatic fibrosis in the cohort, and the use of less sensitive bioelectrical impedance to measure appendicular skeletal muscle mass, this study stresses the ethnical/geographical differences in the prevalence of sarcopenia in MASLD patients.

According to one meta-analysis, sarcopenia was strongly associated with MASLD progression and markedly correlated with MASLD-associated mortality[11]. A follow-up study over 23 years showed that sarcopenia was associated with increased all-cause mortality only in individuals with MASLD, whereas this association was absent in those without MASLD. Individuals with both sarcopenia and MASLD had a higher risk of all-cause mortality [hazard ratio (HR) = 1.28, 95%CI: 1.06-1.55] compared with those without sarcopenia and MASLD[13]. The association between sarcopenia and MASLD is complex and multifactorial, involving shared pathophysiological mechanisms, including insulin resistance, inflammation, and metabolic dysregulation[14-16]. It is well established that insulin resistance not only contributes to the development of MASLD but also exacerbates muscle loss by reducing protein synthesis, promoting catabolism[17] and also changes in myokines, which are critical for muscle metabolism[18,19]. Furthermore, elevated levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) are frequently observed in MASLD and are known to promote muscle degradation[20,21]. This inflammatory milieu may lead to a vicious cycle in which sarcopenia worsens liver function, further enhancing insulin resistance and inflammation[22]. Vitamin D deficiency has also been implicated in the association between sarcopenia and MASLD. Low vitamin D levels are common in patients with MASLD and are associated with accelerated loss of muscle mass[23]. This deficiency may exacerbate the risk of sarcopenia, highlighting the importance of nutritional factors in managing MASLD and its complications[16]. It was shown that, the presence of sarcopenia in patients with MASLD has been linked to increased severity of liver fibrosis, which is a critical determinant of long-term outcomes in these patients[22,24-26]. Studies have shown that sarcopenia is associated with increased liver fibrosis and a higher risk of adverse outcomes including mortality[25].

Sarcopenia is not only a consequence of MASLD but may also contribute to its risk and progression. Several meta-analyses have estimated the risk of MASLD among patients with sarcopenia and showed that individuals with sarcopenia are at a higher risk of developing MASLD[27,28]. This relationship is underscored by findings suggesting that lower skeletal muscle mass is an independent predictor of MASLD, regardless of other metabolic risk factors[28,29]. The contribution of relative muscle mass in the development of MASLD was demonstrated during the 7-year longitudinal cohort study in which 1864 (14.8%) of the 12624 subjects without the disease at baseline developed MASLD. Cox proportional hazard analysis of skeletal muscle mass index (SMI) estimated by bioelectrical impedance analysis during the follow-up showed that the highest SMI tertile was inversely associated with incident MASLD [adjusted HR (AHR) = 0.44, 95%CI: 0.38-0.51] and positively associated with the resolution of baseline MASLD (AHR = 2.09, 95%CI: 1.02-4.28) in comparison with the lowest sex-specific SMI tertile at baseline. Furthermore, compared with the lowest tertile of change in SMI over a year, the highest tertile exhibited a significant beneficial association with incident MASLD and resolution of baseline MASLD even after adjustment for many covariates, including age, sex, waist circumference, diabetes status, hypertension, smoking, regular exercise, and baseline SMI[30]. The results of this study demonstrated that the increase in relative skeletal muscle mass over time may have a protective effect against MASLD and support the concept that physical activity, which increases muscle mass and prevents sarcopenia, is one of the pillars in the treatment of the disease.

MYOSTEATOSIS

Myosteatosis, characterized by the excessive accumulation of fat within skeletal muscle, has emerged as a significant pathological condition linked to various metabolic disorders, including MASLD. The diagnostic criteria for myosteatosis remain underdeveloped, but indicators such as skeletal muscle density and intramuscular adipose tissue are commonly used[31]. The lack of standardized diagnostic criteria complicates the assessment of myosteatosis in clinical practice, particularly in the context of MASLD. Research indicates that myosteatosis is frequently observed in patients with MASLD (from 30% to 50%), highlighting its potential role as a biomarker for liver disease progression and overall metabolic health[32-34]. In a large cohort study of 18154 participants the multivariable-adjusted OR for myosteatosis was elevated in the MASLD group (OR = 1.75, 95%CI: 1.52–2.02), while it was slightly decreased in subjects with cryptogenic steatotic liver disease (OR = 0.52, 95%CI: 0.29–0.95), in whom steatosis was found by abdominal ultrasound, no other causes of steatosis, like alcohol, metabolic factor, viruses or drug use were revealed[35]. These data emphasize that myosteatosis shares a common pathogenesis with MASLD, but not with liver steatosis itself. The prevalence of myosteatosis in advanced liver disease such as liver cirrhosis is even higher (up to 76%-82%)[34,36,37], however it may be related to liver insufficiency independent of the aetiology of liver disease itself and due to excessive amounts of ammonia delivered to the muscle, which led to the loss of muscle quality and quantity, as in the majority of the studies, mixed groups of patients with cirrhosis were studied. However, it was shown that myosteatosis is more common in patients with MASLD-associated HCC compared than in those with viral-associated HCC, suggesting that the underlying liver disease significantly influences the presence of myosteatosis even in end-stage liver disease[38].

