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Molecular Mechanism of Muscle Wasting in CKD

  • Hiroshi WatanabeEmail author
  • Yuki Enoki
  • Toru Maruyama
Chapter
  • 33 Downloads

Abstract

Chronic kidney disease (CKD), a chronic catabolic condition, is characterized by muscle wasting and a decreased muscle endurance. Many insights have made into the molecular mechanisms of muscle atrophy in CKD. A persistent imbalance between protein synthesis and degradation causes a loss of muscle mass. A decrease in insulin/IGF-1-Akt-mTOR signaling and an increased ubiquitin-proteasome system (UPS) have emerged as inducers of muscle loss. During muscle wasting, abnormal levels of reactive oxygen species (ROS) and inflammatory cytokines are detected in skeletal muscle. These increased ROS and inflammatory cytokine levels induce the expression of myostatin. The binding of myostatin to its receptor ActRIIB stimulates the expression of Foxo-dependent atrogenes. An impaired mitochondrial function also contributes to reduced muscle endurance. Increased glucocorticoid, angiotensin II, parathyroid hormone, and protein-bound uremic toxin levels that are observed in CKD all have a negative effect on muscle mass and endurance. The loss of skeletal muscle mass during the progression of CKD further contributes to the development of renal failure. Some potential therapeutic approaches based on the molecular mechanisms of muscle wasting in CKD are currently in the testing stages using animal models and clinical settings.

Keywords

Atrogene Myostatin Mitochondria Oxidative stress Inflammation Uremic toxin 

Notes

Acknowledgement

We are grateful to Professor Masafumi Fukagawa, Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Kanagawa, Japan, Dr. Kazutaka Matsushita and Dr. Motoko Tanaka, Department of Nephrology, Akebono Clinic, Kumamoto, Japan for their valuable advice in the preparation of this manuscript. Our work was supported, in part, by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) (KAKENHI 25460190; 16H05114), the Research Foundation for Pharmaceutical Sciences, Japan and The Nakatomi Foundation.

References

  1. 1.
    Gracia-Iguacel C, González-Parra E, Pérez-Gómez MV, Mahíllo I, Egido J, Ortiz A, Carrero JJ. Prevalence of protein-energy wasting syndrome and its association with mortality in haemodialysis patients in a Centre in Spain. Nefrologia. 2013;33:495–505.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Kalantar-Zadeh K, Rhee C, Sim JJ, Stenvinkel P, Anker SD, Kovesdy CP. Why cachexia kills: examining the causality of poor outcomes in wasting conditions. J Cachexia Sarcopenia Muscle. 2013;4:89–94.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Mak RH, Ikizler AT, Kovesdy CP, Raj DS, Stenvinkel P, Kalantar-Zadeh K. Wasting in chronic kidney disease. J Cachexia Sarcopenia Muscle. 2011;2:9–25.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Sietsema KE, Amato A, Adler SG, Brass EP. Exercise capacity as a predictor of survival among ambulatory patients with end-stage renal disease. Kidney Int. 2004;65:719–24.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Wang AY, Sea MM, Tang N, Sanderson JE, Lui SF, Li PK, Woo J. Resting energy expenditure and subsequent mortality risk in peritoneal dialysis patients. J Am Soc Nephrol. 2004;15:3134–43.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Cohen S, Nathan JA, Goldberg AL. Muscle wasting in disease: molecular mechanisms and promising therapies. Nat Rev Drug Discov. 2015;14:58–74.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Gumucio JP, Mendias CL. Atrogin-1, MuRF-1, and sarcopenia. Endocrine. 2013;43:12–21.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Wang XH, Mitch WE. Mechanisms of muscle wasting in chronic kidney disease. Nat Rev Nephrol. 2014;10:504–16.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Kir S, Komaba H, Garcia AP, Economopoulos KP, Liu W, Lanske B, Hodin RA, Spiegelman BM. PTH/PTHrP receptor mediates Cachexia in models of kidney failure and Cancer. Cell Metab. 2016;23:315–23.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Crowe AV, McArdle A, McArdle F, Pattwell DM, Bell GM, Kemp GJ, Bone JM, Griffiths RD, Jackson MJ. Markers of oxidative stress in the skeletal muscle of patients on haemodialysis. Nephrol Dial Transplant. 