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Association of circulating calciprotein particle levels with skeletal muscle mass and strength in middle-aged and older adults

Hypertension Research volume 45, pages 900–910 (2022)Cite this article

Abstract

Calciprotein particles (CPPs) are tiny mineral–protein aggregates consisting of calcium-phosphate and fetuin-A. Recent studies have suggested that CPPs may contribute to the pathogenesis of chronic inflammation and arteriosclerosis. Reduced skeletal muscle mass and strength reportedly contribute independently to increased serum phosphate levels. This finding suggests that reduced skeletal muscle mass and strength can endogenously induce an increase in circulating CPP levels. Therefore, we investigated the potential association between circulating CPP levels and skeletal muscle mass and strength in middle-aged and older adults. One hundred eighty-two middle-aged and older adults (age, 46–83 years) were included in this cross-sectional study (UMIN000034741). Circulating CPP levels were measured using the gel filtration method. Appendicular skeletal muscle mass was assessed using multifrequency bioelectrical impedance analysis with a tetrapolar eight-point tactile electrode system. The skeletal muscle mass index was calculated from appendicular skeletal muscle mass and height. Handgrip and knee extension strengths were used as measures of skeletal muscle strength. The skeletal muscle mass index was negatively correlated with circulating CPP levels (r = −0.31; P < 0.05). This association remained significant after adjustment for potential covariates (β = −0.34; P < 0.05). In contrast, skeletal muscle strength, represented by handgrip strength and knee extension strength, was not significantly associated with circulating CPP levels. In middle-aged and older adults, a lower skeletal muscle mass index was independently associated with higher circulating CPP levels. The present results suggest that maintaining skeletal muscle mass may prevent an increase in circulating CPP levels.

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References

  1. Lüscher TF. Prevention: some important steps forward, but many unmet needs in a world with cardiovascular disease as the leading cause of death. Eur Heart J. 2016;37:3179–81.

    Article  PubMed  Google Scholar 

  2. Abedin M, Tintut Y, Demer LL. Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol. 2004;24:1161–70.

    Article  CAS  PubMed  Google Scholar 

  3. Rogers MA, Aikawa E. Cardiovascular calcification: artificial intelligence and big data accelerate mechanistic discovery. Nat Rev Cardiol. 2019;16:261–74.

    Article  CAS  PubMed  Google Scholar 

  4. Heiss A, DuChesne A, Denecke B, Grötzinger J, Yamamoto K, Renneé T, et al. Structural basis of calcification inhibition by α2-HS glycoprotein/fetuin-A: formation of colloidal calciprotein particles. J Biol Chem. 2003;278:13333–41. https://doi.org/10.1074/jbc.M210868200.

    Article  CAS  PubMed  Google Scholar 

  5. Hu MC, Shiizaki K, Kuro-o M, Moe OW. Fibroblast growth factor 23 and Klotho: physiology and pathophysiology of an Endocrine Network of Mineral Metabolism. Annu Rev Physiol. 2013;75:503–33. https://doi.org/10.1146/annurev-physiol-030212-183727.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kuro-o M. The Klotho proteins in health and disease. Nat Rev Nephrol. 2019;15:27–44. https://doi.org/10.1038/s41581-018-0078-3.

    Article  CAS  PubMed  Google Scholar 

  7. Kuro-O M. Phosphate as a pathogen of arteriosclerosis and aging. J Atheroscler Thromb. 2021;28:203–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hamano T, Matsui I, Mikami S, Tomida K, Fujii N, Imai E, et al. Fetuin-mineral complex reflects extraosseous calcification stress in CKD. J Am Soc Nephrol. 2010;21:1998–2007. https://doi.org/10.1681/ASN.2009090944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Smith ER, Ford ML, Tomlinson LA, Rajkumar C, McMahon LP, Holt SG. Phosphorylated fetuin-A-containing calciprotein particles are associated with aortic stiffness and a procalcific milieu in patients with pre-dialysis CKD. Nephrol Dial Transplant. 2012;27:1957–66. https://doi.org/10.1093/ndt/gfr609.

    Article  CAS  PubMed  Google Scholar 

  10. Smith ER, Cai MM, McMahon LP, Pedagogos E, Toussaint ND, Brumby C, et al. Serum fetuin-A concentration and fetuin-A-containing calciprotein particles in patients with chronic inflammatory disease and renal failure. Nephrology. 2013;18:215–21. https://doi.org/10.1111/nep.12021.

