Liver muscle bone axis in metabolic dysfunction-associated steatotic liver disease

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the most common chronic liver diseases worldwide. With the introduction of the new nomenclature, the management of MASLD is evolving from a conventional liver-centered approach focused primarily on hepatic steatosis, metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, and cirrhosis risk toward a broader framework that also addresses heterogeneity in metabolic risk, physical function, tolerance to lifestyle interventions, and long-term prognosis. In recent years, impaired skeletal muscle function, sarcopenia, myosteatosis, vitamin D deficiency, and abnormalities in bone metabolism have increasingly been recognized as clinically relevant conditions associated with MASLD severity, progression risk, and adverse extrahepatic outcomes. Although the underlying biological mechanisms remain incompletely understood, these conditions may serve as clinically meaningful risk markers and potential modifiers of disease progression. This review systematically summarizes the epidemiological associations, proposed shared pathogenic mechanisms, clinical recognition pathways, and integrated intervention strategies linking MASLD, sarcopenia, vitamin D deficiency, and bone metabolic abnormalities. We propose that MASLD complicated by sarcopenia and bone vulnerability may represent a clinically relevant liver-muscle-bone metabolic phenotype. Future management of MASLD should therefore place greater emphasis on preserving muscle function, maintaining bone health, and improving patient-centered outcomes.

Keywords

Metabolic dysfunction-associated steatotic liver disease / sarcopenia / vitamin D / liver-muscle-bone axis / integrated management

References

[1] Rinella ME,Lazarus JV,Ratziu V.et al. ; NAFLD Nomenclature consensus group. A multisociety Delphi consensus statement on new fatty liver disease nomenclature Hepatology 2023 78 1966 86 PMC10653297

[2] European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD) J Hepatol 2024 81 492 542 PMC11299976

[3] Cusi K,Isaacs S,Barb D.et al. American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD) Endocr Pract 2022 28 528 62

[4] Rinella ME,Neuschwander-Tetri BA,Siddiqui MS.et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease Hepatology 2023 77 1797 835 PMC10735173

[5] Younossi ZM,Zelber-Sagi S,Henry L,Gerber LH. Lifestyle interventions in nonalcoholic fatty liver disease Nat Rev Gastroenterol Hepatol 2023 20 708 22

[6] Marjot T,Armstrong MJ,Stine JG. Skeletal muscle and MASLD: mechanistic and clinical insights Hepatol Commun 2025 9 e0711 PMC12106243

[7] Donini LM,Busetto L,Bischoff SC.et al. Definition and diagnostic criteria for sarcopenic obesity: ESPEN and EASO consensus statement Obes Facts 2022 15 321 35 PMC9210010

[8] Yuan S,Larsson SC. Epidemiology of sarcopenia: prevalence, risk factors, and consequences Metabolism 2023 144 155533

[9] Cruz-Jentoft AJ,Sayer AA. Sarcopenia Lancet 2019 393 2636 46

[10] Chen LK,Hsiao FY,Akishita M.et al. A focus shift from sarcopenia to muscle health in the Asian Working Group for Sarcopenia 2025 Consensus Update Nat Aging 2025 5 2164 75

[11] Kirk B,Cawthon PM,Arai H.et al. ; Global Leadership Initiative in Sarcopenia (GLIS) group. The conceptual definition of sarcopenia: Delphi consensus from the Global Leadership Initiative in Sarcopenia (GLIS) Age Ageing 2024 53 afae052 PMC10960072

[12] Xia L,Zhao R,Wan Q.et al. Sarcopenia and adverse health-related outcomes: an umbrella review of meta-analyses of observational studies Cancer Med 2020 9 7964 78 PMC7643685

[13] Harring M,Golabi P,Paik JM.et al. Sarcopenia among patients with nonalcoholic fatty liver disease (NAFLD) is associated with advanced fibrosis Clin Gastroenterol Hepatol 2023 21 2876 88.e5

[14] Joo SK,Kim W. Interaction between sarcopenia and nonalcoholic fatty liver disease Clin Mol Hepatol 2023 29 S68 78 PMC10029947

[15] Kuchay MS,Martínez-Montoro JI,Kaur P,Fernández-García JC,Ramos-Molina B. Non-alcoholic fatty liver disease-related fibrosis and sarcopenia: An altered liver-muscle crosstalk leading to increased mortality risk Ageing Res Rev 2022 80 101696

[16] Basil B,Adiri W,Ugwu EL,Okoro NI. Association between vitamin D and metabolic-associated steatotic liver disease in type 2 diabetes mellitus patients: a systematic review and meta-analysis Diabetol Metab Syndr 2025 17 457 PMC12729236

[17] Aggeletopoulou I,Tsounis EP,Triantos C. Vitamin D and metabolic dysfunction-associated steatotic liver disease (MASLD): novel mechanistic insights Int J Mol Sci 2024 25 4901 PMC11084591

[18] Riazi K,Azhari H,Charette JH.et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis Lancet Gastroenterol Hepatol 2022 7 851 61

[19] Lou TW,Yang RX,Fan JG. The global burden of fatty liver disease: the major impact of China Hepatobiliary Surg Nutr 2024 13 119 23 PMC10839728

