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Pathophysiological mechanisms leading to muscle loss in chronic kidney disease

Nature Reviews Nephrology volume 18, pages 138–152 (2022)Cite this article

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Abstract

Loss of muscle proteins is a deleterious consequence of chronic kidney disease (CKD) that causes a decrease in muscle strength and function, and can lead to a reduction in quality of life and increased risk of morbidity and mortality. The effectiveness of current treatment strategies in preventing or reversing muscle protein losses is limited. The limitations largely stem from the systemic nature of diseases such as CKD, which stimulate skeletal muscle protein degradation pathways while simultaneously activating mechanisms that impair muscle protein synthesis and repair. Stimuli that initiate muscle protein loss include metabolic acidosis, insulin and IGF1 resistance, changes in hormones, cytokines, inflammatory processes and decreased appetite. A growing body of evidence suggests that signalling molecules secreted from muscle can enter the circulation and subsequently interact with recipient organs, including the kidneys, while conversely, pathological events in the kidney can adversely influence protein metabolism in skeletal muscle, demonstrating the existence of crosstalk between kidney and muscle. Together, these signals, whether direct or indirect, induce changes in the levels of regulatory and effector proteins via alterations in mRNAs, microRNAs and chromatin epigenetic responses. Advances in our understanding of the signals and processes that mediate muscle loss in CKD and other muscle wasting conditions will support the future development of therapeutic strategies to reduce muscle loss.

Key points

  • Loss of muscle mass in patients with chronic kidney disease (CKD) leads to frailty and is associated with reduced quality of life and increased risks of morbidity and mortality.

  • In healthy individuals, muscle mass is maintained by a balance of processes — including protein synthesis, protein degradation, energy production and utilization — that support muscle growth and turnover.

  • In patients with CKD and other wasting conditions, pathophysiological changes at the cellular and organ system levels disrupt muscle proteostasis and cellular bioenergetics processes, suppress muscle repair and protein synthesis pathways, and increase protein degradation.

  • To date, efforts to develop effective treatments that counter the pathophysiological changes in CKD and ameliorate loss of muscle mass and function have met with limited success.

  • Skeletal muscles can secrete a variety of signalling molecules that circulate and interact with recipient organs, including the kidneys; conversely, pathological events in the kidney can adversely influence protein metabolism in skeletal muscle, highlighting the importance of crosstalk between kidney and muscle.

  • Emerging therapies, including microRNA therapeutics and approaches to target specific pathways involved in kidney–muscle crosstalk, have potential to induce positive changes in muscle cell signalling to maintain muscle homeostasis while simultaneously improving kidney bioenergetics and kidney function.

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Fig. 1: Mechanisms of muscle protein loss.
Fig. 2: Key processes for healthy muscle maintenance and muscle protein loss in CKD.
Fig. 3: Pathophysiological signals collapse proteostasis and induce muscle protein loss.
Fig. 4: Bidirectional communication regulates muscle proteostasis and kidney pathology via muscle–kidney crosstalk.

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References

  1. Janssen, I., Heymsfield, S. B., Wang, Z. M. & Ross, R. Skeletal muscle mass and distribution in 468 men and women aged 18-88 yr. J. Appl. Physiol. 89, 81–88 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Griffiths, R. D. Muscle mass, survival, and the elderly ICU patient. Nutrition 12, 456–458 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Mitch, W. E. & Goldberg, A. L. Mechanisms of muscle wasting. The role of the ubiquitin-proteasome pathway. N. Engl. J. Med. 335, 1897–1905 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Hanna, R. M., Ghobry, L., Wassef, O., Rhee, C. M. & Kalantar-Zadeh, K. A practical approach to nutrition, protein-energy wasting, sarcopenia, and cachexia in patients with chronic kidney disease. Blood Purif. 49, 202–211 (2020).

    Article  CAS  PubMed  Google Scholar 

  5. Moorthi, R. N. & Avin, K. G. Clinical relevance of sarcopenia in chronic kidney disease. Curr. Opin. Nephrol. Hyperten. 26, 219–228 (2017).