    Article  CAS  PubMed  Google Scholar 

  11. Miura Y, Iwazu Y, Shiizaki K, Akimoto T, Kotani K, Kurabayashi M, et al. Identification and quantification of plasma calciprotein particles with distinct physical properties in patients with chronic kidney disease. Sci Rep. 2018;8:1256 https://doi.org/10.1038/s41598-018-19677-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chen YY, Kao TW, Chou CW, Wu CJ, Yang HF, Lai CH, et al. Exploring the link between serum phosphate levels and low muscle strength, dynapenia, and sarcopenia. Sci Rep. 2018;8:3573. https://doi.org/10.1038/s41598-018-21784-1.

  13. Mastorakos G, Valsamakis G, Paltoglou G, Creatsas G. Management of obesity in menopause: diet, exercise, pharmacotherapy and bariatric surgery. Maturitas. 2010;65:219–24.

    Article  CAS  PubMed  Google Scholar 

  14. Zaydun G, Tomiyama H, Hashimoto H, Arai T, Koji Y, Yambe M, et al. Menopause is an independent factor augmenting the age-related increase in arterial stiffness in the early postmenopausal phase. Atherosclerosis. 2006;184:137–42. https://doi.org/10.1016/j.atherosclerosis.2005.03.043.

    Article  CAS  PubMed  Google Scholar 

  15. Enomoto M, Adachi H, Fukami A, Kumagai E, Nakamura S, Nohara Y, et al. A useful tool as a medical checkup in a general population—bioelectrical impedance analysis. Front Cardiovasc Med. 2017;4:3. https://doi.org/10.3389/fcvm.2017.00003.

  16. Lee SY, Ahn S, Kim YJ, Ji MJ, Kim KM, Choi SH, et al. Comparison between dual-energy x-ray absorptiometry and bioelectrical impedance analyses for accuracy in measuring whole body muscle mass and appendicular skeletal muscle mass. Nutrients. 2018;10:738. https://doi.org/10.3390/nu10060738.

  17. Kim KM, Jang HC, Lim S. Differences among skeletal muscle mass indices derived from height-, weight-, and body mass index-adjusted models in assessing sarcopenia. Korean J Intern Med. 2016;31:643–50.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Kamide N, Kamiya R, Nakazono T, Ando M. Reference values for hand grip strength in Japanese community-dwelling elderly: a meta-analysis. Environ Health Prev Med. 2015;20:441–6. https://doi.org/10.1007/s12199-015-0485-z.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Suzuki M, Yamada S, Inamura A, Omori Y, Kirimoto H, Sugimura S, et al. Reliability and validity of measurements of knee extension strength obtained from nursing home residents with dementia. Am J Phys Med Rehabil. 2009;88:924–33. https://doi.org/10.1097/PHM.0b013e3181ae1003.

    Article  PubMed  Google Scholar 

  20. Hiraki K, Yasuda T, Hotta C, Izawa KP, Morio Y, Watanabe S, et al. Decreased physical function in pre-dialysis patients with chronic kidney disease. Clin Exp Nephrol. 2013;17:225–31. https://doi.org/10.1007/s10157-012-0681-8.

    Article  CAS  PubMed  Google Scholar 

  21. Katoh M, Yamasaki H. Comparison of reliability of isometric leg muscle strength measurements made using a hand-held dynamometer with and without a restraining belt. J Phys Ther Sci. 2009;21:37–42. https://doi.org/10.1589/jpts.21.37.

    Article  Google Scholar 

  22. Horio M, Imai E, Yasuda Y, Watanabe T, Matsuo S. GFR estimation using standardized serum cystatin C in Japan. Am J Kidney Dis. 2013;61:197–203. https://doi.org/10.1053/j.ajkd.2012.07.007.

    Article  CAS  PubMed  Google Scholar 

  23. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92. https://doi.org/10.1053/j.ajkd.2008.12.034.

    Article  CAS  PubMed  Google Scholar 

  24. Horio M, Imai E, Yasuda Y, Watanabe T, Matsuo S. Performance of GFR equations in Japanese subjects. Clin Exp Nephrol. 2013;17:352–8. https://doi.org/10.1007/s10157-012-0704-5.

    Article  CAS  PubMed  Google Scholar 

  25. Araki E, Goto A, Kondo T, Noda M, Noto H, Origasa H, et al. Japanese Clinical Practice Guideline for Diabetes 2019. Diabetol Int. 2020;11:165–223. https://doi.org/10.1007/s13340-020-00439-5.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Umemura S, Arima H, Arima S, Asayama K, Dohi Y, Hirooka Y, et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019). Hypertens Res. 2019;42:1235–481. https://doi.org/10.1038/S41440-019-0284-9.

