Skip to main content

Advertisement

SpringerLink
Log in

Bone is Not Alone: the Effects of Skeletal Muscle Dysfunction in Chronic Kidney Disease

  • Kidney and Bone (SM Moe and IB Salusky, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Chronic kidney disease (CKD) is associated with a decline in muscle mass, strength, and function, collectively called “sarcopenia.” Sarcopenia is associated with hospitalizations and mortality in CKD and is therefore important to understand and characterize. While the focus of skeletal health in CKD has traditionally focused on bone and mineral aberrations, it is now recognized that sarcopenia must also play a role in poor musculoskeletal health in this population. In this paper, we present an overview of skeletal muscle changes in CKD, including defects in skeletal muscle catabolism and anabolism in uremic tissue. There are many gaps in knowledge in this field that should be the focus for future research to unravel pathogenesis and therapies for musculoskeletal health in CKD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007;298(17):2038–47.

    Article  CAS  PubMed  Google Scholar 

  2. Kurella Tamura M, Covinsky KE, Chertow GM, Yaffe K, Landefeld CS, McCulloch CE. Functional status of elderly adults before and after initiation of dialysis. N Engl J Med. 2009;361(16):1539–47.

    Article  PubMed  Google Scholar 

  3. Ulutas O, Farragher J, Chiu E, Cook WL, Jassal SV. Functional disability in older adults maintained on peritoneal dialysis therapy. Perit Dial Int. 2014. doi:10.3747/pdi.2013.00293

  4. Farragher J, Chiu E, Ulutas O, Tomlinson G, Cook WL, Jassal SV. Accidental falls and risk of mortality among older adults on chronic peritoneal dialysis. Clin J Am Soc Nephrol. 2014;9(7):1248–53.

    Article  PubMed  Google Scholar 

  5. Cook WL, Tomlinson G, Donaldson M, et al. Falls and fall-related injuries in older dialysis patients. Clin J Am Soc Nephrol. 2006;1(6):1197–204.

    Article  PubMed  Google Scholar 

  6. Johansen KL, Chertow GM, Jin C, Kutner NG. Significance of frailty among dialysis patients. J Am Soc Nephrol. 2007;18(11):2960–7.

    Article  PubMed  Google Scholar 

  7. Bao Y, Dalrymple L, Chertow GM, Kaysen GA, Johansen KL. Frailty, dialysis initiation, and mortality in end-stage renal disease. Arch Intern Med. 2012;172(14):1071–7. Describes the extent of frailty and its important consequences in dialysis patients.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Mushnick R, Fein PA, Mittman N, Goel N, Chattopadhyay J, Avram MM. Relationship of bioelectrical impedance parameters to nutrition and survival in peritoneal dialysis patients. Kidney Int Suppl. 2003;87:S53–6.

    Article  PubMed  Google Scholar 

  9. de Araujo Antunes A, Vannini FD, de Arruda Silveira LV, Barretti P, Martin LC, Caramori JC. Associations between bioelectrical impedance parameters and cardiovascular events in chronic dialysis patients. Int Urol Nephrol. 2013;45(5):1397–40.

  10. Dam TT, Peters KW, Fragala M, et al. An evidence-based comparison of operational criteria for the presence of sarcopenia. J Gerontol A: Biol Med Sci. 2014;69(5):584–90. Reviews criteria that can be used in practice to define sarcopenia. This article provides a summary of the three major classifications of sarcopenia used worldwide.

    Article  Google Scholar 

  11. Jamal SA, Leiter RE, Jassal V, Hamilton CJ, Bauer DC. Impaired muscle strength is associated with fractures in hemodialysis patients. Osteoporos Int. 2006;17(9):1390–7.

    Article  CAS  PubMed  Google Scholar 

  12. West SL, Jamal SA, Lok CE. Tests of neuromuscular function are associated with fractures in patients with chronic kidney disease. Nephrol Dial Transplant. 2012;27(6):2384–8.

    Article  PubMed  Google Scholar 

  13. Hamrick MW. The skeletal muscle secretome: an emerging player in muscle-bone crosstalk. Bone Key Rep. 2012;1:60. Provides a useful summary of the paracrine and endocrine effects of muscle on bone knowledge of the muscle-bone interaction, including areas requiring further exploration.

