The Pathogenesis of Physical Frailty and Sarcopenia

  • Srinivasan DasarathyEmail author


Disordered energy metabolism in cirrhosis contributes to skeletal muscle proteolysis and impaired protein synthesis with dysregulated protein homeostasis (proteostasis) and resultant sarcopenia. Circulating abnormalities including hyperammonemia, hypogonadism, decreased branched chain amino acids, and endotoxemia are potential mediators of the liver-muscle axis. Etiology of liver disease including ethanol and fatty acids also directly affects muscle proteostasis. Transcriptional upregulation of myostatin via ammonia-induced activation of p65NFKB impairs signaling by the protein homeostasis regulatory molecule, mammalian target of rapamycin complex 1 (mTORC1). The recently described hyperammonemic stress response (HASR) is characterized by activation of an amino acid sensor, general control non-derepressible 2 (GCN2) with persistent phosphorylation of eIF2α with reduction in protein synthesis. Hyperammonemia of cirrhosis also increases autophagic proteolysis and mitochondrial dysfunction with cataplerosis. Targeting mediators of the liver-muscle axis, the signaling perturbations in the muscle, and strategies to restore metabolic homeostasis with ammonia-lowering, anaplerotic agents and myostatin antagonists have the potential to be novel and effective therapies to reverse sarcopenia in cirrhosis.


Sarcopenia Cirrhosis Protein homeostasis Autophagy Mitochondria Hyperammonemic stress response 


  1. 1.
    Periyalwar P, Dasarathy S. Malnutrition in cirrhosis: contribution and consequences of sarcopenia on metabolic and clinical responses. Clin Liver Dis. 2012;16:95–131.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Dasarathy S. Consilience in sarcopenia of cirrhosis. J Cachexia Sarcopenia Muscle. 2012;3:225–37.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Ebadi M, Montano-Loza AJ. Insights on clinical relevance of sarcopenia in patients with cirrhosis and sepsis. Liver Int. 2018;38:786–8.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Ebadi M, Montano-Loza AJ. Sarcopenia and frailty in the prognosis of patients on the liver transplant waiting list. Liver Transpl. 2019;25:7–9.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Sinclair M, Poltavskiy E, Dodge JL, Lai JC. Frailty is independently associated with increased hospitalisation days in patients on the liver transplant waitlist. World J Gastroenterol. 2017;23:899–905.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Lai JC, Covinsky KE, McCulloch CE, Feng S. The liver frailty index improves mortality prediction of the subjective clinician assessment in patients with cirrhosis. Am J Gastroenterol. 2018;113:235–42.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Dasarathy S. Cause and management of muscle wasting in chronic liver disease. Curr Opin Gastroenterol. 2016;32:159–65.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Dasarathy S, Merli M. Sarcopenia from mechanism to diagnosis and treatment in liver disease. J Hepatol. 2016;65:1232–44.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Antar R, Wong P, Ghali P. A meta-analysis of nutritional supplementation for management of hospitalized alcoholic hepatitis. Can J Gastroenterol. 2012;26:463–7.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Koretz RL. The evidence for the use of nutritional support in liver disease. Curr Opin Gastroenterol. 2014;30:208–14.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Fialla AD, Israelsen M, Hamberg O, Krag A, Gluud LL. Nutritional therapy in cirrhosis or alcoholic hepatitis: a systematic review and meta-analysis. Liver Int. 2015;35:2072–8.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Ney M, Vandermeer B, van Zanten SJ, Ma MM, Gramlich L, Tandon P. Meta-analysis: oral or enteral nutritional supplementation in cirrhosis. Aliment Pharmacol Ther. 2013;37:672–9.CrossRefGoogle Scholar
  13. 13.