Myosteatosis is prevalent even in non-cirrhotic stages of MASLD and has been linked to poor clinical outcomes, including increased all-cause mortality and cardiovascular events[33]. Myosteatosis is particularly concerning as it can exacerbate the metabolic dysfunction associated with MASLD, leading to a higher risk of developing MASH and liver fibrosis than the loss of muscle mass itself[39,40]. The accumulation of fat in the skeletal muscle, as indicated by lower muscle radiodensity on computed tomography, serves as a significant prognostic indicator for the progression of simple liver steatosis to MASH[41]. However, there are interesting sexual differences in the roles of sarcopenia and miosteatosis in the progression of MASLD. Thus, lower skeletal muscle mass combined with abdominal obesity was strongly associated with the presence of MASH only in men[42], whereas myosteatosis was strongly associated with non-obese MASLD in both sexes after adjusting for various known risk factors of MASLD[43]. Moreover, the relationship between myosteatosis and liver health is underscored by findings suggesting that muscle fat content, rather than muscle mass alone, is a determinant of liver fibrosis in patients with severe obesity[39]. These findings indicate that interventions aimed at reducing myosteatosis even before muscle mass loss could have beneficial effects on MASLD progression. For example, glucagon-like peptide-1 receptor agonists have been shown to improve liver steatosis in patients with MASLD and type 2 diabetes mellitus, suggesting a potential therapeutic avenue for addressing both muscle and liver fat accumulation[44]. Therefore, addressing myosteatosis may be crucial in managing MASLD and preventing its progression to more severe forms such as MASH and cirrhosis[45]. In conclusion, myosteatosis represents a critical area of research in the context of MASLD and in broader metabolic health. Its association with insulin resistance, liver disease progression, and poor clinical outcomes underscores the necessity for further investigation of its pathophysiological mechanisms and potential therapeutic interventions. As our understanding of myosteatosis evolves, it may serve as a valuable biomarker for assessing the severity of MASLD and guiding treatment strategies aimed at improving patient outcomes.

ALTERED MUSCLE METABOLISM

Altered muscle metabolism in MASLD is a complex issue that is intertwined with insulin resistance, muscle mass, and systemic inflammation. Insulin resistance is one of the primary mechanisms linking muscle metabolism to MASLD development. In patients with MASLD, muscle insulin resistance is often observed, which can precede hepatic insulin resistance, suggesting a sequential relationship in which muscle dysfunction aggravates liver pathology[46,47]. This relationship is further complicated by the presence of increased free fatty acids in the bloodstream, which can lead to increased lipolysis and the subsequent accumulation of lipids in both muscle and liver tissues[48]. High-fat diets trigger mammalian target of rapamycin complex (mTORC) hyperactivation in skeletal muscles[49,50]. In these studies, high-fat challenges increased mTORС1 (and, in some instances, mTORС2) activity, which in turn enhanced S6 kinases 1 phosphorylation and induced inhibitory serine phosphorylation of insulin receptor substrate-1. This cascade diminishes protein kinase B activation and compromises insulin signaling, as observed in both skeletal muscle and liver tissues, thereby altering insulin-dependent pathways and promoting lipid accumulation. Exercise training results in the reduction of mTORC activation with the reversal of lipid-induced skeletal muscle insulin resistance[51,52] and identifies mTORC as a potential target for the treatment of SMA in patients with MASLD. Additionally, systemic inflammation through different cytokines plays a crucial role in the altered muscle metabolism observed in MASLD patients. TNF-α levels were elevated in patients with MASH. TNF-α contributes to insulin resistance by interfering with insulin signaling pathways, which can lead to impaired glucose uptake in muscle tissues[53,54]. Additionally, IL-6 is a key player in the inflammatory response associated with MASLD. Elevated IL-6 levels are linked to increased insulin resistance and can affect muscle metabolism by promoting a catabolic state, which may hinder muscle growth and repair[55,56]. The role of cytokines extends beyond direct effects on insulin signaling; they also influence the secretion of myokines from skeletal muscles. Myokines such as IL-15 and irisin are involved in muscle metabolism and can modulate the inflammatory response. Dysregulation of these myokines can exacerbate muscle wasting and metabolic dysfunction[57]. Notably, in the study of Spanish cohort of patients with MASLD, published in the World Journal of Gastroenterology, no significant SMA but a marked increase in serum levels of irisin and fibroblast growth factor 21 (FGF-21) in advanced disease stages were found[12]. Whether these changes in myokine levels precede the development of SMA in the future in patients with further progression of MASLD or reflect a lower predisposition for the development of SMA in Caucasian populations than in Asian cohorts is not clear. Interestingly, irisin and FGF-21 may play a protective role for MASLD[58]; at least in animal models, exercise-induced increase in irisin levels was associated with decreased inflammation and improved MASLD[59].