    Google Scholar 

  14. Bowser M, Herberg S, Arounleut P, et al. Effects of the activin A-myostatin-follistatin system on aging bone and muscle progenitor cells. Exp Gerontol. 2013;48(2):290–7. Investigated the activin A-myostatin-follistatin system in muscle and bone. They found activin A increased mineralization, and follistatin increased the proliferation of young and old primary myoblasts. While myostatin reduced proliferation in aged muscle and bone primary cells; an effect not seen in young myoblasts. Overall, myostatin is thought to impair muscle and bone progenitor cells from aged mice.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Johansen KL, Kaysen GA, Young BS, Hung AM, da Silva M, Chertow GM. Longitudinal study of nutritional status, body composition, and physical function in hemodialysis patients. Am J Clin Nutr. 2003;77(4):842–6.

    CAS  PubMed  Google Scholar 

  16. Lopes AA, Lantz B, Morgenstern H, et al. Associations of self-reported physical activity types and levels with quality of life, depression symptoms, and mortality in hemodialysis patients: the DOPPS. Clin J Am Soc Nephrol. 2014;9(10):1702–12.

    Article  PubMed  Google Scholar 

  17. Goodpaster BH, Park SW, Harris TB, et al. The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study. J Gerontol A Biol Sci Med Sci. 2006;61(10):1059–64.

    Article  PubMed  Google Scholar 

  18. Hughes VA, Frontera WR, Wood M, et al. Longitudinal muscle strength changes in older adults: influence of muscle mass, physical activity, and health. J Gerontol A: Biol Med Sci. 2001;56(5):B209–17.

    Article  CAS  Google Scholar 

  19. Fouque D, Kalantar-Zadeh K, Kopple J, et al. A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease. Kidney Int. 2008;73(4):391–8.

    Article  CAS  PubMed  Google Scholar 

  20. Studenski SA, Peters KW, Alley DE, et al. The FNIH sarcopenia project: rationale, study description, conference recommendations, and final estimates. J Gerontol A: Biol Med Sci. 2014;69(5):547–58.

    Article  Google Scholar 

  21. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing. 2010;39(4):412–23.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Cesari M, Fielding RA, Pahor M, et al. Biomarkers of sarcopenia in clinical trials—recommendations from the International Working Group on Sarcopenia. J Cachex Sarcopenia Muscle. 2012;3(3):181–90. The cumulative efforts from the International Working Group on Sarcopenia. This report is helpful for those interested in sarcopenia by providing the current consensus definitions of sarcopenia, discussing the importance of muscle performance and quality, chronic disease and sarcopenia biomarkers, and applications in clinical trials and studies.

    Article  Google Scholar 

  23. Roshanravan B, Robinson-Cohen C, Patel KV, et al. Association between physical performance and all-cause mortality in CKD. J Am Soc Nephrol. 2013;24(5):822–30. Investigates the profound consequences of loss of physical performance in CKD patients over time. This study follows patients over a relatively long period of time i.e., 3 years.

    Article  PubMed Central  PubMed  Google Scholar 

  24. AbellanvanKan G, Rolland Y, Andrieu S, et al. Gait speed at usual pace as a predictor of adverse outcomes in community-dwelling older people an International Academy on Nutrition and Aging (IANA) Task Force. J Nutr Health Aging. 2009;13(10):881–9.

    Article  CAS  Google Scholar 

  25. Huang JW, Lien YC, Wu HY, et al. Lean body mass predicts long-term survival in Chinese patients on peritoneal dialysis. PLoS One. 2013;8(1):e54976.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. John SG, Sigrist MK, Taal MW, McIntyre CW. Natural history of skeletal muscle mass changes in chronic kidney disease stage 4 and 5 patients: an observational study. PLoS One. 2013;8(5):e65372.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Han DS, Chen YM, Lin SY, et al. Serum myostatin levels and grip strength in normal subjects and patients on maintenance haemodialysis. Clin Endocrinol (Oxf). 2011;75(6):857–63.