    Anthony TG. Mechanisms of protein balance in skeletal muscle. Domest Anim Endocrinol. 2016;56(Suppl):S23–32.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Dasarathy S, Hatzoglou M. Hyperammonemia and proteostasis in cirrhosis. Curr Opin Clin Nutr Metab Care. 2018;21:30–6.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Sirabella D, De Angelis L, Berghella L. Sources for skeletal muscle repair: from satellite cells to reprogramming. J Cachexia Sarcopenia Muscle. 2013;4:125–36.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Fry CS, Lee JD, Mula J, Kirby TJ, Jackson JR, Liu F, et al. Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia. Nat Med. 2015;21:76–80.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    McCarthy JJ, Mula J, Miyazaki M, Erfani R, Garrison K, Farooqui AB, et al. Effective fiber hypertrophy in satellite cell-depleted skeletal muscle. Development. 2011;138:3657–66.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Tandon P, Raman M, Mourtzakis M, Merli M. A practical approach to nutritional screening and assessment in cirrhosis. Hepatology. 2017;65:1044–57.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Fiore P, Merli M, Andreoli A, De Lorenzo A, Masini A, Ciuffa L, et al. A comparison of skinfold anthropometry and dual-energy X-ray absorptiometry for the evaluation of body fat in cirrhotic patients. Clin Nutr. 1999;18:349–51.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Merli M, Riggio O, Dally L. Does malnutrition affect survival in cirrhosis? PINC (Policentrica Italiana Nutrizione Cirrosi). Hepatology. 1996;23:1041–6.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Romiti A, Merli M, Martorano M, Parrilli G, Martino F, Riggio O, et al. Malabsorption and nutritional abnormalities in patients with liver cirrhosis. Ital J Gastroenterol. 1990;22:118–23.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Merli M, Nicolini G, Angeloni S, Riggio O. Malnutrition is a risk factor in cirrhotic patients undergoing surgery. Nutrition. 2002;18:978–86.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Riggio O, Angeloni S, Ciuffa L, Nicolini G, Attili AF, Albanese C, et al. Malnutrition is not related to alterations in energy balance in patients with stable liver cirrhosis. Clin Nutr. 2003;22:553–9.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Schiavo L, Busetto L, Cesaretti M, Zelber-Sagi S, Deutsch L, Iannelli A. Nutritional issues in patients with obesity and cirrhosis. World J Gastroenterol. 2018;24:3330–46.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Eslamparast T, Montano-Loza AJ, Raman M, Tandon P. Sarcopenic obesity in cirrhosis-the confluence of 2 prognostic titans. Liver Int. 2018;38:1706–17.CrossRefGoogle Scholar
  26. 26.
    Stenholm S, Harris TB, Rantanen T, Visser M, Kritchevsky SB, Ferrucci L. Sarcopenic obesity: definition, cause and consequences. Curr Opin Clin Nutr Metab Care. 2008;11:693–700.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Dasarathy J, Alkhouri N, Dasarathy S. Changes in body composition after transjugular intrahepatic portosystemic stent in cirrhosis: a critical review of literature. Liver Int. 2011;31:1250–8.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Tsien C, Garber A, Narayanan A, Shah SN, Barnes D, Eghtesad B, et al. Post-liver transplantation sarcopenia in cirrhosis: a prospective evaluation. J Gastroenterol Hepatol. 2014;29:1250–7.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Carey EJ, Lai JC, Wang CW, Dasarathy S, Lobach I, Montano-Loza AJ, et al. A multicenter study to define sarcopenia in patients with end-stage liver disease. Liver Transpl. 2017;23:625–33.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Ebadi M, Wang CW, Lai JC, Dasarathy S, Kappus MR, Dunn MA, et al. Poor performance of psoas muscle index for identification of patients with higher waitlist mortality risk in cirrhosis. J Cachexia Sarcopenia Muscle. 2018;9:1053–62.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Gallagher D, Visser M, De Meersman RE, Sepulveda D, Baumgartner RN, Pierson RN, et al. Appendicular skeletal muscle mass: effects of age, gender, and ethnicity. J Appl Physiol. (1985) 1997;83:229–39.Google Scholar
  32. 32.
    Heymsfield SB, Peterson CM, Thomas DM, Heo M, Schuna JM Jr. Why are there race/ethnic differences in adult body mass index-adiposity relationships? A quantitative critical review. Obes Rev. 2016;17:262–75.PubMedCrossRefGoogle Scholar
  33. 33.
    Cesari M, Landi F, Vellas B, Bernabei R, Marzetti E. Sarcopenia and physical frailty: two sides of the same coin. Front Aging Neurosci. 2014;6:192.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Kok B, Tandon P. Frailty in patients with cirrhosis. Curr Treat Options Gastroenterol. 2018;16:215–25.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    McDaniel J, Davuluri G, Hill EA, Moyer M, Runkana A, Prayson R, et al. Hyperammonemia results in reduced muscle function independent of muscle mass. Am J Physiol Gastrointest Liver Physiol. 2016;310:G163–70.PubMedCrossRefGoogle Scholar
  36. 36.