2007;22:1177–83.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Han HQ, Zhou X, Mitch WE, Goldberg AL. Myostatin/activin pathway antagonism: molecular basis and therapeutic potential. Int J Biochem Cell Biol. 2013;45:2333–47.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997;387:83–90.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Lokireddy S, McFarlane C, Ge X, Zhang H, Sze SK, Sharma M, Kambadur R. Myostatin induces degradation of sarcomeric proteins through a Smad3 signaling mechanism during skeletal muscle wasting. Mol Endocrinol. 2011;25:1936–49.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Sartori R, Milan G, Patron M, Mammucari C, Blaauw B, Abraham R, Sandri M. Smad2 and 3 transcription factors control muscle mass in adulthood. Am J Physiol Cell Physiol. 2009;296:C1248–57.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Verzola D, Procopio V, Sofia A, Villaggio B, Tarroni A, Bonanni A, Mannucci I, de Cian F, Gianetta E, Saffioti S, Garibotto G. Apoptosis and myostatin mRNA are upregulated in the skeletal muscle of patients with chronic kidney disease. Kidney Int. 2011;79:773–82.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Zhang L, Pan J, Dong Y, Tweardy DJ, Garibotto G, Mitch WE. Stat3 activation links a C/EBPδ to myostatin pathway to stimulate loss of muscle mass. Cell Metab. 2013;18:368–79.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Zhang L, Rajan V, Lin E, Hu Z, Han HQ, Zhou X, Song Y, Min H, Wang X, Du J, Mitch WE. Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease. FASEB J. 2011;25:1653–63.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Lang CH, Silvis C, Nystrom G, Frost RA. Regulation of myostatin by glucocorticoids after thermal injury. FASEB J. 2001;15:1807–9.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Schakman O, Gilson H, Thissen JP. Mechanisms of glucocorticoid-induced myopathy. J Endocrinol. 2008;197:1–10.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Schakman O, Kalista S, Barbé C, Loumaye A, Thissen JP. Glucocorticoid-induced skeletal muscle atrophy. Int J Biochem Cell Biol. 2013;45:2163–72.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Sriram S, Subramanian S, Sathiakumar D, Venkatesh R, Salerno MS, McFarlane CD, Kambadur R, Sharma M. Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF-κB. Aging Cell. 2011;10:931–48.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Mendias CL, Gumucio JP, Davis ME, Bromley CW, Davis CS, Brooks SV. Transforming growth factor-beta induces skeletal muscle atrophy and fibrosis through the induction of atrogin-1 and scleraxis. Muscle Nerve. 2012;45:55–9.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD, Glass DJ. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science. 2001;294:1704–8.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Bonaldo P, Sandri M. Cellular and molecular mechanisms of muscle atrophy. Dis Model Mech. 2013;6:25–39.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Lai KM, Gonzalez M, Poueymirou WT, Kline WO, Na E, Zlotchenko E, Stitt TN, Economides AN, Yancopoulos GD, Glass DJ. Conditional activation of akt in adult skeletal muscle induces rapid hypertrophy. Mol Cell Biol. 2004;24:9295–304.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell. 2004;14:395–403.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Lee SW, Dai G, Hu Z, Wang X, Du J, Mitch WE. Regulation of muscle protein degradation: coordinated control of apoptotic and ubiquitin-proteasome systems by phosphatidylinositol 3 kinase. J Am Soc Nephrol. 2004;15:1537–45.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 2004;117:399–412.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Gamboa JL, Billings FT, Bojanowski MT, Gilliam LA, Yu C, Roshanravan B, Roberts LJ, Himmelfarb J, Ikizler TA, Brown NJ. Mitochondrial dysfunction and oxidative stress in patients with chronic kidney disease. Physiol Rep. 2016;4:e12780.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Arany Z, Lebrasseur N, Morris C, Smith E, Yang W, Ma Y, Chin S, Spiegelman BM. The transcriptional coactivator PGC-1beta drives the formation of oxidative type IIX fibers in skeletal muscle. Cell Metab. 2007;5:35–46.PubMedCrossRefGoogle Scholar
  31. 31.