    Article  Google Scholar 

  6. Go, A. S., Chertow, G. M., Fan, D., McCulloch, C. E. & Hsu, C. Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med. 351, 1296–1305 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Sabatino, A., Cuppari, L., Stenvinkel, P., Lindholm, B. & Avesani, C. M. Sarcopenia in chronic kidney disease: what have we learned so far? J. Nephrol. 34, 1347–1372 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Lowrie, E. G. & Lew, N. L. Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am. J. Kidney Dis. 15, 458–482 (1990).

    Article  CAS  PubMed  Google Scholar 

  9. Carrero, J. J. et al. Global prevalence of protein-energy wasting in kidney disease: a meta-analysis of contemporary observational studies from the International Society of Renal Nutrition and Metabolism. J. Ren. Nutr. 28, 380–392 (2018).

    Article  PubMed  Google Scholar 

  10. Kim, J. C., Kalantar-Zadeh, K. & Kopple, J. D. Frailty and protein-energy wasting in elderly patients with end stage kidney disease. J. Am. Soc. Nephrol. 24, 337–351 (2013).

    Article  PubMed  Google Scholar 

  11. Zelle, D. M. et al. Low physical activity and risk of cardiovascular and all-cause mortality in renal transplant recipients. Clin. J. Am. Soc. Nephrol. 6, 898–905 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Tentori, F. et al. Physical exercise among participants in the Dialysis Outcomes and Practice Patterns Study (DOPPS): correlates and associated outcomes. Nephrol. Dial. Transpl. 25, 3050–3062 (2010).

    Article  Google Scholar 

  13. Kovesdy, C. P. & Kalantar-Zadeh, K. Why is protein-energy wasting associated with mortality in chronic kidney disease? Sem. Nephrol. 29, 3–14 (2009).

    Article  CAS  Google Scholar 

  14. Bailey, J. L. et al. The acidosis of chronic renal failure activates muscle proteolysis in rats by augmenting transcription of genes encoding proteins of the ATP-dependent ubiquitin-proteasome pathway. J. Clin. Invest. 97, 1447–1453 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Stenvinkel, P., Carrero, J. J., von Walden, F., Ikizler, T. A. & Nader, G. A. Muscle wasting in end-stage renal disease promulgates premature death: established, emerging and potential novel treatment strategies. Nephrol. Dial. Transpl. 31, 1070–1077 (2016).

    Article  Google Scholar 

  16. Ikizler, T. A. et al. KDOQI clinical practice guideline for nutrition in CKD: 2020 update. Am. J. Kidney Dis. 76, S1–S107 (2020).

    Article  CAS  PubMed  Google Scholar 

  17. Kim, I. Y., Suh, S. H., Lee, I. K. & Wolfe, R. R. Applications of stable, nonradioactive isotope tracers in in vivo human metabolic research. Exp. Mol. Med. 48, e203 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Clark, A. S. & Mitch, W. E. Comparison of protein synthesis and degradation in incubated and perfused muscle. Biochem. J. 212, 649–653 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang, X. H., Du, J., Klein, J. D., Bailey, J. L. & Mitch, W. E. Exercise ameliorates chronic kidney disease-induced defects in muscle protein metabolism and progenitor cell function. Kidney Int. 76, 751–759 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Chen, C. F., You, Z. H., Yang, W. C. & Lin, C. C. Hypokalaemic paralysis with seemingly pH-neutralized blood gas: liquorice-induced mineralocorticoid effect superimposed on renal tubular acidosis. Acta Clin. Belg. 66, 403 (2011).

    CAS  PubMed  Google Scholar 

  21. Deger, S. M. et al. Systemic inflammation is associated with exaggerated skeletal muscle protein catabolism in maintenance hemodialysis patients. JCI Insight 2, e95185 (2017).