    Lai JC, Covinsky KE, Dodge JL, Boscardin WJ, Segev DL, Roberts JP, et al. Development of a novel frailty index to predict mortality in patients with end-stage liver disease. Hepatology. 2017;66:564–74.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Lai JC, Volk ML, Strasburg D, Alexander N. Performance-based measures associate with frailty in patients with end-stage liver disease. Transplantation. 2016;100:2656–60.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Bosoi CR, Oliveira MM, Ochoa-Sanchez R, Tremblay M, Ten Have GA, Deutz NE, et al. The bile duct ligated rat: a relevant model to study muscle mass loss in cirrhosis. Metab Brain Dis. 2017;32:513–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Dasarathy S, Muc S, Hisamuddin K, Edmison JM, Dodig M, McCullough AJ, et al. Altered expression of genes regulating skeletal muscle mass in the portacaval anastomosis rat. Am J Physiol Gastrointest Liver Physiol. 2007;292:G1105–13.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Qiu J, Thapaliya S, Runkana A, Yang Y, Tsien C, Mohan ML, et al. Hyperammonemia in cirrhosis induces transcriptional regulation of myostatin by an NF-kappaB-mediated mechanism. Proc Natl Acad Sci U S A. 2013;110:18162–7.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Qiu J, Tsien C, Thapalaya S, Narayanan A, Weihl CC, Ching JK, et al. Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis. Am J Physiol Endocrinol Metab. 2012;303:E983–93.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Fortea JI, Fernandez-Mena C, Puerto M, Ripoll C, Almagro J, Banares J, et al. Comparison of two protocols of carbon tetrachloride-induced cirrhosis in Rats- improving yield and reproducibility. Sci Rep. 2018;8:9163.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Jimenez W, Claria J, Arroyo V, Rodes J. Carbon tetrachloride induced cirrhosis in rats: a useful tool for investigating the pathogenesis of ascites in chronic liver disease. J Gastroenterol Hepatol. 1992;7:90–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Munoz Torres E, Paz Bouza JI, Lopez Bravo A, Abad Hernandez MM, Carrascal ME. Experimental thioacetamide-induced cirrhosis of the liver. Histol Histopathol. 1991;6:95–100.PubMedGoogle Scholar
  45. 45.
    Thapaliya S, Runkana A, McMullen MR, Nagy LE, McDonald C, Naga Prasad SV, et al. Alcohol-induced autophagy contributes to loss in skeletal muscle mass. Autophagy. 2014;10:677–90.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Kumar A, Davuluri G, Silva RNE, Engelen M, Ten Have GAM, Prayson R, et al. Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis. Hepatology. 2017;65:2045–58.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Lopez-Lirola A, Gonzalez-Reimers E, Martin Olivera R, Santolaria-Fernandez F, Galindo-Martin L, Abreu-Gonzalez P, et al. Protein deficiency and muscle damage in carbon tetrachloride induced liver cirrhosis. Food Chem Toxicol. 2003;41:1789–97.PubMedCrossRefGoogle Scholar
  48. 48.
    Gayan-Ramirez G, van de Casteele M, Rollier H, Fevery J, Vanderhoydonc F, Verhoeven G, et al. Biliary cirrhosis induces type IIx/b fiber atrophy in rat diaphragm and skeletal muscle, and decreases IGF-I mRNA in the liver but not in muscle. J Hepatol. 1998;29:241–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Burd NA, Tang JE, Moore DR, Phillips SM. Exercise training and protein metabolism: influences of contraction, protein intake, and sex-based differences. J Appl Physiol. 1985) 2009;106:1692–701.CrossRefGoogle Scholar
  50. 50.