    Woldt E, Sebti Y, Solt LA, Duhem C, Lancel S, Eeckhoute J, Hesselink MK, Paquet C, Delhaye S, Shin Y, Kamenecka TM, Schaart G, Lefebvre P, Nevière R, Burris TP, Schrauwen P, Staels B, Duez H. Reverb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy. Nat Med. 2013;19:1039–46.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Tamaki M, Miyashita K, Wakino S, Mitsuishi M, Hayashi K, Itoh H. Chronic kidney disease reduces muscle mitochondria and exercise endurance and its exacerbation by dietary protein through inactivation of pyruvate dehydrogenase. Kidney Int. 2014;85:1330–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Brault JJ, Jespersen JG, Goldberg AL. Peroxisome proliferator-activated receptor gamma coactivator 1alpha or 1beta overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy. J Biol Chem. 2010;285:19460–71.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT. Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci U S A. 2009;106:20405–10.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Balakrishnan VS, Rao M, Menon V, Gordon PL, Pilichowska M, Castaneda F, Castaneda-Sceppa C. Resistance training increases muscle mitochondrial biogenesis in patients with chronic kidney disease. Clin J Am Soc Nephrol. 2010;5:996–1002.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Powers SK, Kavazis AN, DeRuisseau KC. Mechanisms of disuse muscle atrophy: role of oxidative stress. Am J Physiol Regul Integr Comp Physiol. 2005;288:R337–44.PubMedCrossRefGoogle Scholar
  37. 37.
    Axelsson J, Heimbürger O, Stenvinkel P. Adipose tissue and inflammation in chronic kidney disease. Contrib Nephrol. 2006;151:165–74.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Cheung WW, Paik KH, Mak RH. Inflammation and cachexia in chronic kidney disease. Pediatr Nephrol. 2010;25:711–24.PubMedCrossRefGoogle Scholar
  39. 39.
    Carrero JJ, Chmielewski M, Axelsson J, Snaedal S, Heimbürger O, Bárány P, Suliman ME, Lindholm B, Stenvinkel P, Qureshi AR. Muscle atrophy, inflammation and clinical outcome in incident and prevalent dialysis patients. Clin Nutr. 2008;27:557–64.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Derbre F, Ferrando B, Gomez-Cabrera MC, Sanchis-Gomar F, Martinez-Bello VE, Olaso-Gonzalez G, Diaz A, Gratas-Delamarche A, Cerda M, Viña J. Inhibition of xanthine oxidase by allopurinol prevents skeletal muscle atrophy: role of p38 MAPKinase and E3 ubiquitin ligases. PLoS One. 2012;7:e46668.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Hung AM, Ellis CD, Shintani A, Booker C, Ikizler TA. IL-1β receptor antagonist reduces inflammation in hemodialysis patients. J Am Soc Nephrol. 2011;22:437–42.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Semprun-Prieto LC, Sukhanov S, Yoshida T, Rezk BM, Gonzalez-Villalobos RA, Vaughn C, Michael Tabony A, Delafontaine P. Angiotensin II induced catabolic effect and muscle atrophy are redox dependent. Biochem Biophys Res Commun. 2011;409:217–21.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Sukhanov S, Semprun-Prieto L, Yoshida T, Michael Tabony A, Higashi Y, Galvez S, Delafontaine P. Angiotensin II, oxidative stress and skeletal muscle wasting. Am J Med Sci. 2011;342:143–7.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Watson ML, Baehr LM, Reichardt HM, Tuckermann JP, Bodine SC, Furlow JD. A cell-autonomous role for the glucocorticoid receptor in skeletal muscle atrophy induced by systemic glucocorticoid exposure. Am J Physiol Endocrinol Metab. 2012;302:E1210–20.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Artaza JN, Bhasin S, Mallidis C, Taylor W, Ma K, Gonzalez-Cadavid NF. Endogenous expression and localization of myostatin and its relation to myosin heavy chain distribution in C2C12 skeletal muscle cells. J Cell Physiol. 2002;190:170–9.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Gilson H, Schakman O, Combaret L, Lause P, Grobet L, Attaix D, Ketelslegers JM, Thissen JP. Myostatin gene deletion prevents glucocorticoid-induced muscle atrophy. Endocrinology. 2007;148:452–60.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Ma K, Mallidis C, Artaza J, Taylor W, Gonzalez-Cadavid N, Bhasin S. Characterization of 5′-regulatory region of human myostatin gene: regulation by dexamethasone in vitro. Am J Physiol Endocrinol Metab. 2001;281:E1128–36.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Ma K, Mallidis C, Bhasin S, Mahabadi V, Artaza J, Gonzalez-Cadavid N, Arias J, Salehian B. Glucocorticoid-induced skeletal muscle atrophy is associated with upregulation of myostatin gene expression. Am J Physiol Endocrinol Metab. 2003;285:E363–71.PubMedCrossRefGoogle Scholar
  49. 49.
    Gayan-Ramirez G, Vanderhoydonc F, Verhoeven G, Decramer M. Acute treatment with corticosteroids decreases IGF-1 and IGF-2 expression in the rat diaphragm and gastrocnemius. Am J Respir Crit Care Med. 1999;159:283–9.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Inder WJ, Jang C, Obeyesekere VR, Alford FP. Dexamethasone administration inhibits skeletal muscle expression of the androgen receptor and IGF-1--implications for steroid-induced myopathy. Clin Endocrinol. 2010;73:126–32.Google Scholar
  51. 51.
