Journal of Inherited Metabolic Disease

, Volume 38, Issue 4, pp 621–628 | Cite as

Acute rhabdomyolysis and inflammation

  • Yamina Hamel
  • Asmaa Mamoune
  • François-Xavier Mauvais
  • Florence Habarou
  • Laetitia Lallement
  • Norma Beatriz Romero
  • Chris Ottolenghi
  • Pascale de Lonlay
SSIEM 2014


Rhabdomyolysis results from the rapid breakdown of skeletal muscle fibers, which leads to leakage of potentially toxic cellular content into the systemic circulation. Acquired causes by direct injury to the sarcolemma are most frequent. The inherited causes are: i) metabolic with failure of energy production, including mitochondrial fatty acid ß-oxidation defects, LPIN1 mutations, inborn errors of glycogenolysis and glycolysis, more rarely mitochondrial respiratory chain deficiency, purine defects and peroxysomal α-methyl-acyl-CoA-racemase defect (AMACR), ii) structural causes with muscle dystrophies and myopathies, iii) calcium pump disorder with RYR1 gene mutations, iv) inflammatory causes with myositis. Irrespective of the cause of rhabdomyolysis, the pathology follows a common pathway, either by the direct injury to sarcolemma by increased intracellular calcium concentration (acquired causes) or by the failure of energy production (inherited causes), which leads to fiber necrosis. Rhabdomyolysis are frequently precipitated by febrile illness or exercise. These conditions are associated with two events, elevated temperature and high circulating levels of pro-inflammatory mediators such as cytokines and chemokines. To illustrate these points in the context of energy metabolism, protein thermolability and the potential benefits of arginine therapy, we focus on a rare cause of rhabdomyolysis, aldolase A deficiency. In addition, our studies on lipin-1 (LPIN1) deficiency raise the possibility that several diseases involved in rhabdomyolysis implicate pro-inflammatory cytokines and may even represent primarily pro-inflammatory diseases. Thus, not only thermolability of mutant proteins critical for muscle function, but also pro-inflammatory cytokines per se, may lead to metabolic decompensation and rhabdomyolysis.


  1. Accioly MT, Pacheco P, Maya-Monteiro CM et al (2008) Lipid bodies are reservoirs of cyclooxygenase-2 and sites of prostaglandin-E2 synthesis in colon cancer cells. Cancer Res 68(6):1732–1740CrossRefPubMedGoogle Scholar
  2. Alvarez-Guardia D, Palomer X, Coll T et al (2010) The p65 subunit of NF-kappaB binds to PGC-1alpha, linking inflammation and metabolic disturbances in cardiac cells. Cardiovasc Res 87(3):449–458CrossRefPubMedGoogle Scholar
  3. Berardo AS, DiMauro D, Hirano M (2010) A diagnostic algorithm for metabolic myopathies. Curr Neurol Neurosci Rep 10(2):118–126CrossRefPubMedCentralPubMedGoogle Scholar
  4. Bergounioux J, Brassier A, Rambaud C et al (2012) Fatal rhabdomyolysis in 2 children with LPIN1 mutations. J Pediatr 160(6):1052–1054CrossRefPubMedGoogle Scholar
  5. Beutler E, Scott S, Bishop A et al (1973) Red cell aldolase deficiency and hemolytic anemia: a new syndrome. Trans Assoc Am Phys 86:154–166PubMedGoogle Scholar
  6. Brealey D, Brand M, Hargreaves I et al (2002) Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360(9328):219–223CrossRefPubMedGoogle Scholar