    Tsien CD, McCullough AJ, Dasarathy S. Late evening snack: exploiting a period of anabolic opportunity in cirrhosis. J Gastroenterol Hepatol. 2012;27:430–41.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Mitchell WK, Wilkinson DJ, Phillips BE, Lund JN, Smith K, Atherton PJ. Human skeletal muscle protein metabolism responses to amino acid nutrition. Adv Nutr. 2016;7:828S–38S.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Atherton PJ, Smith K. Muscle protein synthesis in response to nutrition and exercise. J Physiol. 2012;590:1049–57.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Kiens B, Essen-Gustavsson B, Christensen NJ, Saltin B. Skeletal muscle substrate utilization during submaximal exercise in man: effect of endurance training. J Physiol. 1993;469:459–78.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Hoppeler H. Skeletal muscle substrate metabolism. Int J Obes Relat Metab Disord. 1999;23(Suppl 3):S7–10.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Westerterp KR. Food quotient, respiratory quotient, and energy balance. Am J Clin Nutr. 1993;57:759S–64S; discussion 764S–765S.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Pozefsky T, Tancredi RG, Moxley RT, Dupre J, Tobin JD. Effects of brief starvation on muscle amino acid metabolism in nonobese man. J Clin Invest. 1976;57:444–9.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Glass C, Hipskind P, Tsien C, Malin SK, Kasumov T, Shah SN, et al. Sarcopenia and a physiologically low respiratory quotient in patients with cirrhosis: a prospective controlled study. J Appl Physiol. 1985) 2013;114:559–65.CrossRefGoogle Scholar
  58. 58.
    Romijn JA, Endert E, Sauerwein HP. Glucose and fat metabolism during short-term starvation in cirrhosis. Gastroenterology. 1991;100:731–7.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Dasarathy J, McCullough AJ, Dasarathy S. Sarcopenia in alcoholic liver disease: clinical and molecular advances. Alcohol Clin Exp Res. 2017;41:1419–31.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Plank LD, Gane EJ, Peng S, Muthu C, Mathur S, Gillanders L, et al. Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomized 12-month trial. Hepatology. 2008;48:557–66.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Muller MJ, Bottcher J, Selberg O. Energy expenditure and substrate metabolism in liver cirrhosis. Int J Obes Relat Metab Disord. 1993;17(Suppl 3):S102–6; discussion S115.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Muller MJ, Lautz HU, Plogmann B, Burger M, Korber J, Schmidt FW. Energy expenditure and substrate oxidation in patients with cirrhosis: the impact of cause, clinical staging and nutritional state. Hepatology. 1992;15:782–94.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Muller MJ, Bottcher J, Selberg O, Weselmann S, Boker KH, Schwarze M, et al. Hypermetabolism in clinically stable patients with liver cirrhosis. Am J Clin Nutr. 1999;69:1194–201.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Muller MJ, Boker KH, Selberg O. Are patients with liver cirrhosis hypermetabolic? Clin Nutr. 1994;13:131–44.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Peng S, Plank LD, McCall JL, Gillanders LK, McIlroy K, Gane EJ. Body composition, muscle function, and energy expenditure in patients with liver cirrhosis: a comprehensive study. Am J Clin Nutr. 2007;85:1257–66.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Morton RW, Traylor DA, Weijs PJM, Phillips SM. Defining anabolic resistance: implications for delivery of clinical care nutrition. Curr Opin Crit Care. 2018;24:124–30.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Rennie MJ, Wilkes EA. Maintenance of the musculoskeletal mass by control of protein turnover: the concept of anabolic resistance and its relevance to the transplant recipient. Ann Transplant. 2005;10:31–4.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Tessari P, Inchiostro S, Barazzoni R, Zanetti M, Orlando R, Biolo G, et al. Fasting and postprandial phenylalanine and leucine kinetics in liver cirrhosis. Am J Phys. 1994;267:E140–9.Google Scholar
  69. 69.