Evidence suggests that muscle-derived FGF-21 improves hepatic insulin sensitivity through several mechanisms. FGF-21 improves hepatic insulin sensitivity by inhibiting mTORC1, which enhances insulin signaling and glycogen synthesis in the liver[60]. Administration of FGF-21 decreases the hepatocellular diacylglycerol content and reduces protein kinase C activation, which is associated with improved insulin sensitivity in the liver[61]. It also enhances the expression and secretion of adiponectin, an insulin-sensitizing adipokine that mediates its effects on liver and muscle insulin sensitivity[62]. Studies using animal models have demonstrated that FGF-21 administration can lead to significant improvements in metabolic parameters, including reductions in body weight, plasma insulin levels, and liver steatosis[63,64]. However, its effects may vary between sexes, with more pronounced benefits observed in males in certain models[65]. FGF-21 plays a crucial role in enhancing hepatic insulin sensitivity through its regulatory effects on lipid and glucose metabolism. Its potential as a therapeutic agent for metabolic diseases has been supported by various studies highlighting its ability to improve insulin sensitivity and reduce liver fat accumulation[66].

Altered amino acid metabolism, which is observed in many liver diseases including MASLD, may affect muscle metabolism and alter muscle function and structure. Metabolomic analysis revealed that several major amino acid pathways are dysregulated in MASLD, with tyrosine metabolism being the most affected[67]. Tyrosine metabolism plays a crucial role in regulating skeletal muscle function and adaptation. Tyrosine phosphorylation, a post-translational modification, is integral to various signaling pathways that influence muscle metabolism, insulin sensitivity, and overall muscle health. Research has shown that tyrosine phosphorylation is involved in the regulation of key metabolic enzymes in skeletal muscle, such as lactate dehydrogenase A and pyruvate dehydrogenase kinase 1, which are critical for glycolytic processes[68]. Furthermore, the phosphorylation state of insulin receptor substrate proteins, particularly insulin receptor substrate-1, is significantly affected by tyrosine modifications, which can lead to insulin resistance—a common issue in metabolic disorders[69,70]. The role of tyrosine phosphorylation extends beyond metabolic regulation and influences the structural aspects of muscle cells. For example, proteins such as paxillin, which are involved in focal adhesion and cytoskeletal dynamics, undergo tyrosine phosphorylation that affects their function in muscle cells[71,72]. This suggests that tyrosine metabolism not only regulates metabolic pathways, but also contributes to the structural integrity and adaptability of skeletal muscles, which are important for the alteration of muscle functions in MASLD. Thus, altered muscle metabolism includes muscle insulin resistance, which may precede hepatic insulin resistance and development of MASLD. The increase in proinflammatory cytokines and disturbances in tyrosine metabolism that occur during the course of MASLD may further alter muscle metabolism, leading to the development of myosteatosis and/or sarcopenia.

