Skeletal muscle alterations in metabolic dysfunction-associated steatotic liver disease: A critical review of diagnostic, mechanistic, and therapeutic intersections

Abstract

Metabolic dysfunction-associated steatotic liver disease is increasingly understood to be closely linked with skeletal muscle alterations, such as sarcopenia, myosteatosis, and metabolic dysregulation, which play a key role in its pathogenesis and progression. Recent literature, including an article by Isakov, highlights the bidirectional interactions between muscle and liver, underscoring shared mechanisms such as insulin resistance, inflammation, and myokine imbalance. This letter reflects on key findings from the review, noting strengths such as its integration of mechanistic insights, discussion of emerging biomarkers, and emphasis on lifestyle and pharmacological interventions. It also identifies areas for further development, including standardization of diagnostic criteria and more rigorous evaluation of translational data. As muscle health gains prominence in metabolic dysfunction-associated steatotic liver disease research, multidisciplinary strategies that target both hepatic and muscular systems may offer more effective avenues for prevention and treatment.

Key Words: Metabolic dysfunction-associated steatotic liver disease; Skeletal muscle alterations; Sarcopenia; Myosteatosis; Muscle metabolism; Physical activity; Glucagon-like peptide-1 receptor agonists

Core Tip: Skeletal muscle alterations, such as sarcopenia, myosteatosis, and metabolic dysregulation, are increasingly common in pathogenesis and progression of metabolic dysfunction-associated steatotic liver disease. Underlying mechanisms, including insulin resistance, inflammation, and myokine imbalance, along with emerging biomarkers offer opportunities to study lifestyle and pharmacological interventions such as glucagon-like peptide-1 agonists. Further development must build on gaps in current literature, standardize diagnostic criteria and evaluate translational data for clinical applicability.

TO THE EDITOR

We are delighted to read the paper by Isakov[1] exploring the different associations between skeletal muscle alterations (SMAs) and metabolic dysfunction-associated steatotic liver disease (MASLD), published in the World Journal of Gastroenterology. MASLD is characterized by the accumulation of fat in the liver and may progress to more severe forms like metabolic dysfunction-associated steatohepatitis, cirrhosis and hepatocellular carcinoma. Interventions promoting weight loss and optimizing metabolism are important to prevent progression to cirrhosis and its complications[2].

STUDY EVALUATION

The paper provides a comprehensive overview of the bidirectional relationship between MASLD and SMAs such as sarcopenia, myosteatosis and altered muscle metabolism, and discusses potential therapeutic targets. The author summarizes the current literature on these topics through a range of meta-analyses and systematic reviews. MASLD is a serious condition which the author concluded worsens with alterations in muscle mass and metabolism. This highlights a crucial target for treatment to control the progression and promote the resolution of MASLD.

Analysis of longitudinal cohort data highlights ethnic and geographical variations in prevalence of sarcopenia through a cohort of Spanish patients studied by Real Martinez et al[3]. The use of bioelectrical impedance in the study for measuring appendicular skeletal muscle mass is noted by Isakov[1] in this paper but could be adequately critiqued against more robust imaging techniques like dual-energy X-ray absorptiometry which may explain the lower sarcopenia detection in this cohort[4]. Sarcopenia and MASLD may be associated through shared pathology mechanisms underlined by insulin resistance, inflammation, and metabolic dysregulation. Patients with increases in relative skeletal muscle mass were found to have protective effects against MASLD over a 7-year period of the longitudinal study cited in this paper[5]. However, this study defined MASLD using the hepatic steatosis index scoring system, not by liver biopsy, and confounders such as exercise status and whether participants were taking any nutritional supplements were not accounted for, hindering the true impact of its results. Myosteatosis is characterized by an excessive accumulation of fat in skeletal muscle and is a relevant contributor to the progression of MASLD and poor clinical outcome. The discussion synthesizes findings from multiple large-scale cohorts and cross-sectional studies, such as the 18154-participant analysis linking higher odds of myosteatosis with MASLD, and increased prevalence with advanced liver disease[6]. However, the inconsistent diagnostic criteria for myosteatosis in the general literature, such as the absence of standardized cutoffs, imaging thresholds, or consensus definitions, significantly limits the comparability and generalizability of cited studies, as also well-acknowledged by the author.