    Article  PubMed Central  Google Scholar 

  22. Garibotto, G. et al. Insulin sensitivity of muscle protein metabolism is altered in patients with chronic kidney disease and metabolic acidosis. Kidney Int. 88, 1419–1426 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Adey, D., Kumar, R., McCarthy, J. T. & Nair, K. S. Reduced synthesis of muscle proteins in chronic renal failure. Am. J. Physiol. Endocrinol. Metab. 278, E219–E225 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Raj, D. S. et al. Coordinated increase in albumin, fibrinogen, and muscle protein synthesis during hemodialysis: role of cytokines. Am. J. Physiol. Endocrinol. Metab. 286, E658–E664 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. van Vliet, S. et al. Dysregulated handling of dietary protein and muscle protein synthesis after mixed-meal ingestion in maintenance hemodialysis patients. Kidney Int. Rep. 3, 1403–1415 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Dumont, N. A., Bentzinger, C. F., Sincennes, M. C. & Rudnicki, M. A. Satellite cells and skeletal muscle regeneration. Comp. Physiol. 5, 1027–1059 (2015).

    Article  Google Scholar 

  27. May, R. C., Kelly, R. A. & Mitch, W. E. Mechanisms for defects in muscle protein metabolism in rats with chronic uremia. Influence of metabolic acidosis. J. Clin. Invest. 79, 1099–1103 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lecker, S. H. et al. Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J. 18, 39–51 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Du, J., Mitch, W. E., Wang, X. & Price, S. R. Glucocorticoids induce proteasome C3 subunit expression in L6 muscle cells by opposing the suppression of its transcription by NF-κB. J. Biol. Chem. 275, 19661–19666 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Meyer-Schwesinger, C. The ubiquitin-proteasome system in kidney physiology and disease. Nat. Rev. Nephrol. 15, 393–411 (2019).

    Article  PubMed  Google Scholar 

  31. Lokireddy, S. et al. Identification of atrogin-1-targeted proteins during the myostatin-induced skeletal muscle wasting. Am. J. Physiol. Cell Physiol. 303, C512–C529 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Cohen, S. et al. During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation. J. Cell Biol. 185, 1083–1095 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li, H. H. et al. Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex. J. Clin. Invest. 114, 1058–1071 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rom, O., Kaisari, S., Reznick, A. Z. & Aizenbud, D. in Oxidative Stress and Cardiorespiratory Function (ed. Pokorski M.) 1–8 (Springer, 2014).

  35. Cohen, S., Zhai, B., Gygi, S. P. & Goldberg, A. L. Ubiquitylation by Trim32 causes coupled loss of desmin, Z-bands, and thin filaments in muscle atrophy. J. Cell Biol. 198, 575–589 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Schwerk, C. & Schulze-Osthoff, K. Non-apoptotic functions of caspases in cellular proliferation and differentiation. Biochem. Pharmacol. 66, 1453–1458 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Schwartz, L. M. Skeletal muscles do not undergo apoptosis during either atrophy or programmed cell death–revisiting the myonuclear domain hypothesis. Front. Physiol. 9, 1887 (2018).

    Article  PubMed  Google Scholar 

  38. Du, J. et al. Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions. J. Clin. Invest. 113, 115–123 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang, X. H. et al. Caspase-3 cleaves specific 19 S proteasome subunits in skeletal muscle stimulating proteasome activity. J. Biol. Chem. 285, 21249–21257 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Workeneh, B. T. et al. Development of a diagnostic method for detecting increased muscle protein degradation in patients with catabolic conditions. J. Am. Soc. Nephrol. 17, 3233–3239 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Hu, J. et al. XIAP reduces muscle proteolysis induced by CKD. J. Am. Soc. Nephrol. 21, 1174–1183 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Su, Z. et al. Chronic kidney disease induces autophagy leading to dysfunction of mitochondria in skeletal muscle. Am. J. Physiol. Ren. Physiol. 312, F1128–F1140 (2017).

