The Molecular Pathogenesis of Sarcopenia/Frailty in Cirrhosis

Huanli Jiao; Han Wang; Jia Li; Ziyi Yang; Chao Sun

doi:10.1055/a-2564-7551

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2025; 45(03): 303-314
DOI: 10.1055/a-2564-7551

Review Article

The Molecular Pathogenesis of Sarcopenia/Frailty in Cirrhosis

Authors

Huanli Jiao‡^*

¹Department of Health Management, Tianjin Hospital, Hexi District, Tianjin, People's Republic of China
Han Wang‡^*

¹Department of Health Management, Tianjin Hospital, Hexi District, Tianjin, People's Republic of China
Jia Li‡^*

²Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Heping District, Tianjin, People's Republic of China
Ziyi Yang‡^*

²Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Heping District, Tianjin, People's Republic of China
Chao Sun

²Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Heping District, Tianjin, People's Republic of China

³Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, Tianjin, People's Republic of China

Abstract

Cirrhosis is an important cause of morbidity and death in patients with chronic liver disease. It can be divided into compensatory and decompensated stages. During the decompensation period, complications such as esophageal and gastric varices hemorrhage, hepatic encephalopathy, infection, and hepatorenal syndrome are often incurred, which has a high mortality rate and leverages huge economic burden on society, healthcare resources, and individuals. Sarcopenia and frailty are common in patients with cirrhosis. The pathogenesis of sarcopenia and frailty in the context of cirrhosis is complicated and multifactorial, including overwhelming systemic inflammation, imbalance of muscle protein metabolism, malnutrition, endocrine and metabolic dysfunctions, intestinal microecological disorders, lack of physical exercise, and other aspects. Notably, accumulating evidence implicates that many patients experience sarcopenia/frailty even before the onset of liver cirrhosis. In this regard, the magnitude of liver fibrosis is closely linked to the progression of sarcopenia with reciprocal impact. In conclusion, this review article will shed light on the pathogenesis of cirrhosis complicated with sarcopenia/frailty, aimed at facilitating early diagnosis and effective management.

