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. 1997 Oct 15;100(8):2125–2132. doi: 10.1172/JCI119747

Responsiveness of muscle protein synthesis to growth hormone administration in HIV-infected individuals declines with severity of disease.

M A McNurlan 1, P J Garlick 1, R T Steigbigel 1, K A DeCristofaro 1, R A Frost 1, C H Lang 1, R W Johnson 1, A M Santasier 1, C J Cabahug 1, J Fuhrer 1, M C Gelato 1
PMCID: PMC508405  PMID: 9329979

Abstract

This study was undertaken to determine if human recombinant growth hormone (hrGH, 6 mg/d for 2 wk) would stimulate muscle protein synthesis in AIDS wasting. Healthy controls were compared with patients who were HIV+, had AIDS without weight loss, and had AIDS with > 10% weight loss. Before hrGH, rates of skeletal muscle protein synthesis, measured with l-[2H5]phenylalanine, were the same in controls and in all stages of disease. Rates of myofibrillar protein degradation, however, assessed from urinary excretion of 3-methyl histidine, were higher in AIDS and AIDS wasting than in HIV+ or healthy individuals. The group with weight loss had significantly higher TNFalpha levels but not higher HIV viral loads. Muscle function, as determined by isokinetic knee extension and shoulder flexion, was significantly higher in controls than all infected individuals. After GH, rates of protein synthesis were stimulated 27% in controls, with a smaller increase (11%) in HIV+, and a significant depression (42%) in AIDS with weight loss, despite fourfold elevation in insulin-like growth factor-I in all groups. There was a significant correlation of hrGH-induced changes in muscle protein synthesis with severity of disease (P = 0.002). The results indicate increased basal muscle protein degradation and decreased responsiveness of muscle protein synthesis to GH in the later stages of disease.

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Selected References

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  1. Aukrust P., Liabakk N. B., Müller F., Lien E., Espevik T., Frøland S. S. Serum levels of tumor necrosis factor-alpha (TNF alpha) and soluble TNF receptors in human immunodeficiency virus type 1 infection--correlations to clinical, immunologic, and virologic parameters. J Infect Dis. 1994 Feb;169(2):420–424. doi: 10.1093/infdis/169.2.420. [DOI] [PubMed] [Google Scholar]
  2. Calder A. G., Anderson S. E., Grant I., McNurlan M. A., Garlick P. J. The determination of low d5-phenylalanine enrichment (0.002-0.09 atom percent excess), after conversion to phenylethylamine, in relation to protein turnover studies by gas chromatography/electron ionization mass spectrometry. Rapid Commun Mass Spectrom. 1992 Jul;6(7):421–424. doi: 10.1002/rcm.1290060704. [DOI] [PubMed] [Google Scholar]
  3. Charters Y., Grimble R. F. Effect of recombinant human tumour necrosis factor alpha on protein synthesis in liver, skeletal muscle and skin of rats. Biochem J. 1989 Mar 1;258(2):493–497. doi: 10.1042/bj2580493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chlebowski R. T., Grosvenor M. B., Bernhard N. H., Morales L. S., Bulcavage L. M. Nutritional status, gastrointestinal dysfunction, and survival in patients with AIDS. Am J Gastroenterol. 1989 Oct;84(10):1288–1293. [PubMed] [Google Scholar]