  7. Brochu ME, Girard S, Lavoie K et al (2011) Developmental regulation of the neuroinflammatory responses to LPS and/or hypoxia-ischemia between preterm and term neonates: an experimental study. J Neuroinflammation 8:55CrossRefPubMedCentralPubMedGoogle Scholar
  8. Calvano SE, Xiao W, Richards DR et al (2005) A network-based analysis of systemic inflammation in humans. Nature 437(7061):1032–1037CrossRefPubMedGoogle Scholar
  9. Cervellin G, Comelli I, Lippi G (2010) Rhabdomyolysis: historical background, clinical, diagnostic and therapeutic features. Clin Chem Lab Med 48(6):749–756CrossRefPubMedGoogle Scholar
  10. Chao CC, Hu S (1994) Tumor necrosis factor-alpha potentiates glutamate neurotoxicity in human fetal brain cell cultures. Dev Neurosci 16(3–4):172–179CrossRefPubMedGoogle Scholar
  11. Chen X, Xun K, Chen L, Wang Y (2009) TNF-alpha, a potent lipid metabolism regulator. Cell Biochem Funct 27(7):407–416CrossRefPubMedGoogle Scholar
  12. Crouser ED, Julian MW, Blaho DV et al (2002) Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med 30(2):276–284CrossRefPubMedGoogle Scholar
  13. Darras BT, Friedman NR (2000) Metabolic myopathies: a clinical approach; part II. Pediatr Neurol 22(3):171–181CrossRefPubMedGoogle Scholar
  14. Devlin CM, Kuriakose G, Hirsch E et al (2002) Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol level and foam cell lesion size. Proc Natl Acad Sci U S A 99(9):6280–6285CrossRefPubMedCentralPubMedGoogle Scholar
  15. DiMauro S, Garone C, Naini A (2010) Metabolic myopathies. Curr Rheumatol Rep 12(5):386–393CrossRefPubMedGoogle Scholar
  16. Donath MY (2014) Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov 13(6):465–476CrossRefPubMedGoogle Scholar
  17. Donkor J, Sariahmetoglu M, Dewald J et al (2007) Three mammalian lipins act as phosphatidate phosphatases with distinct tissue expression patterns. J Biol Chem 282(6):3450–3457CrossRefPubMedGoogle Scholar
  18. East C, Bilheimer DW, Grundy SM (1988) Combination drug therapy for familial combined hyperlipidemia. Ann Intern Med 109(1):25–32CrossRefPubMedGoogle Scholar
  19. El Sabbagh S, Lebre AS, Bahi-Buisson N et al (2010) Epileptic phenotypes in children with respiratory chain disorders. Epilepsia 51(7):1225–1235CrossRefPubMedGoogle Scholar
  20. Esser N, Legrand-Poels S, Piette J et al (2014) Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract 105(2):141–150CrossRefPubMedGoogle Scholar
  21. Febbraio MA (2014) Role of interleukins in obesity: implications for metabolic disease. Trends Endocrinol Metab 25(6):312–319CrossRefPubMedGoogle Scholar
  22. Feingold KR, Grunfeld C (1987) Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vivo. J Clin Invest 80(1):184–190CrossRefPubMedCentralPubMedGoogle Scholar
  23. Feingold KR, Wang Y, Moser A et al (2008) LPS decreases fatty acid oxidation and nuclear hormone receptors in the kidney. J Lipid Res 49(10):2179–2187CrossRefPubMedCentralPubMedGoogle Scholar
  24. Feingold KR, Moser A, Patzek SM et al (2009) Infection decreases fatty acid oxidation and nuclear hormone receptors in the diaphragm. J Lipid Res 50(10):2055–2063CrossRefPubMedCentralPubMedGoogle Scholar
  25. Feingold KR, Shigenaga JK, Patzek SM et al (2011) Endotoxin, zymosan, and cytokines decrease the expression of the transcription factor, carbohydrate response element binding protein, and its target genes. Innate Immun 17(2):174–182CrossRefPubMedGoogle Scholar