    Koh A, Lee MN, Yang YR, Jeong H, Ghim J, Noh J, Kim J, Ryu D, Park S, Song P, Koo SH, Leslie NR, Berggren PO, Choi JH, Suh PG, Ryu SH. C1-ten is a protein tyrosine phosphatase of insulin receptor substrate 1 (IRS-1), regulating IRS-1 stability and muscle atrophy. Mol Cell Biol. 2013;33:1608–20.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Morgan SA, Sherlock M, Gathercole LL, Lavery GG, Lenaghan C, Bujalska IJ, Laber D, Yu A, Convey G, Mayers R, Hegyi K, Sethi JK, Stewart PM, Smith DM, Tomlinson JW. 11beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle. Diabetes. 2009;58:2506–15.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Nakao R, Hirasaka K, Goto J, Ishidoh K, Yamada C, Ohno A, Okumura Y, Nonaka I, Yasutomo K, Baldwin KM, Kominami E, Higashibata A, Nagano K, Tanaka K, Yasui N, Mills EM, Takeda S, Nikawa T. Ubiquitin ligase Cbl-b is a negative regulator for insulin-like growth factor 1 signaling during muscle atrophy caused by unloading. Mol Cell Biol. 2009;29:4798–811.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Zheng B, Ohkawa S, Li H, Roberts-Wilson TK, Price SR. FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin-1/MAFbx expression during glucocorticoid-induced skeletal muscle atrophy. FASEB J. 2010;24:2660–9.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Frost RA, Lang CH. Multifaceted role of insulin-like growth factors and mammalian target of rapamycin in skeletal muscle. Endocrinol Metab Clin N Am. 2012;41:297–322, vi.CrossRefGoogle Scholar
  56. 56.
    Cho JE, Fournier M, Da X, Lewis MI. Time course expression of Foxo transcription factors in skeletal muscle following corticosteroid administration. J Appl Physiol (1985). 2010;108:137–45.CrossRefGoogle Scholar
  57. 57.
    Waddell DS, Baehr LM, van den Brandt J, Johnsen SA, Reichardt HM, Furlow JD, Bodine SC. The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene. Am J Physiol Endocrinol Metab. 2008;295:E785–97.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Menconi MJ, Arany ZP, Alamdari N, Aversa Z, Gonnella P, O'Neal P, Smith IJ, Tizio S, Hasselgren PO. Sepsis and glucocorticoids downregulate the expression of the nuclear cofactor PGC-1beta in skeletal muscle. Am J Physiol Endocrinol Metab. 2010;299:E533–43.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Crossland H, Constantin-Teodosiu D, Greenhaff PL, Gardiner SM. Low-dose dexamethasone prevents endotoxaemia-induced muscle protein loss and impairment of carbohydrate oxidation in rat skeletal muscle. J Physiol. 2010;588:1333–47.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Brink M, Wellen J, Delafontaine P. Angiotensin II causes weight loss and decreases circulating insulin-like growth factor I in rats through a pressor-independent mechanism. J Clin Invest. 1996;97:2509–16.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Brink M, Price SR, Chrast J, Bailey JL, Anwar A, Mitch WE, Delafontaine P. Angiotensin II induces skeletal muscle wasting through enhanced protein degradation and down-regulates autocrine insulin-like growth factor I. Endocrinology. 2001;142:1489–96.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Zhang L, Du J, Hu Z, Han G, Delafontaine P, Garcia G, Mitch WE. IL-6 and serum amyloid A synergy mediates angiotensin II-induced muscle wasting. J Am Soc Nephrol. 2009;20:604–12.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Benigni A, Cassis P, Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med. 2010;2:247–57.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Yabumoto C, Akazawa H, Yamamoto R, Yano M, Kudo-Sakamoto Y, Sumida T, Kamo T, Yagi H, Shimizu Y, Saga-Kamo A, Naito AT, Oka T, Lee JK, Suzuki J, Sakata Y, Uejima E, Komuro I. Angiotensin II receptor blockade promotes repair of skeletal muscle through down-regulation of aging-promoting C1q expression. Sci Rep. 2015;5:14453.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Duranton F, Cohen G, de Smet R, Rodriguez M, Jankowski J, Vanholder R, Argiles A, Group EUTW. Normal and pathologic concentrations of uremic toxins. J Am Soc Nephrol. 2012;23:1258–70.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Vanholder R, Schepers E, Pletinck A, Nagler EV, Glorieux G. The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. J Am Soc Nephrol. 2014;25:1897–907.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Vanholder R, Pletinck A, Schepers E, Glorieux G. Biochemical and clinical impact of organic uremic retention solutes: a comprehensive update. Toxins (Basel). 2018;10:33.CrossRefGoogle Scholar
  68. 68.
