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Chronic hyponatremia exacerbates multiple manifestations of senescence in male rats

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Abstract

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is frequently responsible for chronic hyponatremia in the elderly due to age-related disruption of the inhibitory component of brain osmoregulatory mechanisms. Recent research has indicated that chronic hyponatremia is associated with gait disturbances, increased falls, and bone fragility in humans, and we have found that chronic hyponatremia causes increased bone resorption and reduced bone mineral density in young rats. In this study, we used a model of SIADH to study multi-organ consequences of chronic hyponatremia in aged rats. Sustained hyponatremia for 18 weeks caused progressive reduction of bone mineral density by DXA and decreased bone ash calcium, phosphate and sodium contents at the tibia and lumbar vertebrae. Administration of 10-fold higher vitamin D during the last 8 weeks of the study compensated for the reduction in bone formation and halted bone loss. Hyponatremic rats developed hypogonadism, as indicated by slightly lower serum testosterone and higher serum FSH and LH concentrations, markedly decreased testicular weight, and abnormal testicular histology. Aged hyponatremic rats also manifested decreased body fat, skeletal muscle sarcopenia by densitometry, and cardiomyopathy manifested as increased heart weight and perivascular and interstitial fibrosis by histology. These findings are consistent with recent results in cultured osteoclastic cells, indicating that low extracellular sodium concentrations increased oxidative stress, thereby potentially exacerbating multiple manifestations of senescence. Future prospective studies in patients with SIADH may indicate whether these multi-organ age-related comorbidities may potentially contribute to the observed increased incidence of fractures and mortality in this population.

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References

  • Almeida M, Han L, Martin-Millan M, Plotkin LI, Stewart SA, Roberson PK, Kousteni S, O'Brien CA, Bellido T, Parfitt AM, Weinstein RS, Jilka RL, Manolagas SC (2007) Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem 282:27285–27297

    Article  PubMed  CAS  Google Scholar 

  • Baker DJ, Hepple RT (2006) Elevated caspase and AIF gene expression correlate with progression of sarcopenia during aging in male F344BN rats. Exp Gerontol 41:1149–1156

    Article  PubMed  CAS  Google Scholar 

  • Barsony J, Sugimura Y, Verbalis JG (2010) Osteoclast response to low extracellular sodium and the mechanism of hyponatremia-induced bone loss. J Biol Chem 286(12):10864–10875

    Google Scholar 

  • Bergstrom WH, Wallace WM (1954) Bone as a sodium and potassium reservoir. J Clin Invest 33:867–873

    Article  PubMed  CAS  Google Scholar 

  • Bhasin S (2003) Testosterone supplementation for aging-associated sarcopenia. J Gerontol A Biol Sci Med Sci 58:1002–1008

    Article  PubMed  Google Scholar 

  • Boscoe A, Paramore C, Verbalis JG (2006) Cost of illness of hyponatremia in the United States. Cost Eff Resour Alloc 4:10

    Article  PubMed  Google Scholar 

  • Bourrin S, Toromanoff A, Ammann P, Bonjour JP, Rizzoli R (2000) Dietary protein deficiency induces osteoporosis in aged male rats. J Bone Miner Res 15:1555–1563

    Article  PubMed  CAS  Google Scholar 

  • Boyle AJ, Shih H, Hwang J, Ye J, Lee B, Zhang Y, Kwon D, Jun K, Zheng D, Sievers R, Angeli F, Yeghiazarians Y, Lee R (2011) Cardiomyopathy of aging in the mammalian heart is characterized by myocardial hypertrophy, fibrosis and a predisposition towards cardiomyocyte apoptosis and autophagy. Exp Gerontol 46:549–559

    Article  PubMed  Google Scholar 

  • Bradshaw AD, Baicu CF, Rentz TJ, Van Laer AO, Bonnema DD, Zile MR (2010) Age-dependent alterations in fibrillar collagen content and myocardial diastolic function: role of SPARC in post-synthetic procollagen processing. Am J Physiol Heart Circ Physiol 298:H614–H622

    Article  PubMed  CAS  Google Scholar 

  • Buehring B, Krueger D, Binkley N (2010) Jumping mechanography: a potential tool for sarcopenia evaluation in older individuals. J Clin Densitom 13:283–291