    Article  CAS  Google Scholar 

  43. Morel, E. et al. Autophagy: a druggable process. Ann. Rev. Pharmacol. Toxicol. 57, 375–398 (2017).

    Article  CAS  Google Scholar 

  44. Levine, B. & Kroemer, G. Biological functions of autophagy genes: a disease perspective. Cell 176, 11–42 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hariharan, N. et al. Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes. Circ. Res. 107, 1470–1482 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jang, M. et al. AMPK contributes to autophagosome maturation and lysosomal fusion. Sci. Rep. 8, 12637 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Corona Velazquez, A. F. & Jackson, W. T. So many roads: the multifaceted regulation of autophagy induction. Mol. Cell Biol. 38, e00303–e00318 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang, Y. Y. et al. CKD autophagy activation and skeletal muscle atrophy–a preliminary study of mitophagy and inflammation. Eur. J. Clin. Nutr. 73, 950–960 (2019).

    Article  CAS  PubMed  Google Scholar 

  49. Gunta, S. S. & Mak, R. H. Ghrelin and leptin pathophysiology in chronic kidney disease. Pediatr. Nephrol. 28, 611–616 (2013).

    Article  PubMed  Google Scholar 

  50. Bailey, J. L., Zheng, B., Hu, Z., Price, S. R. & Mitch, W. E. Chronic kidney disease causes defects in signaling through the insulin receptor substrate/phosphatidylinositol 3-kinase/Akt pathway: implications for muscle atrophy. J. Am. Soc. Nephrol. 17, 1388–1394 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Holz, M. K., Ballif, B. A., Gygi, S. P. & Blenis, J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 123, 569–580 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Hodson, N., West, D. W. D., Philp, A., Burd, N. A. & Moore, D. R. Molecular regulation of human skeletal muscle protein synthesis in response to exercise and nutrients: a compass for overcoming age-related anabolic resistance. Am. Physiol. Cell Physiol. 317, C1061–C1078 (2019).

    Article  CAS  Google Scholar 

  54. Bodine, S. C. et al. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294, 1704–1708 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Gomes, M. D., Lecker, S. H., Jagoe, R. T., Navon, A. & Goldberg, A. L. Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc. Natl Acad. Sci. USA 98, 14440–14445 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. O’Neill, B. T. et al. FoxO transcription factors are critical regulators of diabetes-related muscle atrophy. Diabetes 68, 556–570 (2019).

    Article  PubMed  Google Scholar 

  57. von Walden, F. Ribosome biogenesis in skeletal muscle: coordination of transcription and translation. J. Appl. Physiol. 127, 591–598 (2019).

    Article  Google Scholar 

  58. Romanello, V. & Sandri, M. The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass. Cell. Mol. Life Sci. 78, 1305–1328 (2021).

    Article  CAS  PubMed  Google Scholar 

  59. Gao, Y., Ordas, R., Klein, J. D. & Price, S. R. Regulation of caspase-3 activity by insulin in skeletal muscle cells involves both PI3-kinase and MEK-1/2. J. Appl. Physiol. 105, 1772–1778 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Carrero, J. J. et al. Etiology of the protein-energy wasting syndrome in chronic kidney disease: a consensus statement from the International Society of Renal Nutrition and Metabolism (ISRNM). J. Ren. Nutr. 23, 77–90 (2013).

    Article  PubMed  Google Scholar 

  61. de Brito-Ashurst, I., Varagunam, M., Raftery, M. J. & Yaqoob, M. M. Bicarbonate supplementation slows progression of CKD and improves nutritional status. J. Am. Soc. Nephrol. 20, 2075–2084 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Hu, Z., Wang, H., Lee, I. H., Du, J. & Mitch, W. E. Endogenous glucocorticoids and impaired insulin signaling are both required to stimulate muscle wasting under pathophysiological conditions in mice. J. Clin. Invest. 119, 3059–3069 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Graham, K. A., Reaich, D., Channon, S. M., Downie, S. & Goodship, T. H. Correction of acidosis in hemodialysis decreases whole-body protein degradation. J. Am. Soc. Nephrol. 8, 632–637 (1997).

    Article  CAS  PubMed  Google Scholar 

  64. Reaich, D. et al. Correction of acidosis in humans with CRF decreases protein degradation and amino acid oxidation. Am. J. Physiol. 265, E230–E235 (1993).