    Tessari P, Barazzoni R, Kiwanuka E, Davanzo G, De Pergola G, Orlando R, et al. Impairment of albumin and whole body postprandial protein synthesis in compensated liver cirrhosis. Am J Physiol Endocrinol Metab. 2002;282:E304–11.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Tessari P, Biolo G, Inchiostro S, Orlando R, Vettore M, Sergi G. Leucine and phenylalanine kinetics in compensated liver cirrhosis: effects of insulin. Gastroenterology. 1993;104:1712–21.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Tessari P, Kiwanuka E, Vettore M, Barazzoni R, Zanetti M, Cecchet D, et al. Phenylalanine and tyrosine kinetics in compensated liver cirrhosis: effects of meal ingestion. Am J Physiol Gastrointest Liver Physiol. 2008;295:G598–604.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Tessari P. Protein metabolism in liver cirrhosis: from albumin to muscle myofibrils. Curr Opin Clin Nutr Metab Care. 2003;6:79–85.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Tessari P, Zanetti M, Barazzoni R, Biolo G, Orlando R, Vettore M, et al. Response of phenylalanine and leucine kinetics to branched chain-enriched amino acids and insulin in patients with cirrhosis. Gastroenterology. 1996;111:127–37.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    McCullough AJ, Mullen KD, Kalhan SC. Defective nonoxidative leucine degradation and endogenous leucine flux in cirrhosis during an amino acid infusion. Hepatology. 1998;28:1357–64.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    McCullough AJ, Mullen KD, Tavill AS, Kalhan SC. In vivo differences between the turnover rates of leucine and leucine's ketoacid in stable cirrhosis. Gastroenterology. 1992;103:571–8.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Mullen KD, Denne SC, McCullough AJ, Savin SM, Bruno D, Tavill AS, et al. Leucine metabolism in stable cirrhosis. Hepatology. 1986;6:622–30.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Morrison WL, Bouchier IA, Gibson JN, Rennie MJ. Skeletal muscle and whole-body protein turnover in cirrhosis. Clin Sci (Lond). 1990;78:613–9.CrossRefGoogle Scholar
  78. 78.
    Tsien C, Davuluri G, Singh D, Allawy A, Ten Have GA, Thapaliya S, et al. Metabolic and molecular responses to leucine-enriched branched chain amino acid supplementation in the skeletal muscle of alcoholic cirrhosis. Hepatology. 2015;61:2018–29.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Zoli M, Marchesini G, Dondi C, Bianchi GP, Pisi E. Myofibrillar protein catabolic rates in cirrhotic patients with and without muscle wasting. Clin Sci (Lond). 1982;62:683–6.CrossRefGoogle Scholar
  80. 80.
    Marchesini G, Zoli M, Angiolini A, Dondi C, Bianchi FB, Pisi E. Muscle protein breakdown in liver cirrhosis and the role of altered carbohydrate metabolism. Hepatology. 1981;1:294–9.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Dasarathy S, McCullough AJ, Muc S, Schneyer A, Bennett CD, Dodig M, et al. Sarcopenia associated with portosystemic shunting is reversed by follistatin. J Hepatol. 2011;54:915–21.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Davuluri G, Allawy A, Thapaliya S, Rennison JH, Singh D, Kumar A, et al. Hyperammonaemia-induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress. J Physiol. 2016;594:7341–60.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Davuluri G, Krokowski D, Guan BJ, Kumar A, Thapaliya S, Singh D, et al. Metabolic adaptation of skeletal muscle to hyperammonemia drives the beneficial effects of l-leucine in cirrhosis. J Hepatol. 2016;65:929–37.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Nieuwoudt S, Mulya A, Fealy CE, Martelli E, Dasarathy S, Naga Prasad SV, et al. In vitro contraction protects against palmitate-induced insulin resistance in C2C12 myotubes. Am J Physiol Cell Physiol. 2017;313:C575–83.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Dasarathy S, Mookerjee RP, Rackayova V, Rangroo Thrane V, Vairappan B, Ott P, et al. Ammonia toxicity: from head to toe? Metab Brain Dis. 2017;32:529–38.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Jackson RJ, Hellen CU, Pestova TV. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat Rev Mol Cell Biol. 2010;11:113–27.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Tachiyama G, Sakon M, Kambayashi J, Iijima S, Tsujinaka T, Mori T. Endogenous endotoxemia in patients with liver cirrhosis--a quantitative analysis of endotoxin in portal and peripheral blood. Jpn J Surg. 1988;18:403–8.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Macallan DC, Cook EB, Preedy VR, Griffin GE. The effect of endotoxin on skeletal muscle protein gene expression in the rat. Int J Biochem Cell Biol. 1996;28:511–20.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Chen HW, Dunn MA. Muscle at risk: the multiple impacts of Ammonia on sarcopenia and frailty in cirrhosis. Clin Transl Gastroenterol. 2016;7:e170.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Adeva MM, Souto G, Blanco N, Donapetry C. Ammonium metabolism in humans. Metabolism. 2012;61:1495–511.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Dimski DS. Ammonia metabolism and the urea cycle: function and clinical implications. J Vet Intern Med. 1994;8:73–8.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Schutz Y. Protein turnover, ureagenesis and gluconeogenesis. Int J Vitam Nutr Res. 2011;81:101–7.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Rudman D, DiFulco TJ, Galambos JT, Smith RB 3rd, Salam AA, Warren WD. Maximal rates of excretion and synthesis of urea in normal and cirrhotic subjects. J Clin Invest. 1973;52:2241–9.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Shangraw RE, Jahoor F. Effect of liver disease and transplantation on urea synthesis in humans: relationship to acid-base status. Am J Phys. 1999;276:G1145–52.Google Scholar
  95. 95.