    Watanabe H, Miyamoto Y, Otagiri M, Maruyama T. Update on the pharmacokinetics and redox properties of protein-bound uremic toxins. J Pharm Sci. 2011;100:3682–95.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Miyamoto Y, Watanabe H, Otagiri M, Maruyama T. New insight into the redox properties of uremic solute indoxyl sulfate as a pro- and anti-oxidant. Ther Apher Dial. 2011b;15:129–31.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Miyamoto Y, Iwao Y, Mera K, Watanabe H, Kadowaki D, Ishima Y, Chuang VT, Sato K, Otagiri M, Maruyama T. A uremic toxin, 3-carboxy-4-methyl-5-propyl-2-furanpropionate induces cell damage to proximal tubular cells via the generation of a radical intermediate. Biochem Pharmacol. 2012;84:1207–14.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Niwa T. Role of indoxyl sulfate in the progression of chronic kidney disease and cardiovascular disease: experimental and clinical effects of oral sorbent AST-120. Ther Apher Dial. 2011;15:120–4.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Watanabe H, Miyamoto Y, Honda D, Tanaka H, Wu Q, Endo M, Noguchi T, Kadowaki D, Ishima Y, Kotani S, Nakajima M, Kataoka K, Kim-Mitsuyama S, Tanaka M, Fukagawa M, Otagiri M, Maruyama T. p-Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidase. Kidney Int. 2013a;83:582–92.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Watanabe H, Miyamoto Y, Enoki Y, Ishima Y, Kadowaki D, Kotani S, Nakajima M, Tanaka M, Matsushita K, Mori Y, Kakuta T, Fukagawa M, Otagiri M, Maruyama T. p-Cresyl sulfate, a uremic toxin, causes vascular endothelial and smooth muscle cell damages by inducing oxidative stress. Pharmacol Res Perspect. 2015;3:e00092.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Yamamoto S, Kazama JJ, Omori K, Matsuo K, Takahashi Y, Kawamura K, Matsuto T, Watanabe H, Maruyama T, Narita I. Continuous reduction of protein-bound uraemic toxins with improved oxidative stress by using the oral charcoal adsorbent AST-120 in haemodialysis patients. Sci Rep. 2015;5:14381.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Tamaki M, Hagiwara A, Miyashita K, Wakino S, Inoue H, Fujii K, Fujii C, Sato M, Mitsuishi M, Muraki A, Hayashi K, Doi T, Itoh H. Improvement of physical decline through combined effects of muscle enhancement and mitochondrial activation by a gastric hormone ghrelin in male 5/6Nx CKD model mice. Endocrinology. 2015;156:3638–48.CrossRefGoogle Scholar
  76. 76.
    Poesen R, Mutsaers HA, Windey K, van den Broek PH, Verweij V, Augustijns P, Kuypers D, Jansen J, Evenepoel P, Verbeke K, Meijers B, Masereeuw R. The influence of dietary protein intake on mammalian tryptophan and phenolic metabolites. PLoS One. 2015;10:e0140820.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Deguchi T, Ohtsuki S, Otagiri M, Takanaga H, Asaba H, Mori S, Terasaki T. Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney. Kidney Int. 2002;61:1760–8.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Deguchi T, Kusuhara H, Takadate A, Endou H, Otagiri M, Sugiyama Y. Characterization of uremic toxin transport by organic anion transporters in the kidney. Kidney Int. 2004;65:162–74.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Deguchi T, Kouno Y, Terasaki T, Takadate A, Otagiri M. Differential contributions of rOat1 (Slc22a6) and rOat3 (Slc22a8) to the in vivo renal uptake of uremic toxins in rats. Pharm Res. 2005;22:619–27.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Miyamoto Y, Watanabe H, Noguchi T, Kotani S, Nakajima M, Kadowaki D, Otagiri M, Maruyama T. Organic anion transporters play an important role in the uptake of p-cresyl sulfate, a uremic toxin, in the kidney. Nephrol Dial Transplant. 2011a;26:2498.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Ohtsuki S, Asaba H, Takanaga H, Deguchi T, Hosoya K, Otagiri M, Terasaki T. Role of blood-brain barrier organic anion transporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance from the brain. J Neurochem. 2002;83:57–66.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Tanaka H, Iwasaki Y, Yamato H, Mori Y, Komaba H, Watanabe H, Maruyama T, Fukagawa M. p-Cresyl sulfate induces osteoblast dysfunction through activating JNK and p38 MAPK pathways. Bone. 2013;56:347–54.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Watanabe H, Sakaguchi Y, Sugimoto R, Kaneko KI, Iwata H, Kotani S, Nakajima M, Ishima Y, Otagiri M, Maruyama T. Human organic anion transporters function as a high-capacity transporter for p-cresyl sulfate, a uremic toxin. Clin Exp Nephrol. 2014;18:814–20PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Sallée M, Dou L, Cerini C, Poitevin S, Brunet P, Burtey S. The aryl hydrocarbon receptor-activating effect of uremic toxins from tryptophan metabolism: a new concept to understand cardiovascular complications of chronic kidney disease. Toxins (Basel). 2014;6:934–49.CrossRefGoogle Scholar
  85. 85.