  26. Ferguson PJ, Sandu M (2012) Current understanding of the pathogenesis and management of chronic recurrent multifocal osteomyelitis. Curr Rheumatol Rep 14(2):130–141CrossRefPubMedCentralPubMedGoogle Scholar
  27. Finck BN, Gropler MC, Chen Z et al (2006) Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell Metab 4(3):199–210CrossRefPubMedGoogle Scholar
  28. Flores EA, Bistrian BR, Pomposelli JJ et al (1989) Infusion of tumor necrosis factor/cachectin promotes muscle catabolism in the rat. A synergistic effect with interleukin 1. J Clin Invest 83(5):1614–1622CrossRefPubMedCentralPubMedGoogle Scholar
  29. Frisard MI, McMillan RP, Marchand J et al (2010) Toll-like receptor 4 modulates skeletal muscle substrate metabolism. Am J Physiol Endocrinol Metab 298(5):E988–E998CrossRefPubMedCentralPubMedGoogle Scholar
  30. Gataullina S, Dellatolas G, Perdry H et al (2012) Comorbidity and metabolic context are crucial factors determining neurological sequelae of hypoglycaemia. Dev Med Child Neurol 54(11):1012–1017CrossRefPubMedGoogle Scholar
  31. Grunfeld C, Adi S, Soued M et al (1990) Search for mediators of the lipogenic effects of tumor necrosis factor: potential role for interleukin 6. Cancer Res 50(14):4233–4238PubMedGoogle Scholar
  32. Gu H, Yang M, Zhao X et al (2014) Pretreatment with hydrogen-rich saline reduces the damage caused by glycerol-induced rhabdomyolysis and acute kidney injury in rats. J Surg Res 188(1):243–249CrossRefPubMedGoogle Scholar
  33. Han GS, Wu WI, Carman GM (2006) The Saccharomyces cerevisiae Lipin homolog is a Mg2 + −dependent phosphatidate phosphatase enzyme. J Biol Chem 281(14):9210–9218CrossRefPubMedCentralPubMedGoogle Scholar
  34. Herlin T, Fiirgaard B, Bjerre M et al (2012) Efficacy of anti-IL-1 treatment in Majeed syndrome. Ann Rheum Dis 72(3):410–413CrossRefPubMedCentralPubMedGoogle Scholar
  35. Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259(5091):87–91CrossRefPubMedGoogle Scholar
  36. Janeway CA, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216CrossRefPubMedGoogle Scholar
  37. Kanda H, Tateya S, Tamori Y et al (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116(6):1494–1505CrossRefPubMedCentralPubMedGoogle Scholar
  38. Kapina V, Sedel F, Truffert A et al (2010) Relapsing rhabdomyolysis due to peroxisomal alpha-methylacyl-coa racemase deficiency. Neurology 75(14):1300–1302CrossRefPubMedGoogle Scholar
  39. Kim HB, Kumar A, Wang L et al (2010) Lipin 1 represses NFATc4 transcriptional activity in adipocytes to inhibit secretion of inflammatory factors. Mol Cell Biol 30(12):3126–3139CrossRefPubMedCentralPubMedGoogle Scholar
  40. Kishi H, Mukai T, Hirono A et al (1987) Human aldolase A deficiency associated with a hemolytic anemia: thermolabile aldolase due to a single base mutation. Proc Natl Acad Sci U S A 84(23):8623–8627CrossRefPubMedCentralPubMedGoogle Scholar
  41. Kolker S, Koeller DM, Okun JG et al (2004) Pathomechanisms of neurodegeneration in glutaryl-CoA dehydrogenase deficiency. Ann Neurol 55(1):7–12CrossRefPubMedGoogle Scholar
  42. Kreuder J, Borkhardt A, Repp R, Pekrun A, Göttsche B et al (1996) Brief report: inherited metabolic myopathy and hemolysis due to a mutation in aldolase A. N Engl J Med 334(17):1100–1104CrossRefPubMedGoogle Scholar