    Article  PubMed  Google Scholar 

  • Buford TW, Anton SD, Judge AR, Marzetti E, Wohlgemuth SE, Carter CS, Leeuwenburgh C, Pahor M, Manini TM (2010) Models of accelerated sarcopenia: critical pieces for solving the puzzle of age-related muscle atrophy. Ageing Res Rev 9:369–383

    Article  PubMed  Google Scholar 

  • Capasso JM, Palackal T, Olivetti G, Anversa P (1990) Severe myocardial dysfunction induced by ventricular remodeling in aging rat hearts. Am J Physiol 259:H1086–H1096

    PubMed  CAS  Google Scholar 

  • Carter CS, Giovaninni S, Seo DO, Dupree J, Morgan D, Chung HY, Lees H, Daniels M, Hubbard GB, Lee S, Ikeno Y, Foster TC, Buford TW, Marzetti E (2010) Differential effects of enalapril and losartan on body composition and indices of muscle quality in aged male Fischer 344 × Brown Norway rats. Age (Dordr) 33(2):167–183

    Google Scholar 

  • Ferron M, McKee MD, Levine RL, Ducy P, Karsenty G (2011) Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice. doi:10.1016/j.bone.2011.04.017

  • Fielding RA, Vellas B, Evans WJ, Bhasin S, Morley JE, Newman AB, van Abellan KG, Andrieu S, Bauer J, Breuille D, Cederholm T, Chandler J, De MC, Donini L, Harris T, Kannt A, Keime GF, Onder G, Papanicolaou D, Rolland Y, Rooks D, Sieber C, Souhami E, Verlaan S, Zamboni M (2011) Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia. J Am Med Dir Assoc 12:249–256

    Article  PubMed  Google Scholar 

  • Frisoli A Jr, Chaves PH, Ingham SJ, Fried LP (2010) Severe osteopenia and osteoporosis, sarcopenia, and frailty status in community-dwelling older women: Results from the Women's Health and Aging Study (WHAS) II. Bone 48(4):952–957

    Google Scholar 

  • Fulzele K, Riddle RC, DiGirolamo DJ, Cao X, Wan C, Chen D, Faugere MC, Aja S, Hussain MA, Bruning JC, Clemens TL (2010) Insulin receptor signaling in osteoblasts regulates postnatal bone acquisition and body composition. Cell 142:309–319

    Article  PubMed  CAS  Google Scholar 

  • Gankam KF, Andres C, Sattar L, Melot C, Decaux G (2008) Mild hyponatremia and risk of fracture in the ambulatory elderly. Q J Med 101:583–588

    Article  Google Scholar 

  • Greenberg A, Verbalis JG (2006) Vasopressin receptor antagonists. Kidney Int 189(12):2124–2130

    Google Scholar 

  • Hacker TA, McKiernan SH, Douglas PS, Wanagat J, Aiken JM (2006) Age-related changes in cardiac structure and function in Fischer 344 × Brown Norway hybrid rats. Am J Physiol Heart Circ Physiol 290:H304–H311

    Article  PubMed  CAS  Google Scholar 

  • Hawkins RC (2003) Age and gender as risk factors for hyponatremia and hypernatremia. Clin Chim Acta 337:169–172

    Article  PubMed  CAS  Google Scholar 

  • Hoorn EJ, Rivadeneira F, van Meurs JB, Ziere G, Stricker BH, Hofman A, Pols HA, Zietse R, Uitterlinden AG, Zillikens MC (2011) Mild hyponatremia as a risk factor for fractures: The Rotterdam Study. J Bone Miner Res 26(8):1822–1828

    Google Scholar 

  • Jung EM, Choi KC, Jeung EB (2011) Expression of calbindin-D28k is inversely correlated with proapototic gene expression in hydrogen peroxide-induced cell death in endometrial cancer cells. Int J Oncol 38:1059–1066

    PubMed  CAS  Google Scholar 

  • Kakarla SK, Fannin JC, Keshavarzian S, Katta A, Paturi S, Nalabotu SK, Wu M, Rice KM, Manzoor K, Walker EM Jr, Blough ER (2010) Chronic acetaminophen attenuates age-associated increases in cardiac ROS and apoptosis in the Fischer Brown Norway rat. Basic Res Cardiol 105:535–544

    Article  PubMed  CAS  Google Scholar 

  • Kinsella S, Moran S, Sullivan MO, Molloy MG, Eustace JA (2010) Hyponatremia independent of osteoporosis is associated with fracture occurrence. Clin J Am Soc Nephrol 5:275–280