Keywords

cirrhosis - sarcopenia - frailty - pathogenesis - molecular mechanism

Full Text

References

References
1 Ginès P, Krag A, Abraldes JG, Solà E, Fabrellas N, Kamath PS. Liver cirrhosis. Lancet 2021; 398 (10308): 1359-1376
2 Huang DQ, Terrault NA, Tacke F. et al. Global epidemiology of cirrhosis - aetiology, trends and predictions. Nat Rev Gastroenterol Hepatol 2023; 20 (06) 388-398
3 Sayer AA, Cruz-Jentoft A. Sarcopenia definition, diagnosis and treatment: consensus is growing. Age Ageing 2022; 51 (10) 51
4 Lai JC, Tandon P, Bernal W. et al. Malnutrition, frailty, and sarcopenia in patients with cirrhosis: 2021 practice guidance by the American Association for the study of liver diseases. Hepatology 2021; 74 (03) 1611-1644
5 Cruz-Jentoft AJ, Baeyens JP, Bauer JM. et al; European Working Group on Sarcopenia in Older People. Sarcopenia: European consensus on definition and diagnosis: report of the European working group on sarcopenia in older people. Age Ageing 2010; 39 (04) 412-423
6 Sun C, Zhao T, Yang W. et al. Reduced muscle strength is closely linked to computed tomography-defined myosteatosis among inpatients with cirrhosis. Postgrad Med J 2023; 100 (1179) 12-19
7 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 (04) 601
8 Sinclair M. Controversies in diagnosing sarcopenia in cirrhosis-moving from research to clinical practice. Nutrients 2019; 11 (10) 11
9 Kolle AT, Lewis KB, Lalonde M, Backman C. Reversing frailty in older adults: a scoping review. BMC Geriatr 2023; 23 (01) 751
10 Kojima G, Iliffe S, Walters K. Frailty index as a predictor of mortality: a systematic review and meta-analysis. Age Ageing 2018; 47 (02) 193-200
11 Rohrmann S. Epidemiology of frailty in older people. Adv Exp Med Biol 2020; 1216: 21-27
12 Di Sabatino A, Lenti MV, Cammalleri L, Corazza GR, Pilotto A. Frailty and the gut. Dig Liver Dis 2018; 50 (06) 533-541
13 Soysal P, Arik F, Smith L, Jackson SE, Isik AT. Inflammation, frailty and cardiovascular disease. Adv Exp Med Biol 2020; 1216: 55-64
14 Deng Y, Hui Y, Cui B, Xie W, Sun C. Accumulating awareness on the clinical significance and relevance of frailty in cirrhosis: time to dig deeper into mechanistic basis!. Liver Int 2023; 43 (08) 1629-1643
15 Tandon P, Montano-Loza AJ, Lai JC, Dasarathy S, Merli M. Sarcopenia and frailty in decompensated cirrhosis. J Hepatol 2021; 75 (Suppl. 01) S147-S162
16 Kok B, Tandon P. Frailty in patients with cirrhosis. Curr Treat Options Gastroenterol 2018; 16 (02) 215-225
17 Dichtel LE, Corey KE, Haines MS. et al. The GH/IGF-1 axis is associated with intrahepatic lipid content and hepatocellular damage in overweight/obesity. J Clin Endocrinol Metab 2022; 107 (09) e3624-e3632
18 Wiedmer P, Jung T, Castro JP. et al. Sarcopenia - molecular mechanisms and open questions. Ageing Res Rev 2021; 65: 101200
19 Saeki C, Kanai T, Nakano M. et al. Low serum branched-chain amino acid and insulin-like growth factor-1 levels are associated with sarcopenia and slow gait speed in patients with liver cirrhosis. J Clin Med 2020; 9 (10) 9
20 Stitt TN, Drujan D, Clarke BA. et al. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell 2004; 14 (03) 395-403
21 Philippou A, Halapas A, Maridaki M, Koutsilieris M. Type I insulin-like growth factor receptor signaling in skeletal muscle regeneration and hypertrophy. J Musculoskelet Neuronal Interact 2007; 7 (03) 208-218
22 Yoshida T, Delafontaine P. Mechanisms of IGF-1-mediated regulation of skeletal muscle hypertrophy and atrophy. Cells 2020; 9 (09) 9
23 Yu M, Wang H, Xu Y. et al. Insulin-like growth factor-1 (IGF-1) promotes myoblast proliferation and skeletal muscle growth of embryonic chickens via the PI3K/Akt signalling pathway. Cell Biol Int 2015; 39 (08) 910-922
24 Valdés JA, Flores S, Fuentes EN, Osorio-Fuentealba C, Jaimovich E, Molina A. IGF-1 induces IP3 -dependent calcium signal involved in the regulation of myostatin gene expression mediated by NFAT during myoblast differentiation. J Cell Physiol 2013; 228 (07) 1452-1463
25 Allen SL, Quinlan JI, Dhaliwal A. et al. Sarcopenia in chronic liver disease: mechanisms and countermeasures. Am J Physiol Gastrointest Liver Physiol 2021; 320 (03) G241-G257
26 Chrysavgis L, Adamantou M, Angelousi A, Cholongitas E. The association of testosterone with sarcopenia and frailty in chronic liver disease. Eur J Clin Invest 2024; 54 (02) e14108