    CAS  PubMed  Google Scholar 

  65. Kraut, J. A. & Madias, N. E. Adverse deffects of the metabolic acidosis of chronic kidney disease. Adv. Chronic Kidney Dis. 24, 289–297 (2017).

    Article  PubMed  Google Scholar 

  66. Franch, H. A. et al. Acidosis impairs insulin receptor substrate-1-associated phosphoinositide 3-kinase signaling in muscle cells: consequences on proteolysis. Am. J. Physiol. Ren. Physiol. 287, F700–F706 (2004).

    Article  CAS  Google Scholar 

  67. Mitch, W. E. et al. Metabolic acidosis stimulates muscle protein degradation by activating the adenosine triphosphate-dependent pathway involving ubiquitin and proteasomes. J. Clin. Invest. 93, 2127–2133 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Isozaki, U., Mitch, W. E., England, B. K. & Price, S. R. Protein degradation and increased mRNAs encoding proteins of the ubiquitin-proteasome proteolytic pathway in BC3H1 myocytes require an interaction between glucocorticoids and acidification. Proc. Natl Acad. Sci. USA 93, 1967–1971 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. May, R. C., Kelly, R. A. & Mitch, W. E. Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism. J. Clin. Invest. 77, 614–621 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Price, S. R., England, B. K., Bailey, J. L., Van Vreede, K. & Mitch, W. E. Acidosis and glucocorticoids concomitantly increase ubiquitin and proteasome subunit mRNAs in rat muscle. Am. J. Physiol. Cell Physiol. 267, C955–C960 (1994).

    Article  CAS  Google Scholar 

  71. Garibotto, G. et al. Skeletal muscle protein synthesis and degradation in patients with chronic renal failure. Kidney Int. 45, 1432–1439 (1994).

    Article  CAS  PubMed  Google Scholar 

  72. Wing, S. S. & Goldberg, A. L. Glucocorticoids activate the ATP-ubiquitin-dependent proteolytic system in skeletal muscle during fasting. Am. J. Physiol. Endocrinol. Metab. 264, E668–E676 (1993).

    Article  CAS  Google Scholar 

  73. Mihai, S. et al. Inflammation-related mechanisms in chronic kidney disease prediction, progression, and outcome. J. Immunol. Res. 2018, 2180373 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Tidball, J. G. & Villalta, S. A. Regulatory interactions between muscle and the immune system during muscle regeneration. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R1173–R1187 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Collins, R. A. & Grounds, M. D. The role of tumor necrosis factor-alpha (TNF-α) in skeletal muscle regeneration. Studies in TNF-α(-/-) and TNF-α(-/-)/LT-α(-/-) mice. J. Histochem. Cytochem. 49, 989–1001 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Hu, L. et al. Low-frequency electrical stimulation attenuates muscle atrophy in CKD–a potential treatment strategy. J. Am. Soc. Nephrol. 26, 626–635 (2015).

    Article  CAS  PubMed  Google Scholar 

  77. Zhang, C. et al. Interleukin-6/signal transducer and activator of transcription 3 (STAT3) pathway is essential for macrophage infiltration and myoblast proliferation during muscle regeneration. J. Biol. Chem. 288, 1489–1499 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Raj, D. S. et al. Interleukin-6 modulates hepatic and muscle protein synthesis during hemodialysis. Kidney Int. 73, 1054–1061 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Thoma, A. & Lightfoot, A. P. in Muscle Atrophy (ed. Xiao J.) 267–279 (Springer, 2018).