    Article  PubMed  Google Scholar 

  27. Rogerson PA. Statistical Methods for Geography. SAGE Publ Ltd; Thousand Oaks, CA, USA. 2001.

  28. Kim KM, Lim S, Oh TJ, Moon JH, Choi SH, Lim JY, et al. Longitudinal changes in muscle mass and strength, and bone mass in older adults: gender-specific associations between muscle and bone losses. J Gerontol Ser A Biol Sci Med Sci. 2018;73:1062–9. https://doi.org/10.1093/gerona/glx188.

    Article  CAS  Google Scholar 

  29. Anagnostis P, Gkekas NK, Achilla C, Pananastasiou G, Taouxidou P, Mitsiou M, et al. Type 2 diabetes mellitus is associated with increased risk of sarcopenia: a systematic review and meta-analysis. Calcif Tissue Int. 2020;107:453–63.

    Article  CAS  PubMed  Google Scholar 

  30. Bai T, Fang F, Li F, Ren Y, Hu J, Cao J. Sarcopenia is associated with hypertension in older adults: a systematic review and meta-analysis. BMC Geriatr. 2020;20:279. https://doi.org/10.1186/s12877-020-01672-y.

  31. Gatate Y, Nakano S, Mizuno Y, Muramatsu T, Senbonmatsu T, Nishimura S, et al. Mid-term predictive value of calciprotein particles in maintenance hemodialysis patients based on a gel-filtration assay. Atherosclerosis. 2020;303:46–52. https://doi.org/10.1016/j.atherosclerosis.2020.03.016.

  32. Suzuki Y, Mitsushima S, Kato A, Yamaguchi T, Ichihara S. High-phosphorus/zinc-free diet aggravates hypertension and cardiac dysfunction in a rat model of the metabolic syndrome. Cardiovasc Pathol. 2014;23:43–49. https://doi.org/10.1016/j.carpath.2013.06.004.

    Article  CAS  PubMed  Google Scholar 

  33. Bozic M, Panizo S, Sevilla MA, Riera M, Soler MJ, Pascual J, et al. High phosphate diet increases arterial blood pressure via a parathyroid hormone mediated increase of renin. J Hypertens. 2014;32:1822–32. https://doi.org/10.1097/HJH.0000000000000261.

    Article  CAS  PubMed  Google Scholar 

  34. Mohammad J, Scanni R, Bestmann L, Hulter HN, Krapf R. A controlled increase in dietary phosphate elevates BP in healthy human subjects. J Am Soc Nephrol. 2018;29:2089–98. https://doi.org/10.1681/ASN.2017121254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kuro-o M. Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism. Nat Rev Nephrol. 2013;9:650–60. https://doi.org/10.1038/nrneph.2013.111.

    Article  CAS  PubMed  Google Scholar 

  36. Gruber M, Greisen P, Junker CM, Hélix-Nielsen C. Phosphorus binding sites in proteins: structural preorganization and coordination. J Phys Chem B. 2014;118:1207–15. https://doi.org/10.1021/jp408689x.

    Article  CAS  PubMed  Google Scholar 

  37. Westheimer FH. Why nature chose phosphates. Science. 1987;235:1173–8. https://doi.org/10.1126/science.2434996.

    Article  CAS  PubMed  Google Scholar 

  38. Morley JE, Anker SD, von Haehling S. Prevalence, incidence, and clinical impact of sarcopenia: facts, numbers, and epidemiology—update 2014. J Cachexia Sarcopenia Muscle. 2014;5:253–9.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Walston JD. Sarcopenia in older adults. Curr Opin Rheumatol. 2012;24:623–7. https://doi.org/10.1097/BOR.0b013e328358d59b

    Article  PubMed  PubMed Central  Google Scholar 

  40. Doherty TJ. Invited review: aging and sarcopenia. J Appl Physiol. 2003;95:1717–27.

    Article  CAS  PubMed  Google Scholar 

  41. Goodpaster BH, Park SW, Harris TB, Kritchevsky SB, Nevitt M, Schwartz AV, et al. The loss of skeletal muscle strength, mass, and quality in older adults: The Health, Aging and Body Composition Study. J Gerontol Ser A Biol Sci Med Sci. 2006;61:1059–64. https://doi.org/10.1093/gerona/61.10.1059.

    Article  Google Scholar 

  42. Tonelli M, Sacks F, Pfeffer M, Gao Z, Curhan G. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation. 2005;112:2627–33. https://doi.org/10.1161/CIRCULATIONAHA.105.553198.