    Watanabe I, Tatebe J, Namba S, Koizumi M, Yamazaki J, Morita T. Activation of aryl hydrocarbon receptor mediates indoxyl sulfate-induced monocyte chemoattractant protein-1 expression in human umbilical vein endothelial cells. Circ J. 2013c;77:224–30.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Ohtake F, Baba A, Takada I, Okada M, Iwasaki K, Miki H, Takahashi S, Kouzmenko A, Nohara K, Chiba T, Fujii-Kuriyama Y, Kato S. Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. Nature. 2007;446:562–6.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Enoki Y, Watanabe H, Arake R, Sugimoto R, Imafuku T, Tominaga Y, Ishima Y, Kotani S, Nakajima M, Tanaka M, Matsushita K, Fukagawa M, Otagiri M, Maruyama T. Indoxyl sulfate potentiates skeletal muscle atrophy by inducing the oxidative stress-mediated expression of myostatin and atrogin-1. Sci Rep. 2016;6:32084.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Enoki Y, Watanabe H, Arake R, Fujimura R, Ishiodori K, Imafuku T, Nishida K, Sugimoto R, Nagao S, Miyamura S, Ishima Y, Tanaka M, Matsushita K, Komaba H, Fukagawa M, Otagiri M, Maruyama T. Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunction. J Cachexia Sarcopenia Muscle. 2017;8:735–47.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Koppe L, Pillon NJ, Vella RE, Croze ML, Pelletier CC, Chambert S, Massy Z, Glorieux G, Vanholder R, Dugenet Y, Soula HA, Fouque D, Soulage CO. p-Cresyl sulfate promotes insulin resistance associated with CKD. J Am Soc Nephrol. 2013;24:88–99.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Hanatani S, Izumiya Y, Araki S, Rokutanda T, Kimura Y, Walsh K, Ogawa H. Akt1-mediated fast/glycolytic skeletal muscle growth attenuates renal damage in experimental kidney disease. J Am Soc Nephrol. 2014;25:2800–11.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Peng H, Wang Q, Lou T, Qin J, Jung S, Shetty V, Li F, Wang Y, Feng XH, Mitch WE, Graham BH, Hu Z. Myokine mediated muscle-kidney crosstalk suppresses metabolic reprogramming and fibrosis in damaged kidneys. Nat Commun. 2017;8:1493.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Rondon-Berrios H, Wang Y, Mitch WE. Can muscle-kidney crosstalk slow progression of CKD? J Am Soc Nephrol. 2014;25:2681–3.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Morvan F, Rondeau JM, Zou C, Minetti G, Scheufler C, Scharenberg M, Jacobi C, Brebbia P, Ritter V, Toussaint G, Koelbing C, Leber X, Schilb A, Witte F, Lehmann S, Koch E, Geisse S, Glass DJ, Lach-Trifilieff E. Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy. Proc Natl Acad Sci U S A. 2017;114:12448–53.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Bondulich MK, Jolinon N, Osborne GF, Smith EJ, Rattray I, Neueder A, Sathasivam K, Ahmed M, Ali N, Benjamin AC, Chang X, Dick JRT, Ellis M, Franklin SA, Goodwin D, Inuabasi L, Lazell H, Lehar A, Richard-Londt A, Rosinski J, Smith DL, Wood T, Tabrizi SJ, Brandner S, Greensmith L, Howland D, Munoz-Sanjuan I, Lee SJ, Bates GP. Myostatin inhibition prevents skeletal muscle pathophysiology in Huntington's disease mice. Sci Rep. 2017;7:14275.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Jeong Y, Daghlas SA, Kahveci AS, Salamango D, Gentry BA, Brown M, Rector RS, Pearsall RS, Phillips CL. Soluble activin receptor type IIB decoy receptor differentially impacts murine osteogenesis imperfecta muscle function. Muscle Nerve. 2018;57:294–304.