  80. Zhang, L. et al. IL-6 and serum amyloid A synergy mediates angiotensin II-induced muscle wasting. J. Am. Soc. Nephrol. 20, 604–612 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Carson, J. A. & Baltgalvis, K. A. Interleukin 6 as a key regulator of muscle mass during cachexia. Exerc. Sport. Sci. Rev. 38, 168–176 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Hotamisligil, G. S., Arner, P., Caro, J. F., Atkinson, R. L. & Spiegelman, B. M. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J. Clin. Invest. 95, 2409–2415 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ikizler, T. A. et al. Prevention and treatment of protein energy wasting in chronic kidney disease patients: a consensus statement by the International Society of Renal Nutrition and Metabolism. Kidney Int. 84, 1096–1107 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Walker, R. G. et al. Biochemistry and biology of GDF11 and myostatin: similarities, differences, and questions for future investigation. Circ. Res. 118, 1125–1141 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Verzola, D., Barisione, C., Picciotto, D., Garibotto, G. & Koppe, L. Emerging role of myostatin and its inhibition in the setting of chronic kidney disease. Kidney Int. 95, 506–517 (2019).

    Article  CAS  PubMed  Google Scholar 

  86. Lee, S. J. & McPherron, A. C. Regulation of myostatin activity and muscle growth. Proc. Natl Acad. Sci. USA 98, 9306–9311 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kaji, H. Effects of myokines on bone. Bonekey Rep. 5, 826 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Breitbart, A., Auger-Messier, M., Molkentin, J. D. & Heineke, J. Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting. Am. J. Physiol. Heart Circ. Physiol. 300, H1973–H1982 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Goodman, C. A., McNally, R. M., Hoffmann, F. M. & Hornberger, T. A. Smad3 induces atrogin-1, inhibits mTOR and protein synthesis, and promotes muscle atrophy in vivo. Mol. Endocrinol. 27, 1946–1957 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zhang, L. et al. Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease. FASEB J. 25, 1653–1663 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Verzola, D. et al. Apoptosis and myostatin mRNA are upregulated in the skeletal muscle of patients with chronic kidney disease. Kidney Int. 79, 773–782 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Yano, S. et al. Relationship between blood myostatin levels and kidney function: Shimane CoHRE Study. PLoS ONE 10, e0141035 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Mitch, W. E. Proteolytic mechanisms, not malnutrition, cause loss of muscle mass in kidney failure. J. Ren. Nutr. 16, 208–211 (2006).

    Article  PubMed  Google Scholar 

  94. Mitch, W. E. Cachexia in chronic kidney disease: a link to defective central nervous system control of appetite. J. Clin. Invest. 115, 1476–1478 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Butler, A. A. et al. Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nat. Neurosci. 4, 605–611 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Heimburger, O., Lonnqvist, F., Danielsson, A., Nordenstrom, J. & Stenvinkel, P. Serum immunoreactive leptin concentration and its relation to the body fat content in chronic renal failure. J. Am. Soc. Nephrol. 8, 1423–1430 (1997).

    Article  CAS  PubMed  Google Scholar 

  97. Stenvinkel, P., Lindholm, B., Lonnqvist, F., Katzarski, K. & Heimburger, O. Increases in serum leptin levels during peritoneal dialysis are associated with inflammation and a decrease in lean body mass. J. Am. Soc. Nephrol. 11, 1303–1309 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Nishikawa, M. et al. Measurement of serum leptin in patients with chronic renal failure on hemodialysis. Clin. Nephrol. 51, 296–303 (1999).

    CAS  PubMed  Google Scholar 

  99. Arbeiter, A. K. et al. Ghrelin and other appetite-regulating hormones in paediatric patients with chronic renal failure during dialysis and following kidney transplantation. Nephrol. Dial. Transplant. 24, 643–646 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Canpolat, N. et al. Leptin and ghrelin in chronic kidney disease: their associations with protein-energy wasting. Pediatr. Nephrol. 33, 2113–2122 (2018).

    Article  PubMed  Google Scholar 

  101. Monzani, A. et al. Unacylated ghrelin and obestatin: promising biomarkers of protein energy wasting in children with chronic kidney disease. Pediatr. Nephrol. 33, 661–672 (2018).

    Article  PubMed  Google Scholar 

  102. Buscher, A. K., Buscher, R., Hauffa, B. P. & Hoyer, P. F. Alterations in appetite-regulating hormones influence protein-energy wasting in pediatric patients with chronic kidney disease. Pediatr. Nephrol. 25, 2295–2301 (2010).