  43. Kuijk LM, Beekman JM, Koster J et al (2008) HMG-CoA reductase inhibition induces IL-1beta release through Rac1/PI3K/PKB-dependent caspase-1 activation. Blood 112(9):3563–3573CrossRefPubMedGoogle Scholar
  44. Laforet P, Vianey-Saban C (2010) Disorders of muscle lipid metabolism: diagnostic and therapeutic challenges. Neuromuscul Disord 20(11):693–700CrossRefPubMedGoogle Scholar
  45. Lamp J, Keyser B, Koeller DM et al (2011) Glutaric aciduria type 1 metabolites impair the succinate transport from astrocytic to neuronal cells. J Biol Chem 286(20):17777–17784CrossRefPubMedCentralPubMedGoogle Scholar
  46. Lindegaard B, Matthews VB, Brandt C et al (2013) Interleukin-18 activates skeletal muscle AMPK and reduces weight gain and insulin resistance in mice. Diabetes 62(9):3064–3074CrossRefPubMedCentralPubMedGoogle Scholar
  47. Linden AM, Sandu C, Aller MI et al (2007) TASK-3 knockout mice exhibit exaggerated nocturnal activity, impairments in cognitive functions, and reduced sensitivity to inhalation anesthetics. J Pharmacol Exp Ther 323(3):924–934CrossRefPubMedGoogle Scholar
  48. Lu B, Lu Y, Moser AH et al (2008) LPS and proinflammatory cytokines decrease lipin-1 in mouse adipose tissue and 3 T3-L1 adipocytes. Am J Physiol Endocrinol Metab 295(6):E1502–E1509CrossRefPubMedCentralPubMedGoogle Scholar
  49. Luck RP, Verbin S (2008) Rhabdomyolysis: a review of clinical presentation, etiology, diagnosis, and management. Pediatr Emerg Care 24(4):262–268CrossRefPubMedGoogle Scholar
  50. Majeed HA, Al-Tarawna M, El-Shanti H et al (2001) The syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. Report of a new family and a review. Eur J Pediatr 160(2):705–710CrossRefPubMedGoogle Scholar
  51. Mamoune A, Bahuau M, Hamel Y et al (2014) A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia. PLoS Genet 10(11):e1004711CrossRefPubMedCentralPubMedGoogle Scholar
  52. Mathis D, Shoelson SE (2011) Immunometabolism: an emerging frontier. Nat Rev Immunol 11(2):81CrossRefPubMedGoogle Scholar
  53. Meana C, Pena L, Lorden G et al (2014) Lipin-1 integrates lipid synthesis with proinflammatory responses during TLR activation in macrophages. J Immunol 193(9):4614–4622CrossRefPubMedGoogle Scholar
  54. Michot C, Hubert L, Brivet M et al (2010) LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood. Hum Mutat 31(7):E1564–E1573CrossRefPubMedGoogle Scholar
  55. Michot C, Hubert L, Romero NB et al (2012) Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia. J Inherit Metab Dis 35(6):1119–1128CrossRefPubMedGoogle Scholar
  56. Michot C, Mamoune A, Vamecq J et al (2013) Combination of lipid metabolism alterations and their sensitivity to inflammatory cytokines in human lipin-1-deficient myoblasts. Biochim Biophys Acta 1832(12):2103–2114CrossRefPubMedCentralPubMedGoogle Scholar
  57. Miwa S, Fujii H, Tani K, Takahashi K et al (1981) Two cases of red cell aldolase deficiency associated with hereditary hemolytic anemia in a Japanese family. Am J Hematol 11(4):425–437CrossRefPubMedGoogle Scholar
  58. Molenaar JP, Voermans NC, van Hoeve BJ et al (2014) Fever-induced recurrent rhabdomyolysis due to a novel mutation in the ryanodine receptor type 1 gene. Intern Med J 44(8):819–820CrossRefPubMedGoogle Scholar
  59. Navratil AR, Brummett AM, Bryan JD et al (2014) Francisella tularensis LVS induction of prostaglandin biosynthesis by infected macrophages requires specific host phospholipases and lipid phosphatases. Infect Immun 82(8):3299–3311CrossRefPubMedCentralPubMedGoogle Scholar