    Article  CAS  Google Scholar 

  28. Turner NJ, Badylak SF. Regeneration of skeletal muscle. Cell Tissue Res. 2012;347(3):759–74.

    Article  PubMed  Google Scholar 

  29. Conboy IM, Conboy MJ, Smythe GM, Rando TA. Notch-mediated restoration of regenerative potential to aged muscle. Science. 2003;302(5650):1575–7.

    Article  CAS  PubMed  Google Scholar 

  30. Nnodim JO. Satellite cell numbers in senile rat levator ani muscle. Mech Ageing Dev. 2000;112(2):99–111.

    Article  CAS  PubMed  Google Scholar 

  31. Zhang L, Wang XH, Wang H, Du J, Mitch WE. Satellite cell dysfunction and impaired IGF-1 signaling cause CKD-induced muscle atrophy. J Am Soc Nephrol. 2010;21(3):419–27.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Serra C, Tangherlini F, Rudy S, et al. Testosterone improves the regeneration of old and young mouse skeletal muscle. J Gerontol A: Biol Med Sci. 2013;68(1):17–26. Investigated if the well-known androgen, testosterone, improves skeletal muscle regeneration. Following cardiotoxin injury to the tibialis anterior in young (2-month-old) and aged (24-month-old) male mice, testosterone increased the number of proliferating satellite cells, and the number and cross-sectional area of regenerating fibers. This study lends to potential benefit of testosterone in skeletal muscle with impaired regeneration.

    Article  CAS  Google Scholar 

  33. Griggs RC, Kingston W, Jozefowicz RF, Herr BE, Forbes G, Halliday D. Effect of testosterone on muscle mass and muscle protein synthesis. J Appl Physiol. 1989;66(1):498–503.

    CAS  PubMed  Google Scholar 

  34. Carrero JJ, Qureshi AR, Nakashima A, et al. Prevalence and clinical implications of testosterone deficiency in men with end-stage renal disease. Nephrol Dial Transplant. 2011;26(1):184–90.

    Article  CAS  PubMed  Google Scholar 

  35. Cigarran S, Pousa M, Castro MJ, et al. Endogenous testosterone, muscle strength, and fat-free mass in men with chronic kidney disease. J Ren Nutr. 2013;23(5):e89–95.

    Article  CAS  PubMed  Google Scholar 

  36. Johansen KL, Mulligan K, Schambelan M. Anabolic effects of nandrolone decanoate in patients receiving dialysis: a randomized controlled trial. JAMA. 1999;281(14):1275–81.

    Article  CAS  PubMed  Google Scholar 

  37. Johansen KL, Painter PL, Sakkas GK, Gordon P, Doyle J, Shubert T. Effects of resistance exercise training and nandrolone decanoate on body composition and muscle function among patients who receive hemodialysis: a randomized, controlled trial. J Am Soc Nephrol. 2006;17(8):2307–14.

    Article  CAS  PubMed  Google Scholar 

  38. Borst SE, Shuster JJ, Zou B, et al. Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta-analysis. BMC Med. 2014;12:211.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Garcia LA, Ferrini MG, Norris KC, Artaza JN. 1,25(OH)(2)vitamin D(3) enhances myogenic differentiation by modulating the expression of key angiogenic growth factors and angiogenic inhibitors in C(2)C(12) skeletal muscle cells. J Steroid Biochem Mol Biol. 2013;133:1–11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Salles J, Chanet A, Giraudet C, et al. 1,25(OH)2-vitamin D3 enhances the stimulating effect of leucine and insulin on protein synthesis rate through Akt/PKB and mTOR mediated pathways in murine C2C12 skeletal myotubes. Mol Nutr Food Res. 2013;57(12):2137–46.

    Article  CAS  PubMed  Google Scholar 

  41. Girgis CM, Clifton-Bligh RJ, Mokbel N, Cheng K, Gunton JE. Vitamin D signaling regulates proliferation, differentiation, and myotube size in C2C12 skeletal muscle cells. Endocrinology. 2014;155(2):347–57.

    Article  CAS  PubMed  Google Scholar 

  42. Bhat M, Kalam R, Qadri SS, Madabushi S, Ismail A. Vitamin D deficiency-induced muscle wasting occurs through the ubiquitin proteasome pathway and is partially corrected by calcium in male rats. Endocrinology. 2013;154(11):4018–29.