    Article  CAS  PubMed  Google Scholar 

  43. Narang R, Ridout D, Nonis C, Kooner JS. Serum calcium, phosphorus and albumin levels in relation to the angiographic severity of coronary artery disease. Int J Cardiol. 1997;60:73–79. https://doi.org/10.1016/S0167-5273(97)02971-9.

    Article  CAS  PubMed  Google Scholar 

  44. Peri-Okonny P, Baskin KK, Iwamoto G, Mitchell JH, Smith SA, Kim HK, et al. High-phosphate diet induces exercise intolerance and impairs fatty acid metabolism in mice. Circulation. 2019;139:1422–34. https://doi.org/10.1161/CIRCULATIONAHA.118.037550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Schaap LA, Pluijm SMF, Deeg DJH, Visser M. Inflammatory markers and loss of muscle mass (Sarcopenia) and strength. Am J Med. 2006;119:526.e9–17. https://doi.org/10.1016/j.amjmed.2005.10.049.

  46. Navarro-González JF, Mora-Fernández C, Muros M, Herrera H, García J. Mineral metabolism and inflammation in chronic kidney disease patients: a cross-sectional study. Clin J Am Soc Nephrol. 2009;4:1646–54. https://doi.org/10.2215/CJN.02420409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Li X, Moody MR, Engel D, Walker S, Clubb FJ, Sivasubramanian N, et al. Cardiac-specific overexpression of tumor necrosis factor-α causes oxidative stress and contractile dysfunction in mouse diaphragm. Circulation. 2000;102:1690–6. https://doi.org/10.1161/01.CIR.102.14.1690.

    Article  CAS  PubMed  Google Scholar 

  48. Hughes VA, Frontera WR, Wood M, Evans WJ, Dallal GE, Roubenoff R, et al. Longitudinal muscle strength changes in older adults: Influence of muscle mass, physical activity, and health. J Gerontol Ser A Biol Sci Med Sci. 2001;56:209–17. https://doi.org/10.1093/gerona/56.5.B209.

    Article  Google Scholar 

  49. Karlsson MK, Obrant KJ, Nilsson BE, Johnell O. Changes in bone mineral, lean body mass and fat content as measured by dual energy X-ray absorptiometry: a longitudinal study. Calcif Tissue Int. 2000;66:97–99. https://doi.org/10.1007/s002230010020.

    Article  CAS  PubMed  Google Scholar 

  50. Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ. Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev. 1999;107:123–36. https://doi.org/10.1016/S0047-6374(98)00130-4.

    Article  CAS  PubMed  Google Scholar 

  51. Waters DL, Yau CL, Montoya GD, Baumgartner RN. Serum sex hormones, IGF-1, and IGFBP3 exert a sexually dimorphic effect on lean body mass in aging. J Gerontol Ser A Biol Sci Med Sci. 2003;58:648–52. https://doi.org/10.1093/gerona/58.7.m648.

    Article  Google Scholar 

  52. Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996;335:1–7. https://doi.org/10.1056/NEJM199607043350101.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank all participants in the study. We also thank our (SM’s) laboratory members and Michiru Hotta at the University of Tsukuba for their technical assistance.

Funding

This work was supported in part by a Grant-in-Aid for Scientific Research KAKENHI from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (19H03995) and MEXT Leading Initiative for Excellent Young Researchers Grant Number JPMXS0320200234. MY and MM were recipients of a Grant-in-Aid for Research Fellowships of Japan Society for the Promotion of Science for Young Scientists (21J10316, 20J20892).

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Authors and Affiliations

  1. Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8574, Japan

    Masaki Yoshioka, Masahiro Matsui & Naoya Okabe

  2. Japan Society for the Promotion of Science, 5-3-1 Kouzimachi, Chiyoda-ku, Tokyo, 102-8472, Japan

    Masaki Yoshioka & Masahiro Matsui

  3. Faculty of Health and Sport Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8574, Japan

    Keisei Kosaki & Seiji Maeda

  4. Department of Nephrology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8574, Japan

    Chie Saito & Kunihiro Yamagata

  5. R&D Center for Smart Wellness City Policies, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8574, Japan

    Kunihiro Yamagata

  6. Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan

    Makoto Kuro-O

  7. Faculty of Sport Sciences, Waseda University, 2-579-15 Tokorozawa, Saitama, 359-1192, Japan

    Seiji Maeda

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  1. Masaki Yoshioka
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Yoshioka, M., Kosaki, K., Matsui, M. et al. Association of circulating calciprotein particle levels with skeletal muscle mass and strength in middle-aged and older adults. Hypertens Res 45, 900–910 (2022). https://doi.org/10.1038/s41440-022-00870-y

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