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Gilson H, Schakman O, Kalista S, Lause P, Tsuchida K, Thissen JP. Follistatin induces muscle hypertrophy through satellite cell proliferation and inhibition of both myostatin and activin. Am J Physiol Endocrinol Metab. 2009;297:E157–64.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Kalista S, Schakman O, Gilson H, Lause P, Demeulder B, Bertrand L, Pende M, Thissen JP. The type 1 insulin-like growth factor receptor (IGF-IR) pathway is mandatory for the follistatin-induced skeletal muscle hypertrophy. Endocrinology. 2012;153:241–53.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Lee SJ, McPherron AC. Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci U S A. 2001;98:9306–11.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Chang F, Fang R, Wang M, Zhao X, Chang W, Zhang Z, Li N, Meng Q. The transgenic expression of human follistatin-344 increases skeletal muscle mass in pigs. Transgenic Res. 2017;26:25–36.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Mendell JR, Sahenk Z, Al-Zaidy S, Rodino-Klapac LR, Lowes LP, Alfano LN, Berry K, Miller N, Yalvac M, Dvorchik I, Moore-Clingenpeel M, Flanigan KM, Church K, Shontz K, Curry C, Lewis S, McColly M, Hogan MJ, Kaspar BK. Follistatin gene therapy for sporadic inclusion body myositis improves functional outcomes. Mol Ther. 2017;25:870–9.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Castonguay R, Lachey J, Wallner S, Strand J, Liharska K, Watanabe AE, Cannell M, Davies MV, Sako D, Troy ME, Krishnan L, Mulivor AW, Li H, Keates S, Alexander MJ, Pearsall RS, Kumar R. Follistatin-288-fc fusion protein promotes localized growth of skeletal muscle. J Pharmacol Exp Ther. 2019;368:435–45.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Iskenderian A, Liu N, Deng Q, Huang Y, Shen C, Palmieri K, Crooker R, Lundberg D, Kastrapeli N, Pescatore B, Romashko A, Dumas J, Comeau R, Norton A, Pan J, Rong H, Derakhchan K, Ehmann DE. Myostatin and activin blockade by engineered follistatin results in hypertrophy and improves dystrophic pathology in mdx mouse more than myostatin blockade alone. Skelet Muscle. 2018;8:34.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Schumann C, Nguyen DX, Norgard M, Bortnyak Y, Korzun T, Chan S, Lorenz AS, Moses AS, Albarqi HA, Wong L, Michaelis K, Zhu X, Alani AWG, Taratula OR, Krasnow S, Marks DL, Taratula O. Increasing lean muscle mass in mice via nanoparticle-mediated hepatic delivery of follistatin mRNA. Theranostics. 2018;8:5276–88.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Levitan MD, Murphy JT, Sherwood WG, Deck J, Sawa GM. Adult onset systemic carnitine deficiency: favorable response to L-carnitine supplementation. Can J Neurol Sci. 1987;14:50–4.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Pistone G, Marino A, Leotta C, Dell’Arte S, Finocchiaro G, Malaguarnera M. Levocarnitine administration in elderly subjects with rapid muscle fatigue: effect on body composition, lipid profile and fatigue. Drugs Aging. 2003;20:761–7.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Hansotia T, Maida A, Flock G, Yamada Y, Tsukiyama K, Seino Y, Drucker DJ. Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. J Clin Invest. 2007;117:143–52.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Kang MY, Oh TJ, Cho YM. Glucagon-like peptide-1 increases mitochondrial biogenesis and function in INS-1 rat insulinoma cells. Endocrinol Metab (Seoul). 2015;30:216–20.CrossRefGoogle Scholar
  108. 108.