  5. Clemmons D. R., Smith-Banks A., Underwood L. E. Reversal of diet-induced catabolism by infusion of recombinant insulin-like growth factor-I in humans. J Clin Endocrinol Metab. 1992 Jul;75(1):234–238. doi: 10.1210/jcem.75.1.1619015. [DOI] [PubMed] [Google Scholar]
  6. Douglas R. G., Humberstone D. A., Haystead A., Shaw J. H. Metabolic effects of recombinant human growth hormone: isotopic studies in the postabsorptive state and during total parenteral nutrition. Br J Surg. 1990 Jul;77(7):785–790. doi: 10.1002/bjs.1800770722. [DOI] [PubMed] [Google Scholar]
  7. Ellis K. J., Lee P. D., Pivarnik J. M., Bukar J. G., Gesundheit N. Changes in body composition of human immunodeficiency virus-infected males receiving insulin-like growth factor I and growth hormone. J Clin Endocrinol Metab. 1996 Aug;81(8):3033–3038. doi: 10.1210/jcem.81.8.8768870. [DOI] [PubMed] [Google Scholar]
  8. Espat N. J., Copeland E. M., Moldawer L. L. Tumor necrosis factor and cachexia: a current perspective. Surg Oncol. 1994 Oct;3(5):255–262. doi: 10.1016/0960-7404(94)90027-2. [DOI] [PubMed] [Google Scholar]
  9. Essén P., McNurlan M. A., Sonnenfeld T., Milne E., Vinnars E., Wernerman J., Garlick P. J. Muscle protein synthesis after operation: effects of intravenous nutrition. Eur J Surg. 1993 Apr;159(4):195–200. [PubMed] [Google Scholar]
  10. Fong Y., Rosenbaum M., Tracey K. J., Raman G., Hesse D. G., Matthews D. E., Leibel R. L., Gertner J. M., Fischman D. A., Lowry S. F. Recombinant growth hormone enhances muscle myosin heavy-chain mRNA accumulation and amino acid accrual in humans. Proc Natl Acad Sci U S A. 1989 May;86(9):3371–3374. doi: 10.1073/pnas.86.9.3371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Froesch E. R., Zenobi P. D., Hussain M. Metabolic and therapeutic effects of insulin-like growth factor I. Horm Res. 1994;42(1-2):66–71. doi: 10.1159/000184148. [DOI] [PubMed] [Google Scholar]
  12. Frost R. A., Fuhrer J., Steigbigel R., Mariuz P., Lang C. H., Gelato M. C. Wasting in the acquired immune deficiency syndrome is associated with multiple defects in the serum insulin-like growth factor system. Clin Endocrinol (Oxf) 1996 May;44(5):501–514. doi: 10.1046/j.1365-2265.1996.705526.x. [DOI] [PubMed] [Google Scholar]
  13. Fryburg D. A., Barrett E. J. Growth hormone acutely stimulates skeletal muscle but not whole-body protein synthesis in humans. Metabolism. 1993 Sep;42(9):1223–1227. doi: 10.1016/0026-0495(93)90285-v. [DOI] [PubMed] [Google Scholar]
  14. Fryburg D. A., Gelfand R. A., Barrett E. J. Growth hormone acutely stimulates forearm muscle protein synthesis in normal humans. Am J Physiol. 1991 Mar;260(3 Pt 1):E499–E504. doi: 10.1152/ajpendo.1991.260.3.E499. [DOI] [PubMed] [Google Scholar]
  15. Fryburg D. A. Insulin-like growth factor I exerts growth hormone- and insulin-like actions on human muscle protein metabolism. Am J Physiol. 1994 Aug;267(2 Pt 1):E331–E336. doi: 10.1152/ajpendo.1994.267.2.E331. [DOI] [PubMed] [Google Scholar]
  16. Fryburg D. A., Louard R. J., Gerow K. E., Gelfand R. A., Barrett E. J. Growth hormone stimulates skeletal muscle protein synthesis and antagonizes insulin's antiproteolytic action in humans. Diabetes. 1992 Apr;41(4):424–429. doi: 10.2337/diab.41.4.424. [DOI] [PubMed] [Google Scholar]
  17. Gore D. C., Honeycutt D., Jahoor F., Wolfe R. R., Herndon D. N. Effect of exogenous growth hormone on whole-body and isolated-limb protein kinetics in burned patients. Arch Surg. 1991 Jan;126(1):38–43. doi: 10.1001/archsurg.1991.01410250042006. [DOI] [PubMed] [Google Scholar]