    Article  CAS  PubMed  Google Scholar 

  43. Gordon PL, Sakkas GK, Doyle JW, Shubert T, Johansen KL. Relationship between vitamin D and muscle size and strength in patients on hemodialysis. J Ren Nutr. 2007;17(6):397–407.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Taskapan H, Baysal O, Karahan D, Durmus B, Altay Z, Ulutas O. Vitamin D and muscle strength, functional ability and balance in peritoneal dialysis patients with vitamin D deficiency. Clin Nephrol. 2011;76(2):110–6.

    Article  CAS  PubMed  Google Scholar 

  45. Graziani G, Badalamenti S, Del Bo A, et al. Abnormal hemodynamics and elevated angiotensin II plasma levels in polydipsic patients on regular hemodialysis treatment. Kidney Int. 1993;44(1):107–14.

    Article  CAS  PubMed  Google Scholar 

  46. Wray DW, Nishiyama SK, Harris RA, Richardson RS. Angiotensin II in the elderly: impact of angiotensin II type 1 receptor sensitivity on peripheral hemodynamics. Hypertension. 2008;51(6):1611–6.

    Article  CAS  PubMed  Google Scholar 

  47. Danser AH, Koning MM, Admiraal PJ, et al. Production of angiotensins I and II at tissue sites in intact pigs. Am J Physiol. 1992;263(2 Pt 2):H429–37.

    CAS  PubMed  Google Scholar 

  48. Zhang L, Du J, Hu Z, et al. IL-6 and serum amyloid A synergy mediates angiotensin II-induced muscle wasting. J Am Soc Nephrol. 2009;20(3):604–12.

    Article  PubMed Central  PubMed  Google Scholar 

  49. Yoshida T, Galvez S, Tiwari S, et al. Angiotensin II inhibits satellite cell proliferation and prevents skeletal muscle regeneration. J Biol Chem. 2013;288(33):23823–32. Explored if skeletal muscle regeneration is impaired by increased expression of angiotensin II. This is important because angiotensin II is often increased in CKD patients. They found using in vitro and in vivo techniques, that angiotensin does impair regeneration; resulting in a reduced number of regenerating myofibers and decreased expression of myogenic-related factors.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Sanders PM, Russell ST, Tisdale MJ. Angiotensin II directly induces muscle protein catabolism through the ubiquitin-proteasome proteolytic pathway and may play a role in cancer cachexia. Br J Cancer. 2005;93(4):425–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Song YH, Li Y, Du J, Mitch WE, Rosenthal N, Delafontaine P. Muscle-specific expression of IGF-1 blocks angiotensin II-induced skeletal muscle wasting. J Clin Invest. 2005;115(2):451–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Coolican SA, Samuel DS, Ewton DZ, McWade FJ, Florini JR. The mitogenic and myogenic actions of insulin-like growth factors utilize distinct signaling pathways. J Biol Chem. 1997;272(10):6653–62.

    Article  CAS  PubMed  Google Scholar 

  53. Tureckova J, Wilson EM, Cappalonga JL, Rotwein P. Insulin-like growth factor-mediated muscle differentiation: collaboration between phosphatidylinositol 3-kinase-Akt-signaling pathways and myogenin. J Biol Chem. 2001;276(42):39264–70.

    Article  CAS  PubMed  Google Scholar 

  54. Lewis MI, Horvitz GD, Clemmons DR, Fournier M. Role of IGF-I and IGF-binding proteins within diaphragm muscle in modulating the effects of nandrolone. Am J Physiol Endocrinol Metab. 2002;282(2):E483–90.

    Article  CAS  PubMed  Google Scholar 

  55. da Costa JAC, Ikizler TA. Inflammation and insulin resistance as novel mechanisms of wasting in chronic dialysis patients. Semin Dial. 2009;22(6):652–7.

    Article  PubMed  Google Scholar 

  56. Mahan JD, Warady BA, Consensus C. Assessment and treatment of short stature in pediatric patients with chronic kidney disease: a consensus statement. Pediatr Nephrol. 2006;21(7):917–30.