    Vilstrup H. Synthesis of urea after stimulation with amino acids: relation to liver function. Gut. 1980;21:990–5.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Olde Damink SW, Jalan R, Dejong CH. Interorgan ammonia trafficking in liver disease. Metab Brain Dis. 2009;24:169–81.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Ganda OP, Ruderman NB. Muscle nitrogen metabolism in chronic hepatic insufficiency. Metabolism. 1976;25:427–35.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Lockwood AH, McDonald JM, Reiman RE, Gelbard AS, Laughlin JS, Duffy TE, et al. The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia. J Clin Invest. 1979;63:449–60.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Kant S, Davuluri G, Alchirazi KA, Welch N, Heit C, Kumar A, et al. Ethanol sensitizes skeletal muscle to ammonia-induced molecular perturbations. J Biol Chem. 2019;294:7231–44.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Ono Y, Sakamoto K. Lipopolysaccharide inhibits myogenic differentiation of C2C12 myoblasts through the toll-like receptor 4-nuclear factor-kappaB signaling pathway and myoblast-derived tumor necrosis factor-alpha. PLoS One. 2017;12:e0182040.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    de la Garza RG, Morales-Garza LA, Martin-Estal I, Castilla-Cortazar I. Insulin-like growth Factor-1 deficiency and cirrhosis establishment. J Clin Med Res. 2017;9:233–47.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Bucuvalas JC, Horn JA, Chernausek SD. Resistance to growth hormone in children with chronic liver disease. Pediatr Transplant. 1997;1:73–9.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Sinclair M, Grossmann M, Hoermann R, Angus PW, Gow PJ. Testosterone therapy increases muscle mass in men with cirrhosis and low testosterone: a randomised controlled trial. J Hepatol. 2016;65:906–13.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Verboeket-van de Venne WP, Westerterp KR, van Hoek B, Swart GR. Energy expenditure and substrate metabolism in patients with cirrhosis of the liver: effects of the pattern of food intake. Gut. 1995;36:110–6.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Berzigotti A, Saran U, Dufour JF. Physical activity and liver diseases. Hepatology. 2016;63:1026–40.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Sinclair M, Grossmann M, Gow PJ, Angus PW. Testosterone in men with advanced liver disease: abnormalities and implications. J Gastroenterol Hepatol. 2015;30:244–51.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Dasarathy S, Mullen KD, Dodig M, Donofrio B, McCullough AJ. Inhibition of aromatase improves nutritional status following portacaval anastomosis in male rats. J Hepatol. 2006;45:214–20.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    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;151:628–38.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Adamek A, Kasprzak A. Insulin-like growth factor (IGF) system in liver diseases. Int J Mol Sci. 2018;19.Google Scholar
  110. 110.