  60. Ohashi K, Shibata R, Murohara T et al (2014) Role of anti-inflammatory adipokines in obesity-related diseases. Trends Endocrinol Metab 25(7):348–355CrossRefPubMedGoogle Scholar
  61. Ostrowski K, Rohde T, Asp S, Schjerling P et al (2001) Chemokines are elevated in plasma after strenuous exercise in humans. Eur J Appl Physiol 84(3):244–245CrossRefPubMedGoogle Scholar
  62. Padfield KE, Astrakas LG, Zhang Q et al (2005) Burn injury causes mitochondrial dysfunction in skeletal muscle. Proc Natl Acad Sci U S A 102(15):5368–5373CrossRefPubMedCentralPubMedGoogle Scholar
  63. Pailla K, El-Mir MY, Cynober L et al (2001) Cytokine-mediated inhibition of ketogenesis is unrelated to nitric oxide or protein synthesis. Clin Nutr 20(4):313–317CrossRefPubMedGoogle Scholar
  64. Palomer X, Alvarez-Guardia D, Rodriguez-Calvo R et al (2009) TNF-alpha reduces PGC-1alpha expression through NF-kappaB and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model. Cardiovasc Res 81(4):703–712CrossRefPubMedGoogle Scholar
  65. Peterson TR, Sengupta SS, Harris TE et al (2011) mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146(3):408–420CrossRefPubMedCentralPubMedGoogle Scholar
  66. Quinlivan R, Jungbluth H (2012) Myopathic causes of exercise intolerance with rhabdomyolysis. Dev Med Child Neurol 54(10):886–891CrossRefPubMedGoogle Scholar
  67. Rosenberg H, Davis M, James D et al (2007) Malignant hyperthermia. Orphanet J Rare Dis 2:21CrossRefPubMedCentralPubMedGoogle Scholar
  68. Salles J, Tardif N, LandrierCombaret JF et al (2012) TNFalpha gene knockout differentially affects lipid deposition in liver and skeletal muscle of high-fat-diet mice. J Nutr Biochem 23(12):1685–1693CrossRefPubMedGoogle Scholar
  69. Sauer SW, Okun JG, Schwab MA et al (2005) Bioenergetics in glutaryl-coenzyme A dehydrogenase deficiency: a role for glutaryl-coenzyme A. J Biol Chem 280(23):21830–21836CrossRefPubMedGoogle Scholar
  70. Sauret JM, Marinides G, Wang GK (2002) Rhabdomyolysis. Am Fam Physician 65(5):907–912PubMedGoogle Scholar
  71. Shapiro ML, Baldea A, Luchette FA (2012) Rhabdomyolysis in the intensive care unit. J Intensive Care Med 27(6):335–342CrossRefPubMedGoogle Scholar
  72. Spate U, Schulze PC (2004) Proinflammatory cytokines and skeletal muscle. Curr Opin Clin Nutr Metab Care 7(3):265–269CrossRefPubMedGoogle Scholar
  73. Sugden MC, Caton PW, Holness MJ (2010) PPAR control: it's SIRTainly as easy as PGC. J Endocrinol 204(2):93–104CrossRefPubMedGoogle Scholar
  74. Tein I, DiMauro S, DeVivo DC (1990) Recurrent childhood myoglobinuria. Adv Pediatr 37:77–117PubMedGoogle Scholar
  75. Tonin P, Lewis P, Servidei S et al (1990) Metabolic causes of myoglobinuria. Ann Neurol 27(2):181–185CrossRefPubMedGoogle Scholar
  76. Tsuchiya Y, Takahashi N, Yoshizaki T et al (2009) A Jak2 inhibitor, AG490, reverses lipin-1 suppression by TNF-alpha in 3 T3-L1 adipocytes. Biochem Biophys Res Commun 382(2):348–352CrossRefPubMedGoogle Scholar
  77. Valdearcos M, Esquinas E, Meana C et al (2011) Subcellular localization and role of lipin-1 in human macrophages. J Immunol 186(10):6004–6013CrossRefPubMedGoogle Scholar