TREATMENT OF SMA IN MASLD PATIENTS

No specific pharmacological treatment for SMA in MASLD patients has been approved yet. However, common factors preceding both conditions, such as insulin resistance, may be potential targets for non-pharmacological and pharmacological interventions to correct them. Diet and nutritional interventions in combination with physical activity are still the cornerstones of the treatment of MASLD[1]. Specific dietary patterns are related to MASLD and sarcopenic obesity[73] and to MASLD in lean subjects[74]; therefore, addressing them through dietary counseling, such as reducing sugar-sweetened beverage intake[75], may help manage both sarcopenia and MASLD by mitigating visceral fat accumulation and improving insulin sensitivity. Caloric restriction is a key factor for effective weight reduction, which is associated with the resolution of MASLD and improvement of MASH/fibrosis[76,77]. However, muscles are major consumers of energy; therefore, specific nutrition should be prescribed to reduce fat tissue and preserve muscle mass. Usually, an isocaloric diet or diet with high protein content, especially enriched with leucin, can preserve muscle mass and provide adequate weight control if patients with MASLD are compliant with long-term dietary interventions[78-80]. Controlled trials showed that the Mediterranean dietary pattern was at least as effective as using diets with caloric restriction but provided better compliance in patients with MASLD[81,82]. Adherence to a Mediterranean diet is generally associated with positive effects on muscle mass and function. However, evidence regarding its impact on muscle strength is less clear and no definitive positive effect on sarcopenia has been established[83,84]. Greater adherence to the Mediterranean diet was associated with a lower risk of probable sarcopenia. This association is particularly evident in observational studies, suggesting that the diet may help maintain muscle function in older adults[85,86]. The Mediterranean diet is rich in anti-inflammatory and antioxidant nutrients, such as extra virgin olive oil, fruits, vegetables, and fish, which may contribute to its protective effects against muscle deterioration[87]. While observational studies suggest benefits, there is a notable lack of interventional studies to confirm the effectiveness of the Mediterranean diet in preventing or treating sarcopenia[85,88].

Functional foods rich in specific nutrients may enhance the muscle performance and mitigate the effects of sarcopenia. Nutraceuticals such as curcumin, resveratrol, catechin, soy protein, and ginseng have been reported to improve physical performance, muscle strength, and mitochondrial function in patients with sarcopenia. These products also increase muscle mass and inhibit muscle atrophy without significant side effects[89,90]. Interestingly, a recently published double-blind placebo-controlled trial of 52 patients with biopsy-proven MASH treated with curcumin for 72 weeks demonstrated significant regression of liver inflammation and fibrosis, regardless of changes in body mass index (BMI)[91]. Unfortunately, SMA were not evaluated in this study; however, profound decreases in blood insulin, glucose, cholesterol, truglycerides, and inflammatory marker levels allowed us to speculate that curcumin may have a positive effect on SMA, considering the common pathogenesis of MASLD. A novel food containing omega-3 fatty acids, leucine, and probiotic Lactobacillus paracasei PS23 significantly improved appendicular lean mass, muscle performance, and handgrip strength in elderly sarcopenic patients over a 2-month period[92]. Consumption of antioxidant-rich foods, including fruits and vegetables, along with supplements, such as magnesium, vitamin E, and vitamin D, has been associated with improved muscle strength and function. These interventions according to meta-analyses have shown to reduce the time to complete physical tasks and increase handgrip strength[93,94]. Although these findings are promising, further longitudinal and clinical studies are necessary to establish definitive treatment strategies.

Physical activity and different exercise protocols have been confirmed by numerous meta-analyses to be effective tools for decreasing insulin resistance and therefore for the prevention and treatment of MASLD[95-98]. Similarly, the most effective exercise protocols for improving muscle mass and function in individuals with sarcopenia involve a combination of resistance training, high-intensity interval training, and nutritional intervention. Conventional high-intensity resistance training is effective for improving muscle mass and strength. Low-load resistance training with blood flow restriction is an alternative that improves muscle strength and cardiovascular health, making it suitable for individuals who may not tolerate high-intensity exercise and has been shown to significantly enhance appendicular SMI and physical performance measures[99]. High-intensity interval training is a potent method for enhancing muscle function, strength, and hypertrophy in older adults. It improves body composition and cardiorespiratory capacity, which are crucial for sarcopenia management[100]. Combining resistance exercise with nutritional support provides better results than exercise alone, and usually includes a diet that is well balanced for protein consumption. Protein intake of ≥ 0.8 g/kg body weight/day has shown beneficial effects on muscle mass, particularly when combined with exercise[88], whereas a higher protein intake of 1.0–1.2 g/kg/day is suggested for healthy older adults[101]. Instead of increasing protein consumption, additional amino acid intake or their metabolites can enhance muscle protein synthesis and improve muscle mass and function[102]. Although protein intake is crucial for muscle health, the multifactorial nature of sarcopenia suggests that a holistic approach may yield better outcomes. Using vitamin D and omega-3 fatty acids together with a high-protein diet significantly improves muscle regeneration, strength, and lipid profiles[101]; however, a whole diet approach, including fruits, vegetables, and adherence to the Mediterranean diet, is associated with better patient compliance with similar physical performance and muscle function[88]. Therefore, for both MASLD and SMA, a combination of specific diet and physical activity/exercise is crucial for successful treatment; however, there are no results of the study published yet in which both conditions were taken into account, monitored, and specifically treated with different diets and exercise protocols to find the best one for long-term outcomes and good patient adherence. This is a key direction for future research.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been introduced for the treatment of diabetes mellitus; however, they are increasingly used for weight loss in obese individuals, who often have MASLD, and their effects on muscle mass during this process are complex and can vary depending on the context and specific GLP-1 agonist used. Elevated blood GLP-1 levels have been associated with reduced myogenic differentiation, which potentially negatively affects muscle health. Thus, patients with sarcopenia exhibit elevated plasma levels of GLP-1, in contrast to non-sarcopenic individuals. This can be explained by the effect of GLP-1 on both the membrane translocation of glucose transporter 4 and dispersion of mitochondria, which significantly hinders glucose uptake and the production of mitochondrial adenosine triphosphate necessary for the myogenic program, leading to a reduction in myogenic differentiation[103]. Despite these concerns, a large pharmacovigilance study found no significant association between GLP-1 RAs and sarcopenia, suggesting that these drugs do not inherently increase sarcopenia risk[104]. Moreover, dulaglutide, a GLP-1 RA, protects against muscle injury in diabetic sarcopenia by reducing inflammation and promoting myoblast differentiation[105]. This suggests its potential therapeutic role in the management of sarcopenia-related muscle damage.