27 Deng N, Mallepally N, Peng FB, Kanji A, Marcelli M, Hernaez R. Serum testosterone levels and testosterone supplementation in cirrhosis: a systematic review. Liver Int 2021; 41 (10) 2358-2370
28 Saad F, Röhrig G, von Haehling S, Traish A. Testosterone deficiency and testosterone treatment in older men. Gerontology 2017; 63 (02) 144-156
29 Sinha-Hikim I, Cornford M, Gaytan H, Lee ML, Bhasin S. Effects of testosterone supplementation on skeletal muscle fiber hypertrophy and satellite cells in community-dwelling older men. J Clin Endocrinol Metab 2006; 91 (08) 3024-3033
30 Basualto-Alarcón C, Jorquera G, Altamirano F, Jaimovich E, Estrada M. Testosterone signals through mTOR and androgen receptor to induce muscle hypertrophy. Med Sci Sports Exerc 2013; 45 (09) 1712-1720
31 Estrada M, Espinosa A, Müller M, Jaimovich E. Testosterone stimulates intracellular calcium release and mitogen-activated protein kinases via a G protein-coupled receptor in skeletal muscle cells. Endocrinology 2003; 144 (08) 3586-3597
32 Kovacheva EL, Hikim AP, Shen R, Sinha I, Sinha-Hikim I. Testosterone supplementation reverses sarcopenia in aging through regulation of myostatin, c-Jun NH2-terminal kinase, Notch, and Akt signaling pathways. Endocrinology 2010; 151 (02) 628-638
33 Lilienbaum A. Relationship between the proteasomal system and autophagy. Int J Biochem Mol Biol 2013; 4 (01) 1-26
34 Masiero E, Sandri M. Autophagy inhibition induces atrophy and myopathy in adult skeletal muscles. Autophagy 2010; 6 (02) 307-309
35 Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13 (01) 6-65
36 Xia Z, Cholewa J, Zhao Y. et al. Targeting inflammation and downstream protein metabolism in sarcopenia: a brief up-dated description of concurrent exercise and leucine-based multimodal intervention. Front Physiol 2017; 8: 434
37 Beyer I, Mets T, Bautmans I. Chronic low-grade inflammation and age-related sarcopenia. Curr Opin Clin Nutr Metab Care 2012; 15 (01) 12-22
38 Bian AL, Hu HY, Rong YD, Wang J, Wang JX, Zhou XZ. A study on relationship between elderly sarcopenia and inflammatory factors IL-6 and TNF-α. Eur J Med Res 2017; 22 (01) 25
39 Qiu J, Tsien C, Thapalaya S. et al. Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis. Am J Physiol Endocrinol Metab 2012; 303 (08) E983-E993
40 Kumar A, Davuluri G, Silva RNE. et al. Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis. Hepatology 2017; 65 (06) 2045-2058
41 Chen HW, Dunn MA. Muscle at risk: the multiple impacts of ammonia on sarcopenia and frailty in cirrhosis. Clin Transl Gastroenterol 2016; 7 (05) e170
42 Dasarathy S, Hatzoglou M. Hyperammonemia and proteostasis in cirrhosis. Curr Opin Clin Nutr Metab Care 2018; 21 (01) 30-36
43 Kumar R, Prakash SS, Priyadarshi RN, Anand U. Sarcopenia in chronic liver disease: a metabolic perspective. J Clin Transl Hepatol 2022; 10 (06) 1213-1222
44 Dasarathy S, McCullough AJ, Muc S. et al. Sarcopenia associated with portosystemic shunting is reversed by follistatin. J Hepatol 2011; 54 (05) 915-921
45 Ecker N, Mor A, Journo D, Abeliovich H. Induction of autophagic flux by amino acid deprivation is distinct from nitrogen starvation-induced macroautophagy. Autophagy 2010; 6 (07) 879-890
46 Churchward-Venne TA, Breen L, Phillips SM. Alterations in human muscle protein metabolism with aging: protein and exercise as countermeasures to offset sarcopenia. Biofactors 2014; 40 (02) 199-205
47 Nishikawa H, Enomoto H, Nishiguchi S, Iijima H. Liver cirrhosis and sarcopenia from the viewpoint of dysbiosis. Int J Mol Sci 2020; 21 (15) 21
48 Donaghy A, Ross R, Wicks C. et al. Growth hormone therapy in patients with cirrhosis: a pilot study of efficacy and safety. Gastroenterology 1997; 113 (05) 1617-1622
49 Frost RA, Lang CH. Multifaceted role of insulin-like growth factors and mammalian target of rapamycin in skeletal muscle. Endocrinol Metab Clin North Am 2012; 41 (02) 297-322 , vi vi
50 Mordier S, Deval C, Béchet D, Tassa A, Ferrara M. Leucine limitation induces autophagy and activation of lysosome-dependent proteolysis in C2C12 myotubes through a mammalian target of rapamycin-independent signaling pathway. J Biol Chem 2000; 275 (38) 29900-29906
51 Nishikawa H, Osaki Y. Clinical significance of therapy using branched-chain amino acid granules in patients with liver cirrhosis and hepatocellular carcinoma. Hepatol Res 2014; 44 (02) 149-158
