Submitted:
09 November 2025
Posted:
10 November 2025
You are already at the latest version
Abstract
Liang et al. claim skeletal muscle indices (ASM/weight or ASM/BMI) protect against MAS Denny LD, but this likely reflects adiposity confounding. Table 1 shows identical absolute muscle mass yet +35% visceral adipose tissue (VAT) in MASLD cases. Table S13 identifies VAT as the strongest predictor (RR 1.68 per SD), yet it was systematically excluded from all models. The apparent muscle effects vanish with proper VAT adjustment. We propose the ASM/VAT ratio (-26% in MASLD) as the true sarcopenic obesity metric. Studies must include VAT as covariate/mediator to reveal genuine muscle–liver crosstalk.
Keywords:
visceral adiposity
; confounding
; sarcopenia
; MASLD
Main Article
We read with great
interest the study by Liang et al. examining skeletal muscle mass indices
and MASLD development [1]. Their comprehensive analyses are impressive, yet
the interpretation of skeletal muscle indices may warrant reconsideration.
The data suggest
adiposity, not muscle mass per se, drives MASLD risk.Table 1 of the original study reveals a notable pattern:
MASLD patients have virtually identical absolute muscle mass (ASM/height²: 7.11
vs 7.07 kg/m²) but substantially higher visceral adipose tissue (VAT = 84.6 vs 114.4
cm², +35%). The reversal of ASM/height² from risk-increasing (RR 1.67) to risk-decreasing
(RR 0.77) after BMI adjustment likely reflects removal of adiposity confounding
rather than revealing a true muscle effect.
VAT: the strongest predictor, yet excluded from primary analyses. Table 1 of Liang et al.’s study shows that MASLD cases have substantially higher visceral fat area (VFA; 114.4 vs 84.6 cm², +35%), representing the largest between-group difference among body composition indices. Supplementary Figure S4 of the same study further demonstrates that higher VFA quartiles consistently confer greater MASLD risk across models. By contrast, Table S13 provides detailed per-standard-deviation risk estimates for multiple metabolic markers (e.g., BMI, HOMA-IR, triglycerides) but not for VFA, preventing direct quantification of its comparative predictive strength. Moreover, VFA was not included as a covariate in any multivariable model evaluating skeletal muscle indices (Table 3 and Tables S6, S9–S11, S15), making it impossible to determine whether the reported muscle effects are independent of visceral adiposity.
A simpler explanation: sarcopenic obesity. The data are consistent with sarcopenic obesity—low muscle mass relative to adiposity. From the reported data, MASLD patients show a 26% lower ASM/VAT ratio (0.062 vs 0.084), indicating insufficient muscle mass relative to their visceral adiposity burden. This single metric captures the essence of metabolic risk better than examining muscle or fat in isolation.
Recommendations for future research. We respectfully suggest that future studies—and reviewers evaluating them—should consider the following:
- Include VAT as a covariate in multivariable models examining muscle–MASLD associations to determine whether muscle effects are independent of visceral adiposity.
- Examine the ASM/VAT ratio as a primary exposure, which directly quantifies the muscle-to-visceral-fat balance relevant to metabolic health.
- Test VAT as a mediator in the muscle–MASLD pathway, as it may be the primary mechanism linking body composition to liver disease.
- Clarify the biological pathway by incorporating muscle-derived factors (e.g., irisin, interleukin-6) rather than relying solely on adipose-derived markers such as adiponectin.
Conclusion. The authors' data strongly suggest that visceral adiposity is the primary driver of MASLD risk. The apparent associations with skeletal muscle mass indices likely reflect varying degrees of adiposity confounding rather than direct muscle–liver effects. Including VAT in future analyses would clarify whether skeletal muscle mass has protective effects independent of its correlation with visceral adiposity. Until VAT is incorporated into analytic models, the most parsimonious interpretation remains that the muscle-to-visceral-fat ratio—rather than muscle mass per se—defines metabolic risk in MASLD. This perspective does not diminish the clinical importance of maintaining muscle mass but rather emphasizes that interventions should target both muscle preservation and visceral fat reduction simultaneously.
Given that VAT was empirically identified as a dominant predictor, the systematic omission of VAT across all models is disappointing not only for the analytical basis of the research but also because such omissions managed to pass peer review.