    Article  PubMed  CAS  Google Scholar 

  • LaMothe JM, Hepple RT, Zernicke RF (2003) Selected contribution: bone adaptation with aging and long-term caloric restriction in Fischer 344 × Brown-Norway F1-hybrid rats. J Appl Physiol 95:1739–1745

    PubMed  Google Scholar 

  • Lee DS, Austin PC, Rouleau JL, Liu PP, Naimark D, Tu JV (2003) Predicting mortality among patients hospitalized for heart failure: derivation and validation of a clinical model. JAMA 290:2581–2587

    Article  PubMed  CAS  Google Scholar 

  • Lin J, Lopez EF, Jin Y, Van RH, Bauch T, Han HC, Lindsey ML (2008) Age-related cardiac muscle sarcopenia: Combining experimental and mathematical modeling to identify mechanisms. Exp Gerontol 43:296–306

    Article  PubMed  CAS  Google Scholar 

  • Manolagas SC (2010) From estrogen-centric to aging and oxidative stress: a revised perspective of the Pathogenesis of osteoporosis. Endocr Rev 31(3):266–300

    Google Scholar 

  • Manolagas SC, Parfitt AM (2010) What old means to bone. Trends Endocrinol Metab 21:369–374

    Article  PubMed  CAS  Google Scholar 

  • Miyazaki T, Ohmoto K, Hirose T, Fujiki H (2010) Chronic hyponatremia impairs memory in rats: effects of vasopressin antagonist tolvaptan. J Endocrinol 206:105–111

    Article  PubMed  CAS  Google Scholar 

  • Nakane M, Fey TA, Dixon DB, Ma J, Brune ME, Li YC, Wu-Wong JR (2006) Differential effects of Vitamin D analogs on bone formation and resorption. J Steroid Biochem Mol Biol 98:72–77

    Article  PubMed  CAS  Google Scholar 

  • Oury F, Sumara G, Sumara O, Ferron M, Chang H, Smith CE, Hermo L, Suarez S, Roth BL, Ducy P, Karsenty G (2011) Endocrine regulation of male fertility by the skeleton. Cell 144:796–809

    Article  PubMed  CAS  Google Scholar 

  • Packer M, Lee WH, Kessler PD, Gottlieb SS, Bernstein JL, Kukin ML (1987) Role of neurohormonal mechanisms in determining survival in patients with severe chronic heart failure. Circulation 75:IV80–IV92

    PubMed  CAS  Google Scholar 

  • Paturi S, Gutta AK, Katta A, Kakarla SK, Arvapalli RK, Gadde MK, Nalabotu SK, Rice KM, Wu M, Blough E (2010) Effects of aging and gender on muscle mass and regulation of Akt-mTOR-p70s6k related signaling in the F344BN rat model. Mech Ageing Dev 131:202–209

    Article  PubMed  CAS  Google Scholar 

  • Perrien DS, Akel NS, Dupont-Versteegden EE, Skinner RA, Siegel ER, Suva LJ, Gaddy D (2007) Aging alters the skeletal response to disuse in the rat. Am J Physiol Regul Integr Comp Physiol 292:R988–R996

    Article  PubMed  CAS  Google Scholar 

  • Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G (2006) Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med 119:71–78

    Article  PubMed  CAS  Google Scholar 

  • Rolland Y, Dupuy C, van KG Abellan, Gillette S, Vellas B (2011) Treatment strategies for sarcopenia and frailty. Med Clin North Am 95:427–438, ix

    Article  PubMed  CAS  Google Scholar 

  • Sampson N, Untergasser G, Plas E, Berger P (2007) The ageing male reproductive tract. J Pathol 211:206–218

    Article  PubMed  CAS  Google Scholar 

  • Sandhu HS, Gilles E, DeVita MV, Panagopoulos G, Michelis MF (2009) Hyponatremia associated with large-bone fracture in elderly patients. Int Urol Nephrol 41:733–737

    Article  PubMed  Google Scholar 

  • Schwartz WB, Bennett W, Curelop S, Bartter FC (1957) A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 23:529–542

    Article  PubMed  CAS  Google Scholar 

  • Simon MR (1984) The rat as an animal model for the study of senile idiopathic osteoporosis. Acta Anat (Basel) 119:248–250