[20] Younossi ZM,Kalligeros M,Henry L. Epidemiology of metabolic dysfunction-associated steatotic liver disease Clin Mol Hepatol 2025 31 S32 50 PMC11925440

[21] Nishikawa H,Kim SK,Yoshio S,Asai A. Metabolic dysfunction-associated steatotic liver disease and sarcopenia: review of literature J Clin Med 2026 15 1661 PMC12942498

[22] Linge J,Ekstedt M,Dahlqvist Leinhard O. Adverse muscle composition is linked to poor functional performance and metabolic comorbidities in NAFLD JHEP Rep 2021 3 100197 PMC7868647

[23] Cruz-Jentoft AJ,Bahat G,Bauer J.et al. ; Writing Group for the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), and the Extended Group for EWGSOP2. Sarcopenia: revised European consensus on definition and diagnosis Age Ageing 2019 48 16 31 PMC6593317

[24] Li X,He J,Sun Q. The prevalence and effects of sarcopenia in patients with metabolic dysfunction-associated steatotic liver disease (MASLD): a systematic review and meta-analysis Clin Nutr 2024 43 2005 16

[25] Malik A,Javaid S,Malik MI,Qureshi S. Relationship between sarcopenia and metabolic dysfunction-associated steatotic liver disease (MASLD): a systematic review and meta-analysis Ann Hepatol 2024 29 101544

[26] Xia N,Wang J,Lu Q,Fan X,Jiang Z,Yu Q. Relationship between metabolic dysfunction-associated steatotic liver disease and sarcopenia: a systematic review and meta-analyses Clin Nutr ESPEN 2025 68 679 90

[27] Giustina A,Bilezikian JP,Adler RA.et al. Consensus statement on vitamin D status assessment and supplementation: whys, whens, and hows Endocr Rev 2024 45 625 54 PMC11405507

[28] Demay MB,Pittas AG,Bikle DD.et al. Vitamin D for the prevention of Disease: An Endocrine Society Clinical Practice Guideline J Clin Endocrinol Metab 2024 109 1907 47

[29] Man PW,van der Meer IM,Lips P,Middelkoop BJ. Vitamin D status and bone mineral density in the Chinese population: a review Arch Osteoporos 2016 11 14 PMC4819723

[30] Yodoshi T,Orkin S,Arce-Clachar AC.et al. Vitamin D deficiency: prevalence and association with liver disease severity in pediatric nonalcoholic fatty liver disease Eur J Clin Nutr 2020 74 427 35 PMC8006544

[31] Heo NJ,Park HE,Yoon JW.et al. The association between vitamin D and nonalcoholic fatty liver disease assessed by controlled attenuation parameter J Clin Med 2021 10 2611 PMC8231966

[32] Ebrahimpour-Koujan S,Sohrabpour AA,Giovannucci E,Vatannejad A,Esmaillzadeh A. Effects of vitamin D supplementation on liver fibrogenic factors, vitamin D receptor and liver fibrogenic microRNAs in metabolic dysfunction-associated steatotic liver disease (MASLD) patients: an exploratory randomized clinical trial Nutr J 2024 23 24 PMC10898146

[33] Khanmohammadi S,Kuchay MS. Effects of metabolic dysfunction-associated steatotic liver disease on bone density and fragility fractures: associations and mechanisms J Obes Metab Syndr 2024 33 108 20 PMC11224928

[34] Goldscheitter GM,Seneshaw M,Mirshahi F.et al. Sexual dimorphism of MASLD-driven bone loss Sci Rep 2025 15 23090 PMC12215454

[35] Bo T,Gao L,Yao Z.et al. Hepatic selective insulin resistance at the intersection of insulin signaling and metabolic dysfunction-associated steatotic liver disease Cell Metab 2024 36 947 68

[36] Carli F,Della Pepa G,Sabatini S,Vidal Puig A,Gastaldelli A. Lipid metabolism in MASLD and MASH: from mechanism to the clinic JHEP Rep 2024 6 101185 PMC11582433

[37] Liu CH,Zeng QM,Kim W.et al. Sarcopenia and MASLD: novel insights and the future Nat Rev Endocrinol 2026 22 139 52

[38] Wang P,Liu X,Du X.et al. Prevalence and risk of metabolic dysfunction-associated steatotic liver disease in patients with sarcopenic obesity: a systematic review and meta-analysis Nutr Metab 2025 22 101 PMC12392554

[39] Milani I,Codini M,Guarisco G.et al. Hepatokines and MASLD: the GLP1-Ras-FGF21-Fetuin-A crosstalk as a therapeutic target Int J Mol Sci 2024 25 10795 PMC11477334

[40] Pezzino S,Puleo S,Luca T,Castorina M,Castorina S. Adipokine and hepatokines in metabolic dysfunction-associated steatotic liver disease (MASLD): current and developing trends Biomedicines 2025 13 1854 PMC12383407

[41] Nishikawa H,Kim SK,Asai A. The role of myokines in liver diseases Int J Mol Sci 2025 26 1043 PMC11817747