    Article  PubMed  Google Scholar 

  103. Caliskan, Y. et al. Comparison of markers of appetite and inflammation between hemodialysis patients with and without failed renal transplants. J. Ren. Nutr. 22, 258–267 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Cheung, W. W. & Mak, R. H. Melanocortin antagonism ameliorates muscle wasting and inflammation in chronic kidney disease. Am. J. Physiol. Ren. Physiol. 303, F1315–F1324 (2012).

    Article  CAS  Google Scholar 

  105. Chaves, F. M., Mansano, N. S., Frazao, R. & Donato, J. Jr Tumor necrosis factor α and interleukin-1β acutely inhibit AgRP neurons in the arcuate nucleus of the hypothalamus. Int. J. Mol. Sci. 21, 8928 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  106. Mak, R. H. et al. Wasting in chronic kidney disease. J. Cachexia Sarcopenia Muscle 2, 9–25 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Gordon, B. S., Kelleher, A. R. & Kimball, S. R. Regulation of muscle protein synthesis and the effects of catabolic states. Int. J. Biochem. Cell Biol. 45, 2147–2157 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Zhang, L. et al. Mechanisms regulating muscle protein synthesis in chronic kidney disease. J. Am. Soc. Nephrol. 31, 2573–2587 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wang, X. H. et al. Decreased miR-29 suppresses myogenesis in CKD. J. Am. Soc. Nephrol. 22, 2068–2076 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Hudson, M. B. et al. miR-23a is decreased during muscle atrophy by a mechanism that includes calcineurin signaling and exosome-mediated export. Am. J. Physiol. Cell Physiol. 306, C551–C558 (2014).

    Article  CAS  PubMed  Google Scholar 

  111. Xu, J. et al. Transcription factor FoxO1, the dominant mediator of muscle wasting in chronic kidney disease, is inhibited by microRNA-486. Kidney Int. 82, 401–411 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wang, B. et al. MicroRNA-23a and microRNA-27a mimic exercise by ameliorating CKD-induced muscle atrophy. J. Am. Soc. Nephrol. 28, 2631–2640 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hudson, M. B. et al. miR-182 attenuates atrophy-related gene expression by targeting FoxO3 in skeletal muscle. Am. J. Physiol. Cell Physiol. 307, C314–C319 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gamboa, J. L. et al. Mitochondrial dysfunction and oxidative stress in patients with chronic kidney disease. Physiol. Rep. 4, e12780 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Roshanravan, B. et al. CKD and muscle mitochondrial energetics. Am. J. Kidney Dis. 68, 658–659 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Yazdi, P. G., Moradi, H., Yang, J. Y., Wang, P. H. & Vaziri, N. D. Skeletal muscle mitochondrial depletion and dysfunction in chronic kidney disease. Int. J. Clin. Exp. Med. 6, 532–539 (2013).

    PubMed  PubMed Central  Google Scholar 

  117. Zhang, L., Wang, X. H., Wang, H., Du, J. & Mitch, W. E. Satellite cell dysfunction and impaired IGF-1 signaling cause CKD-induced muscle atrophy. J. Am. Soc. Nephrol. 21, 419–427 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Heron-Milhavet, L., Mamaeva, D., LeRoith, D., Lamb, N. J. & Fernandez, A. Impaired muscle regeneration and myoblast differentiation in mice with a muscle-specific KO of IGF-IR. J. Cell. Physiol. 225, 1–6 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. McFarlane, C. et al. Myostatin signals through Pax7 to regulate satellite cell self-renewal. Exp. Cell Res. 314, 317–329 (2008).

    Article  CAS  PubMed  Google Scholar 

  120. Levin, A. et al. Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy. Lancet 390, 1888–1917 (2017).

    Article  PubMed  Google Scholar 

  121. Bellizzi, V. et al. Very low protein diet supplemented with ketoanalogs improves blood pressure control in chronic kidney disease. Kidney Int. 71, 245–251 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Di Micco, L., Di Lullo, L., Bellasi, A. & Di Iorio, B. R. Very low protein diet for patients with chronic kidney disease: recent insights. J. Clin. Med. 8, 718 (2019).