  18. Grunfeld C., Feingold K. R. Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. N Engl J Med. 1992 Jul 30;327(5):329–337. doi: 10.1056/NEJM199207303270506. [DOI] [PubMed] [Google Scholar]
  19. Guenter P., Muurahainen N., Simons G., Kosok A., Cohan G. R., Rudenstein R., Turner J. L. Relationships among nutritional status, disease progression, and survival in HIV infection. J Acquir Immune Defic Syndr. 1993 Oct;6(10):1130–1138. [PubMed] [Google Scholar]
  20. Hammarqvist F., Strömberg C., von der Decken A., Vinnars E., Wernerman J. Biosynthetic human growth hormone preserves both muscle protein synthesis and the decrease in muscle-free glutamine, and improves whole-body nitrogen economy after operation. Ann Surg. 1992 Aug;216(2):184–191. doi: 10.1097/00000658-199208000-00009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Horber F. F., Haymond M. W. Human growth hormone prevents the protein catabolic side effects of prednisone in humans. J Clin Invest. 1990 Jul;86(1):265–272. doi: 10.1172/JCI114694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kotler D. P., Grunfeld C. Pathophysiology and treatment of the AIDS wasting syndrome. AIDS Clin Rev. 1995:229–275. [PubMed] [Google Scholar]
  23. Kotler D. P., Tierney A. R., Wang J., Pierson R. N., Jr Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS. Am J Clin Nutr. 1989 Sep;50(3):444–447. doi: 10.1093/ajcn/50.3.444. [DOI] [PubMed] [Google Scholar]
  24. Kotler D. P., Wang J., Pierson R. N. Body composition studies in patients with the acquired immunodeficiency syndrome. Am J Clin Nutr. 1985 Dec;42(6):1255–1265. doi: 10.1093/ajcn/42.6.1255. [DOI] [PubMed] [Google Scholar]
  25. Krentz A. J., Koster F. T., Crist D. M., Finn K., Johnson L. Z., Boyle P. J., Schade D. S. Anthropometric, metabolic, and immunological effects of recombinant human growth hormone in AIDS and AIDS-related complex. J Acquir Immune Defic Syndr. 1993 Mar;6(3):245–251. [PubMed] [Google Scholar]
  26. Lundeberg S., Belfrage M., Wernerman J., von der Decken A., Thunell S., Vinnars E. Growth hormone improves muscle protein metabolism and whole body nitrogen economy in man during a hyponitrogenous diet. Metabolism. 1991 Mar;40(3):315–322. doi: 10.1016/0026-0495(91)90116-e. [DOI] [PubMed] [Google Scholar]
  27. Macallan D. C., McNurlan M. A., Milne E., Calder A. G., Garlick P. J., Griffin G. E. Whole-body protein turnover from leucine kinetics and the response to nutrition in human immunodeficiency virus infection. Am J Clin Nutr. 1995 Apr;61(4):818–826. doi: 10.1093/ajcn/61.4.818. [DOI] [PubMed] [Google Scholar]
  28. Macallan D. C., Noble C., Baldwin C., Jebb S. A., Prentice A. M., Coward W. A., Sawyer M. B., McManus T. J., Griffin G. E. Energy expenditure and wasting in human immunodeficiency virus infection. N Engl J Med. 1995 Jul 13;333(2):83–88. doi: 10.1056/NEJM199507133330202. [DOI] [PubMed] [Google Scholar]
  29. Mauras N., Beaufrere B. Recombinant human insulin-like growth factor-I enhances whole body protein anabolism and significantly diminishes the protein catabolic effects of prednisone in humans without a diabetogenic effect. J Clin Endocrinol Metab. 1995 Mar;80(3):869–874. doi: 10.1210/jcem.80.3.7533772. [DOI] [PubMed] [Google Scholar]