Additionally, some studies suggest myosteatosis may have a stronger prognostic role than sarcopenia itself; hence, an exploration of their potential interplay in liver health could have benefited the paper[7,8]. For example, a United Kingdom-based study by Linge et al[9] reported that approximately 24% of patients with MASLD had myosteatosis, 10% had sarcopenia, and 14% had both SMA conditions. Moreover, preclinical models of MASLD have shown that myosteatosis, rather than sarcopenia, can serve as an early and independent marker of MASLD disease severity, with strong associations to hepatic inflammation and fibrosis[10]. These findings underscore the importance of assessing both muscle quality and quantity, as their interplay appears to compound risk. Nonetheless, these findings must be interpreted cautiously, as their implications are heavily influenced by the varying definitions and diagnostic criteria for myosteatosis used across studies. MASLD is also closely associated with altered muscle metabolism underpinned by insulin resistance, inflammation, myokine dysregulation, and amino acid metabolism[1]. The notion that muscle insulin resistance may precede hepatic resistance is presented valuably as it reframes skeletal muscle as an active driver of MASLD pathogenesis, rather than just a passive consequence.

The detailed discussion of mechanistic target of rapamycin complex 1 hyperactivation in skeletal muscle and its reversibility through exercise is commendable as it highlights a clinically plausible pathway to restore metabolic function and mitigate MASLD progression. The inclusion of tyrosine metabolism is also noteworthy as it is rarely discussed in literature but brings a key conceptual expansion of MASLD pathogenesis by extending beyond the typical triad of steatosis, inflammation, and fibrosis. Additionally, the roles of irisin and fibroblast growth factor 21 as biomarkers and therapeutic targets, along with consideration of ethnic and sex-based variability highlights the promising role of myokines in MASLD. However, their translational relevance remains uncertain given the reliance on preclinical data. While these findings are promising, critical discussion of receptor variability and bioavailability of these molecules, as discussed by Falamarzi et al[11], would have strengthened the paper’s clinical application.

Lifestyle interventions such as dietary modification and physical activity are cornerstones in the management of both SMA and MASLD. The consideration and evaluation of evidence-based strategies, particularly the Mediterranean diet, is a strength as it balances metabolic improvements with patient adherence. Incorporating resistance training and targeted supplementation offers a practical approach. However, the paper occasionally blurs the line between exploratory and validated strategies. For example, curcumin is highlighted based on a single trial without muscle assessment, although other parameters studied in the trial are used to simply speculate a change in SMA. The discussion would benefit from a structured hierarchy of evidence distinguishing between well-validated interventions and those that are still exploratory. Additionally, while the paper mentions sex-based and population-based heterogeneity elsewhere, adherence and response to lifestyle changes can differ markedly by socioeconomic factors[12].

Glucagon-like peptide-1 receptor agonists are critically discussed as effective agents for weight reduction and improving hepatic markers. The exploration is well-grounded in recent evidence to also consider that muscle quality may be preserved despite reductions in lean mass. However, clinical implications of muscle loss and how it could be prevented, especially in sarcopenic patients, are underexplored[13]. Additionally, while the section acknowledges that glucagon-like peptide-1 receptor agonists are widely used in MASLD patients with diabetes, it would potentially benefit from recommending specific monitoring strategies for muscle mass and function, along with potential strength training in these populations. Overall, while the paper is informative and rich in evaluation, its clinical applicability could potentially be enhanced by an additional focus on treatment risks.

CONCLUSION

Overall, Isakov’s article offers a comprehensive and timely synthesis of the evolving relationship between SMA and MASLD[1]. By integrating insights from epidemiological data, mechanistic studies, and therapeutic interventions, the paper highlights the underappreciated but crucial role of muscle health in the pathogenesis and progression of MASLD. Its strengths lie in the clear articulation of shared metabolic pathways, the thoughtful inclusion of lifestyle and pharmacologic strategies, and the recognition of emerging biomarkers such as irisin and fibroblast growth factor 21. The paper succeeds in framing skeletal muscle as not only a marker but also a modifiable driver of liver disease. Further analysis is warranted in critical areas such as the diagnostic variability of myosteatosis and the translational readiness of preclinical findings. This work sets a strong foundation for future research and clinical practice to incorporate strategies in MASLD management focused on muscle health.