    Article  PubMed  Google Scholar 

  57. Guebre-Egziabher F, Juillard L, Boirie Y, Laville M, Beaufrere B, Fouque D. Short-term administration of a combination of recombinant growth hormone and insulin-like growth factor-I induces anabolism in maintenance hemodialysis. J Clin Endocrinol Metab. 2009;94(7):2299–305.

    Article  CAS  PubMed  Google Scholar 

  58. Hansen TB, Gram J, Jensen PB, et al. Influence of growth hormone on whole body and regional soft tissue composition in adult patients on hemodialysis. A double-blind, randomized, placebo-controlled study. Clin Nephrol. 2000;53(2):99–107.

    CAS  PubMed  Google Scholar 

  59. Siew ED, Pupim LB, Majchrzak KM, Shintani A, Flakoll PJ, Ikizler TA. Insulin resistance is associated with skeletal muscle protein breakdown in non-diabetic chronic hemodialysis patients. Kidney Int. 2007;71(2):146–52.

    Article  CAS  PubMed  Google Scholar 

  60. Sandri M, Sandri C, Gilbert A, et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 2004;117(3):399–412.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Carter ME, Brunet A. FOXO transcription factors. Curr Biol. 2007;17(4):R113–4.

    Article  CAS  PubMed  Google Scholar 

  62. Xu J, Li R, Workeneh B, Dong Y, Wang X, Hu Z. Transcription factor FoxO1, the dominant mediator of muscle wasting in chronic kidney disease, is inhibited by microRNA-486. Kidney Int. 2012;82(4):401–11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Workeneh BT, Rondon-Berrios H, Zhang L, et al. Development of a diagnostic method for detecting increased muscle protein degradation in patients with catabolic conditions. J Am Soc Nephrol. 2006;17(11):3233–9.

    Article  CAS  PubMed  Google Scholar 

  64. Elkina Y, von Haehling S, Anker SD, Springer J. The role of myostatin in muscle wasting: an overview. J Cachex Sarcopenia Muscle. 2011;2(3):143–51.

    Article  Google Scholar 

  65. Garcia PS, Cabbabe A, Kambadur R, Nicholas G, Csete M. Brief-reports: elevated myostatin levels in patients with liver disease: a potential contributor to skeletal muscle wasting. Anesth Analg. 2010;111(3):707–9.

    Article  CAS  PubMed  Google Scholar 

  66. Ju CR, Chen RC. Serum myostatin levels and skeletal muscle wasting in chronic obstructive pulmonary disease. Respir Med. 2012;106(1):102–8.

    Article  PubMed  Google Scholar 

  67. Verzola D, Procopio V, Sofia A, et al. Apoptosis and myostatin mRNA are upregulated in the skeletal muscle of patients with chronic kidney disease. Kidney Int. 2011;79(7):773–82.

    Article  CAS  PubMed  Google Scholar 

  68. Hamrick MW, Arounleut P, Kellum E, Cain M, Immel D, Liang LF. Recombinant myostatin (GDF-8) propeptide enhances the repair and regeneration of both muscle and bone in a model of deep penetrant musculoskeletal injury. J Trauma. 2010;69(3):579–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Attie KM, Borgstein NG, Yang Y, et al. A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers. Muscle Nerve. 2013;47(3):416–23.

    Article  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

KG Avin and RN Moorthi both declare no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Indiana University School of Health and Rehabilitation Sciences, Indianapolis, IN, 46202, USA

    Keith G. Avin

  2. Division of Nephrology, Department of Medicine, Indiana University School of Medicine, 950 W. Walnut St, R2-202, Indianapolis, IN, 46202, USA

    Ranjani N. Moorthi

Authors
  1. Keith G. Avin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ranjani N. Moorthi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ranjani N. Moorthi.

Additional information

This article is part of the Topical Collection on Kidney and Bone

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Avin, K.G., Moorthi, R.N. Bone is Not Alone: the Effects of Skeletal Muscle Dysfunction in Chronic Kidney Disease. Curr Osteoporos Rep 13, 173–179 (2015). https://doi.org/10.1007/s11914-015-0261-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-015-0261-4

Keywords

Search

Navigation