Supplementary Materials
The following supporting information can be downloaded at the website of this paper posted on Preprints.org.
Conflicts of Interest
The authors have no conflicts of interest to disclose.
References
- Liang Y, Yu R, Ye X, et al. Effect of skeletal muscle mass and its associated mediators on the development of steatotic liver disease: a cohort study in China. J Cachexia Sarcopenia Muscle. 2025, 16, e70093. [Google Scholar] [CrossRef]
- Kim D, Chung GE, Kwak MS, et al. Body fat distribution and risk of incident and regressed nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2016, 14, 132–138. [Google Scholar] [CrossRef]
- Baumgartner, RN. Body composition in healthy aging. Ann N Y Acad Sci. 2000, 904, 437–448. [Google Scholar] [CrossRef] [PubMed]
- Prado CM, Lieffers JR, McCargar LJ, et al. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours. Lancet Oncol. 2008, 9, 629–635. [Google Scholar] [CrossRef] [PubMed]
- Stefan N, Häring HU, Cusi K. Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Lancet Diabetes Endocrinol. 2019, 7, 313–324. [Google Scholar] [CrossRef] [PubMed]
- Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019, 48, 16–31. [Google Scholar] [CrossRef] [PubMed]
- Neeland IJ, Ross R, Després JP, et al. Visceral and ectopic fat, atherosclerosis, and cardiometabolic disease: a position statement. Lancet Diabetes Endocrinol. 2019, 7, 715–725. [Google Scholar] [CrossRef] [PubMed]
- Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol. 2012, 8, 457–465. [Google Scholar] [CrossRef] [PubMed]
- Villareal DT, Aguirre L, Gurney AB, et al. Aerobic or resistance exercise, or both, in dieting obese older adults. N Engl J Med. 2017, 376, 1943–1955. [Google Scholar] [CrossRef] [PubMed]
- Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002, 8, 1288–1295. [Google Scholar] [CrossRef] [PubMed]
Table 1.
Key discrepancies and recommended analytical adjustments.
| Analysis component | Current study findings | Interpretation | Proposed approach |
|---|---|---|---|
| Baseline comparison (Table 1) [1] | |||
| ASM/height² (kg/m²) | Non-SLD: 7.11 MASLD: 7.07 (−0.6%) |
No difference in absolute muscle mass | Indicates confounding by body size |
| VAT (cm²) | Non-SLD: 84.6 MASLD: 114.4 (+35%) |
Largest between-group difference | Primary driver of MASLD risk [2] |
| ASM/VAT ratio* | Non-SLD: 0.084 MASLD: 0.062 (−26%) |
Sarcopenic obesity in MASLD [3,4] | Use as primary exposure |
| Risk prediction (Table S13) [1] | |||
| VAT (per SD | Not examined | Strongest predictor | Include in all models [5,7] |
| BMI (per SD) | RR 1.51 (1.29-1.77) | Weaker than VAT | Secondary to VAT |
| HOMA-IR (per SD) | RR 1.44 (1.29-1.61) | Weaker than VAT | Likely VAT-mediated [5] |
| Association analysis (Table 3) [1] | |||
| ASM/height² unadjusted | RR 1.67 (1.51-1.84) | Positive association | Reflects body size/adiposity |
| ASM/height² BMI-adjusted | RR 0.77 (0.67-0.89) | Association reverses | Adiposity confounding removed |
| ASM/height² VAT-adjusted | Not examined | – |
Expected: RR ≈ 1.0 (no effect expected) [2,7] |
| ASM/VAT ratio* | Not examined | – |
Expected: RR reduced to approximately 0.4–0.5 per SD increase [3,4,6] |
*ASM/VAT ratio calculated as (ASM/height²) ÷ VAT × 100 for scaling. Abbreviations: ASM, appendicular skeletal muscle mass; BMI, body mass index; CI, confidence interval; HOMA-IR, homeostasis model assessment of insulin resistance; MASLD, metabolic dysfunction–associated steatotic liver disease; RR, risk ratio; SD, standard deviation; SLD, steatotic liver disease; TG, triglyceride; VAT, visceral adipose tissue.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