  78. Valdearcos M, Esquinas E, Meana C et al (2012) Lipin-2 reduces proinflammatory signaling induced by saturated Fatty acids in macrophages. J Biol Chem 287(14):10894–10904CrossRefPubMedCentralPubMedGoogle Scholar
  79. Vallerie SN, Hotamisligil GS (2010) The role of JNK proteins in metabolism. Sci Transl Med 2(60):60rv65CrossRefGoogle Scholar
  80. van Adel BA, Tarnopolsky MA (2009) Metabolic myopathies: update 2009. J Clin Neuromuscul Dis 10(3):97–121CrossRefPubMedGoogle Scholar
  81. Victor VM, Espulgues JV, Hernandez-Mijares A et al (2009) Oxidative stress and mitochondrial dysfunction in sepsis: a potential therapy with mitochondria-targeted antioxidants. Infect Disord Drug Targets 9(4):376–389CrossRefPubMedGoogle Scholar
  82. Wang X, Rousset CI, Hagberg H et al (2006) Lipopolysaccharide-induced inflammation and perinatal brain injury. Semin Fetal Neonatal Med 11(5):343–353CrossRefPubMedGoogle Scholar
  83. Wang X, Chrysovergis K, Kosak J et al (2014) Lower NLRP3 inflammasome activity in NAG-1 transgenic mice is linked to a resistance to obesity and increased insulin sensitivity. Obesity 22(5):1256–1263CrossRefPubMedCentralPubMedGoogle Scholar
  84. Weisberg SP, McCann D, Desai M et al (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112(12):1796–1808CrossRefPubMedCentralPubMedGoogle Scholar
  85. Xu H, Barnes GT, Yang Q et al (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112(12):1821–1830CrossRefPubMedCentralPubMedGoogle Scholar
  86. Yang Y, Ju D, Zhang M et al (2008) Interleukin-6 stimulates lipolysis in porcine adipocytes. Endocrine 33(3):261–269CrossRefPubMedGoogle Scholar
  87. Yao DC, Tolan DR, Murray MF et al (2004) Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr). Blood 103(6):2401–2403CrossRefPubMedGoogle Scholar
  88. Zeharia A, Shaag A, Houtkooper RH et al (2008) Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood. Am J Hum Genet 83(4):489–494CrossRefPubMedCentralPubMedGoogle Scholar
  89. Zutt R, van der Kooi AJ et al (2014) Rhabdomyolysis: review of the literature. Neuromuscul Disord 24(8):651–659CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM 2015

Authors and Affiliations

  • Yamina Hamel
    • 1
    • 2
    • 3
  • Asmaa Mamoune
    • 1
    • 2
    • 3
  • François-Xavier Mauvais
    • 2
    • 4
  • Florence Habarou
    • 2
    • 3
    • 5
  • Laetitia Lallement
    • 1
    • 2
    • 3
  • Norma Beatriz Romero
    • 6
  • Chris Ottolenghi
    • 2
    • 3
    • 5
  • Pascale de Lonlay
    • 1
    • 2
    • 3
    • 7
  1. 1.Institut Imagine, Institut National de la Santé et de la Recherche Médicale, Unité 1163ParisFrance
  2. 2.Université Paris Descartes, Sorbonne Paris Cité, Faculté de médecine Paris DescartesParisFrance
  3. 3.Centre de Référence des Maladies Héréditaires du MétabolismeHôpital Necker, AP-HPParisFrance
  4. 4.Institut National de la Santé et de la Recherché Médicale, Unité 1151 et Centre National de la Recherche Scientifique, Unité 8253ParisFrance
  5. 5.Service de Biochimie spécialisée, département de BiologieParisFrance
  6. 6.Université Pierre et Marie Curie, UM 76, INSERM U974, CNRS UMR 7215, Institut de Myologie, GHU Pitié-Salpétrière, AP-HP, Centre de Référence des Maladies NeuromusculairesParisFrance
  7. 7.Institut Imagine, INSERM 1163, Paris Descartes University and Reference Center of Metabolic Diseases, Necker HospitalParisFrance

Personalised recommendations