[42] Aguirre F,Valero-Breton M,Cabrera D.et al. Impact of myokines on chronic liver diseases: exploring the effects of metabolic dysfunction-associated steatotic liver disease (MASLD) on skeletal muscle. A narrative review Eur J Transl Myol 2025 35 13365 PMC12536684

[43] Wang JL,Xiao Y,Li ML,Chen GL,Cui MH,Liu JL. Research progress on leptin in metabolic dysfunction-associated fatty liver disease J Clin Transl Hepatol 2025 13 964 75 PMC12643832

[44] Liu J,Song Y,Wang Y,Hong H. Vitamin D/vitamin D receptor pathway in non-alcoholic fatty liver disease Expert Opin Ther Targets 2023 27 1145 57

[45] Gupta V,Krishnamoorthy A. Skeletal muscle alterations in metabolic dysfunction-associated steatotic liver disease: a critical review of diagnostic, mechanistic, and therapeutic intersections World J Gastroenterol 2025 31 110481 PMC12400224

[46] Kerminen H,Jyväkorpi S,Urtamo A.et al. Performance of the SARC-F, SARC-CalF, and calf circumference for sarcopenia case finding in community-dwelling older adults Eur Geriatr Med 2024 15 1817 26 PMC11631994

[47] Ju C,Yao L,Yoon SY.et al. Defining reference values for skeletal muscle metrics on abdominal CT using data from healthy young adult populations: a systematic review and meta-analysis AJR Am J Roentgenol 2025 225 e2532781 PMC13019695

[48] Yang J,Liu Q,Sun C. Quality and quantity? The clinical significance of myosteatosis in various liver diseases: a narrative review J Clin Transl Hepatol 2025 13 1092 106 PMC12745355

[49] European Association for the Study of the Liver. EASL Clinical Practice Guidelines on nutrition in chronic liver disease J Hepatol 2019 70 172 93 PMC6657019

[50] Plauth M,Bernal W,Dasarathy S.et al. ESPEN guideline on clinical nutrition in liver disease Clin Nutr 2019 38 485 521 PMC6686849

[51] Fan JG,Xu XY,Yang RX.et al. ; Chinese Society of Hepatology, Chinese Medical Association. Guideline for the prevention and treatment of metabolic dysfunction-associated fatty liver disease (version 2024) J Clin Transl Hepatol 2024 12 955 74 PMC11557364

[52] Medeiros DG,Ferreira LF,Lamp JDS,Telles da Rosa LH. The impact of resistance training in patients diagnosed with metabolic dysfunction-associated steatotic liver disease: a systematic review Eur J Gastroenterol Hepatol 2025 37 129 36 PMC11658022

[53] Lin YY,Qian D,Lin L,Chen S,Jing XC. Advanced exercise intervention for liver cirrhosis and sarcopenia: a development and feasibility study Medicine 2025 104 e43974 PMC12384846

[54] Hsu HC,Chow LH,Chen YL,Hung HM,Yen M,Lee HF. Effects of exercise and nutrition in improving sarcopenia in liver cirrhosis patients: a systematic review and meta-analysis Hepatobiliary Surg Nutr 2025 14 33 48 PMC11806151

[55] Brown A,Dias I,da Silva Novaes J.et al. A resistance training program on patients with liver cirrhosis: a randomized clinical trial Int J Environ Res Public Health 2025 22 1257 PMC12386610

[56] Yang S,Chen S,Zhang Y,Zhou Z,Li D,Zeng P. Effects of Tai Chi and Baduanjin on muscle mass, muscle function, and activities of daily living in individuals with sarcopenia: a systematic review and meta-analysis Front Public Health 2025 13 1636857 PMC12440739

[57] Linge J,Birkenfeld AL,Neeland IJ. Muscle mass and glucagon-like peptide-1 receptor agonists: adaptive or maladaptive response to weight loss? Circulation 2024;150:1288-98

[58] Martinekova P,Obeidat M,Topala M.et al. Role of vitamin D supplementation in chronic liver disease: a systematic review and meta-analysis of randomized controlled trials Nutr Rev 2025 83 2043 54 PMC12512233

[59] Taheri E,Esmaeili S,Jodeiri F.et al. Vitamin D supplementation for steatotic liver disease: an updated systematic review and dose-response meta-analysis of randomized and nonrandomized interventional studies Curr Dev Nutr 2026 10 107631 PMC12887409

[60] Harrison SA,Bedossa P,Guy CD.et al. ; MAESTRO-NASH Investigators. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis N Engl J Med 2024 390 497 509

[61] Sanyal AJ,Newsome PN,Kliers I.et al. ; ESSENCE Study Group. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis N Engl J Med 2025 392 2089 99

[62] Moscucci F,Baratta F,Pastori D.et al. A narrative review on GLP-1 receptor agonists for obesity in older women: maximizing weight loss while preserving lean mass Nutrients 2026 18 632 PMC12943638

[63] Heymsfield SB,Aronne LJ,Montgomery P.et al. ; BELIEVE trial investigators. Bimagrumab plus semaglutide alone or in combination for the treatment of obesity: a randomized phase 2 trial Nat Med 2026 32 869 82 PMC13004672