While GLP-1 RAs are effective in reducing body weight primarily through fat loss, they also affect lean body mass, which includes muscle. Meta-analyses indicate that semaglutide and liraglutide can lead to reductions in lean body mass, although the percentage of lean mass loss relative to total weight loss is comparable to non-users. This suggests that while there is a loss, it may not be disproportionately large compared with the overall weight loss[106]. Similar to low-calorie diets, GLP-1 RAs can lead to muscle atrophy through caloric restriction, which is a common consequence of weight loss interventions. However, GLP-1 RAs have been shown to ameliorate muscle atrophy by modulating pathways such as the SIRT1 pathway, which is involved in muscle preservation[107]. Treatment with GLP-1 RAs has also been associated with improved muscle quality, as evidenced by enhanced insulin sensitivity and reduced muscle fat infiltration. These changes suggest an adaptive response that may help maintain muscle function despite reduction in muscle volume[108,109]. Even in elderly obese patients, GLP-1 RAs such as semaglutide have shown potential in preserving lean body mass during weight loss, with studies indicating a significant reduction in fat mass while maintaining lean mass[110]. In patients with sarcopenic obesity, which is often associated with MASLD, the combination of GLP-1 RAs with future drugs, such as myostatin and activin A inhibitors, is a promising strategy. Animal models have shown that such combinations can preserve or even increase muscle mass while enhancing fat loss[111,112].

A dozen clinical trials on GLP-1 RAs in patients with MASLD have reported inconsistent results. However, according to meta-analyses, they significantly improved hepatic function markers, hepatic steatosis, inflammation, and fibrosis as well as reduced BMI, subcutaneous fat mass, and waist circumference[113,114]. GLP-1 RAs have not yet been approved for the treatment of MASLD; they are actively used in at least 1/3 of patients with MASLD who have diabetes[115], which provides an excellent opportunity to evaluate their long-term safety and efficacy for MASLD and SMA. Tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and GLP-1 receptors, has shown promising therapeutic effects in MASH. Compared to other treatments, such as semaglutide, tirzepatide has shown superior effects in reducing hepatic fat deposition and improving liver inflammation in animal models[116]. In clinical settings, switching from other GLP-1 analogs to tirzepatide resulted in improved liver enzyme levels and a trend towards reduced fibrosis, indicating its potential for broader application in liver disease management[117]. In a phase 2 study involving 157 patients with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to the resolution of MASH without worsening of fibrosis[118]. However, the small sample size did not provide adequate statistical power to evaluate the effects of turzepatide on liver fibrosis. While GLP-1 RAs offer significant benefits in terms of weight loss and metabolic improvements, as well as liver inflammation and steatosis, the potential for muscle mass loss remains a concern, particularly in MASLD populations with SMA or those at high risk for sarcopenia, such as elderly patients.

CONCLUSION

The development of new diagnostic approaches, new combination therapies, and exploration of mechanisms to preserve muscle mass are critical areas for future research. Additionally, more comprehensive assessments of muscle health, including function and strength, in different groups of patients with MASL/MASH are needed to fully understand the impact of existing and future treatment strategies of MASLD on SMA and vice versa.