    Baruch Y, Assy N, Amit T, Krivoy N, Strickovsky D, Orr ZS, et al. Spontaneous pulsatility and pharmacokinetics of growth hormone in liver cirrhotic patients. J Hepatol. 1998;29:559–64.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Liu W, Thomas SG, Asa SL, Gonzalez-Cadavid N, Bhasin S, Ezzat S. Myostatin is a skeletal muscle target of growth hormone anabolic action. J Clin Endocrinol Metab. 2003;88:5490–6.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Raetz CR, Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem. 2002;71:635–700.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Lin RS, Lee FY, Lee SD, Tsai YT, Lin HC, Lu RH, et al. Endotoxemia in patients with chronic liver diseases: relationship to severity of liver diseases, presence of esophageal varices, and hyperdynamic circulation. J Hepatol. 1995;22:165–72.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Bode C, Kugler V, Bode JC. Endotoxemia in patients with alcoholic and non-alcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess. J Hepatol. 1987;4:8–14.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Tarabees R, Hill D, Rauch C, Barrow PA, Loughna PT. Endotoxin transiently inhibits protein synthesis through Akt and MAPK mediating pathways in C2C12 myotubes. Am J Physiol Cell Physiol. 2011;301:C895–902.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Ghosh S, Lertwattanarak R, Garduno Jde J, Galeana JJ, Li J, Zamarripa F, et al. Elevated muscle TLR4 expression and metabolic endotoxemia in human aging. J Gerontol A Biol Sci Med Sci. 2015;70:232–46.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Han HQ, Mitch WE. Targeting the myostatin signaling pathway to treat muscle wasting diseases. Curr Opin Support Palliat Care. 2011;5:334–41.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Trendelenburg AU, Meyer A, Rohner D, Boyle J, Hatakeyama S, Glass DJ. Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. Am J Physiol Cell Physiol. 2009;296:C1258–70.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Dasarathy S. Myostatin and beyond in cirrhosis: all roads lead to sarcopenia. J Cachexia Sarcopenia Muscle. 2017;8:864–9.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Egerman MA, Glass DJ. Signaling pathways controlling skeletal muscle mass. Crit Rev Biochem Mol Biol. 2014;49:59–68.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Yoon MS. mTOR as a key regulator in maintaining skeletal muscle mass. Front Physiol. 2017;8:788.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Huang J, Manning BD. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J. 2008;412:179–90.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Johansen ML, Bak LK, Schousboe A, Iversen P, Sorensen M, Keiding S, et al. The metabolic role of isoleucine in detoxification of ammonia in cultured mouse neurons and astrocytes. Neurochem Int. 2007;50:1042–51.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Guan BJ, Krokowski D, Majumder M, Schmotzer CL, Kimball SR, Merrick WC, et al. Translational control during endoplasmic reticulum stress beyond phosphorylation of the translation initiation factor eIF2alpha. J Biol Chem. 2014;289:12593–611.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8:519–29.PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Dasarathy S, Dodig M, Muc SM, Kalhan SC, McCullough AJ. Skeletal muscle atrophy is associated with an increased expression of myostatin and impaired satellite cell function in the portacaval anastamosis rat. Am J Physiol Gastrointest Liver Physiol. 2004;287:G1124–30.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Wek RC, Jiang HY, Anthony TG. Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans. 2006;34:7–11.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Dong J, Qiu H, Garcia-Barrio M, Anderson J, Hinnebusch AG. Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain. Mol Cell. 2000;6:269–79.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Schousboe A, Scafidi S, Bak LK, Waagepetersen HS, McKenna MC. Glutamate metabolism in the brain focusing on astrocytes. Adv Neurobiol. 2014;11:13–30.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Kafri M, Metzl-Raz E, Jona G, Barkai N. The cost of protein production. Cell Rep. 2016;14:22–31.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Duarte-Rojo A, Ruiz-Margain A, Montano-Loza AJ, Macias-Rodriguez RU, Ferrando A, Kim WR. Exercise and physical activity for patients with end-stage liver disease: improving functional status and sarcopenia while on the transplant waiting list. Liver Transpl. 2018;24:122–39.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Lai JC. Editorial: advancing adoption of frailty to improve the Care of Patients with cirrhosis: time for a consensus on a frailty index. Am J Gastroenterol. 2016;111:1776–7.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Bay Nielsen H, Secher NH, Clemmesen O, Ott P. Maintained cerebral and skeletal muscle oxygenation during maximal exercise in patients with liver cirrhosis. J Hepatol. 2005;43:266–71.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Lunzer M, Newman SP, Sherlock S. Skeletal muscle blood flow and neurovascular reactivity in liver disease. Gut. 1973;14:354–9.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Jeppesen JB, Mortensen C, Bendtsen F, Moller S. Lactate metabolism in chronic liver disease. Scand J Clin Lab Invest. 2013;73:293–9.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Casaburi R, Oi S. Effect of liver disease on the kinetics of lactate removal after heavy exercise. Eur J Appl Physiol Occup Physiol. 1989;59:89–97.PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Robin ED. Special report: dysoxia. Abnormal tissue oxygen utilization. Arch Intern Med. 1977;137:905–10.PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Brownlee EB. The novelty of research--challenging the post-basic student. SA Nurs J. 1977;44:21.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Gastroenterology, Hepatology, Cleveland ClinicClevelandUSA

Personalised recommendations