52 Tamai Y, Eguchi A, Shigefuku R. et al. Association of lithocholic acid with skeletal muscle hypertrophy through TGR5-IGF-1 and skeletal muscle mass in cultured mouse myotubes, chronic liver disease rats and humans. eLife 2022; 11: 11
53 Nolte W, Hartmann H, Ramadori G. Glucose metabolism and liver cirrhosis. Exp Clin Endocrinol Diabetes 1995; 103 (02) 63-74
54 Changani KK, Jalan R, Cox IJ. et al. Evidence for altered hepatic gluconeogenesis in patients with cirrhosis using in vivo 31-phosphorus magnetic resonance spectroscopy. Gut 2001; 49 (04) 557-564
55 Tajiri K, Shimizu Y. Branched-chain amino acids in liver diseases. World J Gastroenterol 2013; 19 (43) 7620-7629
56 Tsien C, Davuluri G, Singh D. et al. Metabolic and molecular responses to leucine-enriched branched chain amino acid supplementation in the skeletal muscle of alcoholic cirrhosis. Hepatology 2015; 61 (06) 2018-2029
57 Redman JS, Kaspar M, Puri P. Implications of pre-transplant sarcopenia and frailty in patients with non-alcoholic steatohepatitis and alcoholic liver disease. Transl Gastroenterol Hepatol 2022; 7: 29
58 Ebadi M, Bhanji RA, Mazurak VC, Montano-Loza AJ. Sarcopenia in cirrhosis: from pathogenesis to interventions. J Gastroenterol 2019; 54 (10) 845-859
59 Paradies G, Paradies V, Ruggiero FM, Petrosillo G. Oxidative stress, cardiolipin and mitochondrial dysfunction in nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20 (39) 14205-14218
60 Marzetti E, Calvani R, Cesari M. et al. Mitochondrial dysfunction and sarcopenia of aging: from signaling pathways to clinical trials. Int J Biochem Cell Biol 2013; 45 (10) 2288-2301
61 Zhang F, Liu L, Li W. Correlation of sarcopenia with progression of liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease: a study from two cohorts in China and the United States. Nutr J 2025; 24 (01) 6
62 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 (11) 2876-2888.e5
63 Lee YH, Kim SU, Song K. et al. Sarcopenia is associated with significant liver fibrosis independently of obesity and insulin resistance in nonalcoholic fatty liver disease: nationwide surveys (KNHANES 2008-2011). Hepatology 2016; 63 (03) 776-786
64 Han E, Lee YH, Kim BK. et al. Sarcopenia is associated with the risk of significant liver fibrosis in metabolically unhealthy subjects with chronic hepatitis B. Aliment Pharmacol Ther 2018; 48 (03) 300-312
65 Koo BK, Kim D, Joo SK. et al. Sarcopenia is an independent risk factor for non-alcoholic steatohepatitis and significant fibrosis. J Hepatol 2017; 66 (01) 123-131
66 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
67 Kurosawa T, Goto M, Kaji N. et al. Liver fibrosis-induced muscle atrophy is mediated by elevated levels of circulating TNFα. Cell Death Dis 2021; 12 (01) 11
68 Welch N, Dasarathy J, Runkana A. et al. Continued muscle loss increases mortality in cirrhosis: impact of aetiology of liver disease. Liver Int 2020; 40 (05) 1178-1188
69 Dasarathy J, McCullough AJ, Dasarathy S. Sarcopenia in alcoholic liver disease: clinical and molecular advances. Alcohol Clin Exp Res 2017; 41 (08) 1419-1431
70 Koyama Y, Brenner DA. Liver inflammation and fibrosis. J Clin Invest 2017; 127 (01) 55-64
71 Sakuma K, Aoi W, Yamaguchi A. Current understanding of sarcopenia: possible candidates modulating muscle mass. Pflugers Arch 2015; 467 (02) 213-229
72 Dalle S, Rossmeislova L, Koppo K. The role of inflammation in age-related sarcopenia. Front Physiol 2017; 8: 1045
73 Wang X, Wu M. Research progress of gut microbiota and frailty syndrome. Open Med (Wars) 2021; 16 (01) 1525-1536
74 Wintermeyer E, Ihle C, Ehnert S. et al. Crucial role of vitamin D in the musculoskeletal system. Nutrients 2016; 8 (06) 8
75 Okubo T, Atsukawa M, Tsubota A. et al. Relationship between serum vitamin D level and sarcopenia in chronic liver disease. Hepatol Res 2020; 50 (05) 588-597
76 Drittanti L, de Boland AR, Boland R. Modulation of DNA synthesis in cultured muscle cells by 1,25-dihydroxyvitamin D-3. Biochim Biophys Acta 1989; 1014 (02) 112-119
77 Garcia LA, King KK, Ferrini MG, Norris KC, Artaza JN. 1,25(OH)2vitamin D3 stimulates myogenic differentiation by inhibiting cell proliferation and modulating the expression of promyogenic growth factors and myostatin in C2C12 skeletal muscle cells. Endocrinology 2011; 152 (08) 2976-2986
78 Amthor H, Nicholas G, McKinnell I. et al. Follistatin complexes myostatin and antagonises myostatin-mediated inhibition of myogenesis. Dev Biol 2004; 270 (01) 19-30