    Fukuda-Tsuru S, Kakimoto T, Utsumi H, Kiuchi S, Ishii S. The novel dipeptidyl peptidase-4 inhibitor teneligliptin prevents high-fat diet-induced obesity accompanied with increased energy expenditure in mice. Eur J Pharmacol. 2014;723:207–15.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Rupprecht LE, Mietlicki-Baase EG, Zimmer DJ, McGrath LE, Olivos DR, Hayes MR. Hindbrain GLP-1 receptor-mediated suppression of food intake requires a PI3K-dependent decrease in phosphorylation of membrane-bound Akt. Am J Physiol Endocrinol Metab. 2013;305:E751–9.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Kimura S, Inoguchi T, Yamasaki T, Yamato M, Ide M, Sonoda N, Yamada K, Takayanagi R. A novel DPP-4 inhibitor teneligliptin scavenges hydroxyl radicals: in vitro study evaluated by electron spin resonance spectroscopy and in vivo study using DPP-4 deficient rats. Metabolism. 2016;65:138–45.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Wang WJ, Chang CH, Sun MF, Hsu SF, Weng CS. DPP-4 inhibitor attenuates toxic effects of indoxyl sulfate on kidney tubular cells. PLoS One. 2014;9:e93447.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Nishikawa M, Ishimori N, Takada S, Saito A, Kadoguchi T, Furihata T, Fukushima A, Matsushima S, Yokota T, Kinugawa S, Tsutsui H. AST-120 ameliorates lowered exercise capacity and mitochondrial biogenesis in the skeletal muscle from mice with chronic kidney disease via reducing oxidative stress. Nephrol Dial Transplant. 2015;30:934–42.CrossRefGoogle Scholar
  113. 113.
    Tamaki M, Miyashita K, Hagiwara A, Wakino S, Inoue H, Fujii K, Fujii C, Endo S, Uto A, Mitsuishi M, Sato M, Doi T, Itoh H. Ghrelin treatment improves physical decline in sarcopenia model mice through muscular enhancement and mitochondrial activation. Endocr J. 2017;64:S47–51.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Borner T, Loi L, Pietra C, Giuliano C, Lutz TA, Riediger T. The ghrelin receptor agonist HM01 mimics the neuronal effects of ghrelin in the arcuate nucleus and attenuates anorexia-cachexia syndrome in tumor-bearing rats. Am J Physiol Regul Integr Comp Physiol. 2016;311:R89–96.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Villars FO, Pietra C, Giuliano C, Lutz TA, Riediger T. Oral treatment with the ghrelin receptor agonist HM01 attenuates Cachexia in mice bearing Colon-26 (C26) tumors. Int J Mol Sci. 2017;18:E986.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Yoshimura M, Shiomi Y, Ohira Y, Takei M, Tanaka T. Z-505 hydrochloride, an orally active ghrelin agonist, attenuates the progression of cancer cachexia via anabolic hormones in Colon 26 tumor-bearing mice. Eur J Pharmacol. 2017;811:30–7.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Mak RH, Cheung WW, Solomon G, Gertler A. Preparation of potent leptin receptor antagonists and their therapeutic use in mouse models of uremic Cachexia and kidney fibrosis. Curr Pharm Des. 2018;24:1012–8.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Cheung WW, Ding W, Gunta SS, Gu Y, Tabakman R, Klapper LN, Gertler A, Mak RH. A pegylated leptin antagonist ameliorates CKD-associated cachexia in mice. J Am Soc Nephrol. 2014;25:119–28.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    McFarlane C, Vajjala A, Arigela H, Lokireddy S, Ge X, Bonala S, Manickam R, Kambadur R, Sharma M. Negative auto-regulation of Myostatin expression is mediated by Smad3 and MicroRNA-27. PLoS One. 2014;9:e87687.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Wang B, Zhang C, Zhang A, Cai H, Price SR, Wang XH. MicroRNA-23a and MicroRNA-27a mimic exercise by ameliorating CKD-induced muscle atrophy. J Am Soc Nephrol. 2017;28:2631–40.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Kukreti H, Amuthavalli K, Harikumar A, Sathiyamoorthy S, Feng PZ, Anantharaj R, Tan SL, Lokireddy S, Bonala S, Sriram S, McFarlane C, Kambadur R, Sharma M. Muscle-specific microRNA1 (miR1) targets heat shock protein 70 (HSP70) during dexamethasone-mediated atrophy. J Biol Chem. 2013;288:6663–78.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Hu L, Klein JD, Hassounah F, Cai H, Zhang C, Xu P, Wang XH. Low-frequency electrical stimulation attenuates muscle atrophy in CKD--a potential treatment strategy. J Am Soc Nephrol. 2015;26:626–35.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  1. 1.Department of Biopharmaceutics, Graduate School of Pharmaceutical SciencesKumamoto UniversityKumamotoJapan
  2. 2.Division of PharmacodynamicsKeio University Faculty of PharmacyTokyoJapan

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