  30. McNurlan M. A., Essén P., Thorell A., Calder A. G., Anderson S. E., Ljungqvist O., Sandgren A., Grant I., Tjäder I., Ballmer P. E. Response of protein synthesis in human skeletal muscle to insulin: an investigation with L-[2H5]phenylalanine. Am J Physiol. 1994 Jul;267(1 Pt 1):E102–E108. doi: 10.1152/ajpendo.1994.267.1.E102. [DOI] [PubMed] [Google Scholar]
  31. McNurlan M. A., Garlick P. J. Influence of nutrient intake on protein turnover. Diabetes Metab Rev. 1989 Mar;5(2):165–189. doi: 10.1002/dmr.5610050206. [DOI] [PubMed] [Google Scholar]
  32. Mjaaland M., Unneberg K., Hotvedt R., Revhaug A. Nitrogen retention caused by growth hormone in patients undergoing gastrointestinal surgery with epidural analgesia and parenteral nutrition. Eur J Surg. 1991 Jan;157(1):21–27. [PubMed] [Google Scholar]
  33. Mulligan K., Grunfeld C., Hellerstein M. K., Neese R. A., Schambelan M. Anabolic effects of recombinant human growth hormone in patients with wasting associated with human immunodeficiency virus infection. J Clin Endocrinol Metab. 1993 Oct;77(4):956–962. doi: 10.1210/jcem.77.4.8408471. [DOI] [PubMed] [Google Scholar]
  34. Møller J., Jørgensen J. O., Møller N., Christiansen J. S., Weeke J. Effects of growth hormone administration on fuel oxidation and thyroid function in normal man. Metabolism. 1992 Jul;41(7):728–731. doi: 10.1016/0026-0495(92)90312-x. [DOI] [PubMed] [Google Scholar]
  35. Møller N., Møller J., Jørgensen J. O., Ovesen P., Schmitz O., Alberti K. G., Christiansen J. S. Impact of 2 weeks high dose growth hormone treatment on basal and insulin stimulated substrate metabolism in humans. Clin Endocrinol (Oxf) 1993 Nov;39(5):577–581. doi: 10.1111/j.1365-2265.1993.tb02412.x. [DOI] [PubMed] [Google Scholar]
  36. Olchovsky D., Bruno J. F., Gelato M. C., Song J., Berelowitz M. Pituitary insulin-like growth factor-I content and gene expression in the streptozotocin-diabetic rat: evidence for tissue-specific regulation. Endocrinology. 1991 Feb;128(2):923–928. doi: 10.1210/endo-128-2-923. [DOI] [PubMed] [Google Scholar]
  37. Ott M., Fischer H., Polat H., Helm E. B., Frenz M., Caspary W. F., Lembcke B. Bioelectrical impedance analysis as a predictor of survival in patients with human immunodeficiency virus infection. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 May 1;9(1):20–25. [PubMed] [Google Scholar]
  38. Ott M., Lembcke B., Fischer H., Jäger R., Polat H., Geier H., Rech M., Staszeswki S., Helm E. B., Caspary W. F. Early changes of body composition in human immunodeficiency virus-infected patients: tetrapolar body impedance analysis indicates significant malnutrition. Am J Clin Nutr. 1993 Jan;57(1):15–19. doi: 10.1093/ajcn/57.1.15. [DOI] [PubMed] [Google Scholar]
  39. Palenicek J. P., Graham N. M., He Y. D., Hoover D. A., Oishi J. S., Kingsley L., Saah A. J. Weight loss prior to clinical AIDS as a predictor of survival. Multicenter AIDS Cohort Study Investigators. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Nov 1;10(3):366–373. [PubMed] [Google Scholar]
  40. Pallarés-Trujillo J., López-Soriano F. J., Argilés J. M. TNF and AIDS: two sides of the same coin? Med Res Rev. 1995 Nov;15(6):533–546. doi: 10.1002/med.2610150605. [DOI] [PubMed] [Google Scholar]