79 Clarembeau F, Bale G, Lanthier N. Cirrhosis and insulin resistance: current knowledge, pathophysiological mechanisms, complications and potential treatments. Clin Sci (Lond) 2020; 134 (16) 2117-2135
80 Pérez-Tasigchana RF, León-Muñoz LM, Lopez-Garcia E. et al. Metabolic syndrome and insulin resistance are associated with frailty in older adults: a prospective cohort study. Age Ageing 2017; 46 (05) 807-812
81 Barzilay JI, Blaum C, Moore T. et al. Insulin resistance and inflammation as precursors of frailty: the cardiovascular health study. Arch Intern Med 2007; 167 (07) 635-641
82 Abbatecola AM, Ferrucci L, Marfella R, Paolisso G. Insulin resistance and cognitive decline may be common soil for frailty syndrome. Arch Intern Med 2007; 167 (19) 2145-2146
83 Jindal A, Jagdish RK. Sarcopenia: ammonia metabolism and hepatic encephalopathy. Clin Mol Hepatol 2019; 25 (03) 270-279
84 Traub J, Reiss L, Aliwa B, Stadlbauer V. Malnutrition in patients with liver cirrhosis. Nutrients 2021; 13 (02) 13
85 Nishikawa H, Asai A, Fukunishi S. The significance of zinc in patients with chronic liver disease. Nutrients 2022; 14 (22) 14
86 Katayama K. Zinc and protein metabolism in chronic liver diseases. Nutr Res 2020; 74: 1-9
87 Nishikawa H, Enomoto H, Yoh K. et al. Serum zinc concentration and sarcopenia: a close linkage in chronic liver diseases. J Clin Med 2019; 8 (03) 8
88 Hernández-Conde M, Llop E, Gómez-Pimpollo L. et al. Adding branched-chain amino acids to an enhanced standard-of-care treatment improves muscle mass of cirrhotic patients with sarcopenia: a placebo-controlled trial. Am J Gastroenterol 2021; 116 (11) 2241-2249
89 Nishikawa H, Yoh K, Enomoto H. et al. Serum zinc level is associated with frailty in chronic liver diseases. J Clin Med 2020; 9 (05) 9
90 Rocha ED, de Brito NJ, Dantas MM, Silva AdeA, Almeida Md, Brandão-Neto J. Effect of zinc supplementation on GH, IGF1, IGFBP3, OCN, and ALP in non-zinc-deficient children. J Am Coll Nutr 2015; 34 (04) 290-299
91 Shapiro H, Thaiss CA, Levy M, Elinav E. The cross talk between microbiota and the immune system: metabolites take center stage. Curr Opin Immunol 2014; 30: 54-62
92 Mello AM, Paroni G, Daragjati J, Pilotto A. Gastrointestinal microbiota and their contribution to healthy aging. Dig Dis 2016; 34 (03) 194-201
93 Ticinesi A, Nouvenne A, Cerundolo N. et al. Gut microbiota, muscle mass and function in aging: a focus on physical frailty and sarcopenia. Nutrients 2019; 11 (07) 11
94 An R, Wilms E, Masclee AAM, Smidt H, Zoetendal EG, Jonkers D. Age-dependent changes in GI physiology and microbiota: time to reconsider?. Gut 2018; 67 (12) 2213-2222
95 Hayashi F, Matsumoto Y, Momoki C. et al. Physical inactivity and insufficient dietary intake are associated with the frequency of sarcopenia in patients with compensated viral liver cirrhosis. Hepatol Res 2013; 43 (12) 1264-1275
96 Román E, García-Galcerán C, Torrades T. et al. Effects of an exercise programme on functional capacity, body composition and risk of falls in patients with cirrhosis: a randomized clinical trial. PLoS One 2016; 11 (03) e0151652
97 Zenith L, Meena N, Ramadi A. et al. Eight weeks of exercise training increases aerobic capacity and muscle mass and reduces fatigue in patients with cirrhosis. Clin Gastroenterol Hepatol 2014; 12 (11) 1920-6.e2
98 Lai JC, Rahimi RS, Verna EC. et al. Frailty associated with waitlist mortality independent of ascites and hepatic encephalopathy in a multicenter study. Gastroenterology 2019; 156 (06) 1675-1682
99 Elsheikh M, El Sabagh A, Mohamed IB, Bhongade M, Hassan MM, Jalal PK. Frailty in end-stage liver disease: Understanding pathophysiology, tools for assessment, and strategies for management. World J Gastroenterol 2023; 29 (46) 6028-6048
100 Ni Lochlainn M, Cox NJ, Wilson T. et al. Nutrition and frailty: opportunities for prevention and treatment. Nutrients 2021; 13 (07) 13
101 Meena BL, Taneja S, Tandon P. et al. Home-based intensive nutrition therapy improves frailty and sarcopenia in patients with decompensated cirrhosis: a randomized clinical trial. J Gastroenterol Hepatol 2023; 38 (02) 210-218
102 Chew J, Tay L, Lim JP. et al. Serum myostatin and IGF-1 as gender-specific biomarkers of frailty and low muscle mass in community-dwelling older adults. J Nutr Health Aging 2019; 23 (10) 979-986