    Article  CAS  Google Scholar 

  • Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 273:59–63

    Article  PubMed  CAS  Google Scholar 

  • Swynghedauw B, Besse S, Assayag P, Carre F, Chevalier B, Charlemagne D, Delcayre C, Hardouin S, Heymes C, Moalic JM (1995) Molecular and cellular biology of the senescent hypertrophied and failing heart. Am J Cardiol 76:2D–7D

    Article  PubMed  CAS  Google Scholar 

  • Terzian C, Frye EB, Piotrowski ZH (1994) Admission hyponatremia in the elderly: factors influencing prognosis. J Gen Intern Med 9:89–91

    Article  PubMed  CAS  Google Scholar 

  • Verbalis JG, Barsony J, Sugimura Y, Tian Y, Adams DJ, Carter EA, Resnick HE (2010) Hyponatremia-induced osteoporosis. J Bone Miner Res 25:554–563

    Article  PubMed  CAS  Google Scholar 

  • Verbalis JG, Drutarosky MD (1988) Adaptation to chronic hypoosmolality in rats. Kidney Int 34:351–360

    Article  PubMed  CAS  Google Scholar 

  • Wahr PA, Michele DE, Metzger JM (2000) Effects of aging on single cardiac myocyte function in Fischer 344 × Brown Norway rats. Am J Physiol Heart Circ Physiol 279:H559–H565

    PubMed  CAS  Google Scholar 

  • Wald R, Jaber BL, Price LL, Upadhyay A, Madias NE (2010) Impact of hospital-associated hyponatremia on selected outcomes. Arch Intern Med 170:294–302

    Article  PubMed  CAS  Google Scholar 

  • Wang C, Leung A, Sinha-Hikim AP (1993) Reproductive aging in the male Brown-Norway rat: a model for the human. Endocrinology 133:2773–2781

    Article  PubMed  CAS  Google Scholar 

  • Wang M, Zhang J, Walker SJ, Dworakowski R, Lakatta EG, Shah AM (2010) Involvement of NADPH oxidase in age-associated cardiac remodeling. J Mol Cell Cardiol 48:765–772

    Article  PubMed  CAS  Google Scholar 

  • Wu X, Itoh N, Taniguchi T, Nakanishi T, Tatsu Y, Yumoto N, Tanaka K (2003) Zinc-induced sodium-dependent vitamin C transporter 2 expression: potent roles in osteoblast differentiation. Arch Biochem Biophys 420:114–120

    Article  PubMed  CAS  Google Scholar 

  • Xiao XH, Liao EY, Zhou HD, Dai RC, Yuan LQ, Wu XP (2005) Ascorbic acid inhibits osteoclastogenesis of RAW264.7 cells induced by receptor activated nuclear factor kappaB ligand (RANKL) in vitro. J Endocrinol Invest 28:253–260

    PubMed  CAS  Google Scholar 

  • Yazama F, Furuta K, Fujimoto M, Sonoda T, Shigetomi H, Horiuchi T, Yamada M, Nagao N, Maeda N (2006) Abnormal spermatogenesis in mice unable to synthesize ascorbic acid. Anat Sci Int 81:115–125

    Article  PubMed  CAS  Google Scholar 

  • Yoshikawa Y, Kode A, Xu L, Mosialou I, Silva BC, Ferron M, Clemens TL, Economides AN, Kousteni S (2011) Genetic evidence points to an osteocalcin-independent influence of osteoblasts on energy metabolism. J Bone Miner Res 26(9):2012–2025

    Google Scholar 

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Acknowledgements

This study was supported by grant R01-AG029477 from the National Institute on Aging. The authors are grateful for imaging technical help to Eva CA Permaul.

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Authors and Affiliations

  1. Division of Endocrinology and Metabolism, Georgetown University, Washington, DC, 20007, USA

    Julia Barsony, Michaele B. Manigrasso, Qin Xu, Helen Tam & Joseph G. Verbalis

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  1. Julia Barsony
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  2. Michaele B. Manigrasso
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  3. Qin Xu
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  4. Helen Tam
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  5. Joseph G. Verbalis
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Correspondence to Julia Barsony or Joseph G. Verbalis.

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Barsony, J., Manigrasso, M.B., Xu, Q. et al. Chronic hyponatremia exacerbates multiple manifestations of senescence in male rats. AGE 35, 271–288 (2013). https://doi.org/10.1007/s11357-011-9347-9

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  • DOI: https://doi.org/10.1007/s11357-011-9347-9

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