  41. Pisters P. W., Pearlstone D. B. Protein and amino acid metabolism in cancer cachexia: investigative techniques and therapeutic interventions. Crit Rev Clin Lab Sci. 1993;30(3):223–272. doi: 10.3109/10408369309084669. [DOI] [PubMed] [Google Scholar]
  42. Rennie M. J., Bennegård K., Edén E., Emery P. W., Lundholm K. Urinary excretion and efflux from the leg of 3-methylhistidine before and after major surgical operation. Metabolism. 1984 Mar;33(3):250–256. doi: 10.1016/0026-0495(84)90046-5. [DOI] [PubMed] [Google Scholar]
  43. Schambelan M., Mulligan K., Grunfeld C., Daar E. S., LaMarca A., Kotler D. P., Wang J., Bozzette S. A., Breitmeyer J. B. Recombinant human growth hormone in patients with HIV-associated wasting. A randomized, placebo-controlled trial. Serostim Study Group. Ann Intern Med. 1996 Dec 1;125(11):873–882. doi: 10.7326/0003-4819-125-11-199612010-00002. [DOI] [PubMed] [Google Scholar]
  44. Serwadda D., Mugerwa R. D., Sewankambo N. K., Lwegaba A., Carswell J. W., Kirya G. B., Bayley A. C., Downing R. G., Tedder R. S., Clayden S. A. Slim disease: a new disease in Uganda and its association with HTLV-III infection. Lancet. 1985 Oct 19;2(8460):849–852. doi: 10.1016/S0140-6736(85)90122-9. [DOI] [PubMed] [Google Scholar]
  45. Sjölin J., Stjernström H., Henneberg S., Andersson E., Mårtensson J., Friman G., Larsson J. Splanchnic and peripheral release of 3-methylhistidine in relation to its urinary excretion in human infection. Metabolism. 1989 Jan;38(1):23–29. doi: 10.1016/0026-0495(89)90175-3. [DOI] [PubMed] [Google Scholar]
  46. Süttmann U., Ockenga J., Selberg O., Hoogestraat L., Deicher H., Müller M. J. Incidence and prognostic value of malnutrition and wasting in human immunodeficiency virus-infected outpatients. J Acquir Immune Defic Syndr Hum Retrovirol. 1995 Mar 1;8(3):239–246. doi: 10.1097/00042560-199503010-00004. [DOI] [PubMed] [Google Scholar]
  47. Voerman B. J., Strack van Schijndel R. J., Groeneveld A. B., de Boer H., Nauta J. P., Thijs L. G. Effects of human growth hormone in critically ill nonseptic patients: results from a prospective, randomized, placebo-controlled trial. Crit Care Med. 1995 Apr;23(4):665–673. doi: 10.1097/00003246-199504000-00014. [DOI] [PubMed] [Google Scholar]
  48. Ward H. C., Halliday D., Sim A. J. Protein and energy metabolism with biosynthetic human growth hormone after gastrointestinal surgery. Ann Surg. 1987 Jul;206(1):56–61. doi: 10.1097/00000658-198707000-00009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Wassner S. J., Schlitzer J. L., Li J. B. A rapid, sensitive method for the determination of 3-methylhistidine levels in urine and plasma using high-pressure liquid chromatography. Anal Biochem. 1980 May 15;104(2):284–289. doi: 10.1016/0003-2697(80)90076-7. [DOI] [PubMed] [Google Scholar]
  50. Wolf R. F., Pearlstone D. B., Newman E., Heslin M. J., Gonenne A., Burt M. E., Brennan M. F. Growth hormone and insulin reverse net whole body and skeletal muscle protein catabolism in cancer patients. Ann Surg. 1992 Sep;216(3):280–290. doi: 10.1097/00000658-199209000-00007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Yarasheski K. E., Zachwieja J. J., Campbell J. A., Bier D. M. Effect of growth hormone and resistance exercise on muscle growth and strength in older men. Am J Physiol. 1995 Feb;268(2 Pt 1):E268–E276. doi: 10.1152/ajpendo.1995.268.2.E268. [DOI] [PubMed] [Google Scholar]

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