    Article  PubMed Central  Google Scholar 

  123. Kalantar-Zadeh, K. & Fouque, D. Nutritional management of chronic kidney disease. N. Engl. J. Med. 377, 1765–1776 (2017).

    Article  CAS  PubMed  Google Scholar 

  124. Milovanova, L. et al. Effect of essential amino acid small ketoanalogues and protein restriction diet on morphogenetic proteins (FGF-23 and Klotho) in 3b-4 stages chronic small kidney disease patients: a randomized pilot study. Clin. Exp. Nephrol. 22, 1351–1359 (2018).

    Article  CAS  PubMed  Google Scholar 

  125. Garneata, L., Stancu, A., Dragomir, D., Stefan, G. & Mircescu, G. Ketoanalogue-supplemented vegetarian very low-protein diet and CKD progression. J. Am. Soc. Nephrol. 27, 2164–2176 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hara, H. et al. Protein energy wasting and sarcopenia in dialysis patients. Cont. Nephrol. 196, 243–249 (2018).

    Article  Google Scholar 

  127. Graham, K. A. et al. Correction of acidosis in CAPD decreases whole body protein degradation. Kidney Int. 49, 1396–1400 (1996).

    Article  CAS  PubMed  Google Scholar 

  128. Mak, R. H. Effect of metabolic acidosis on insulin action and secretion in uremia. Kidney Int. 54, 603–607 (1998).

    Article  CAS  PubMed  Google Scholar 

  129. Reaich, D. et al. Insulin-mediated changes in PD and glucose uptake after correction of acidosis in humans with CRF. Am. J. Physiol. Endocrinol. Metab. 268, E121–E126 (1995).

    Article  CAS  Google Scholar 

  130. Dobre, M., Rahman, M. & Hostetter, T. H. Current status of bicarbonate in CKD. J. Am. Soc. Nephrol. 26, 515–523 (2015).

    Article  CAS  PubMed  Google Scholar 

  131. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. Suppl. 2, 1–138 (2012).

    Google Scholar 

  132. Loniewski, I. & Wesson, D. E. Bicarbonate therapy for prevention of chronic kidney disease progression. Kidney Int. 85, 529–535 (2014).

    Article  CAS  PubMed  Google Scholar 

  133. Wilund, K. R., Viana, J. L. & Perez, L. M. A critical review of exercise training in hemodialysis patients: personalized activity prescriptions are needed. Exerc. Sport. Sci. Rev. 48, 28–39 (2013).

    Article  Google Scholar 

  134. Ikizler, T. A. et al. Metabolic effects of diet and exercise in patients with moderate to severe CKD: a randomized clinical trial. J. Am. Soc. Nephrol. 29, 250–259 (2018).

    Article  CAS  PubMed  Google Scholar 

  135. K/DOQI Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am. J. Kidney Dis. 45, S1–153 (2005).

    Google Scholar 

  136. Gollie, J. M., Harris-Love, M. O., Patel, S. S. & Argani, S. Chronic kidney disease: considerations for monitoring skeletal muscle health and prescribing resistance exercise. Clin. Kidney J. 11, 822–831 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Watson, E. L. et al. The effect of resistance exercise on inflammatory and myogenic markers in patients with chronic kidney disease. Front. Physiol. 8, 541 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Dong, J. et al. The effect of resistance exercise to augment long-term benefits of intradialytic oral nutritional supplementation in chronic hemodialysis patients. J. Ren. Nutr. 21, 149–159 (2011).

    Article  PubMed  Google Scholar 

  139. Cheema, B. et al. Randomized controlled trial of intradialytic resistance training to target muscle wasting in ESRD: the Progressive Exercise for Anabolism in Kidney Disease (PEAK) study. Am. J. Kidney Dis. 50, 574–584 (2007).

    Article  PubMed  Google Scholar 

  140. Molsted, S., Harrison, A. P., Eidemak, I. & Andersen, J. L. The effects of high-load strength training with protein- or non-protein-containing nutritional supplementation in patients undergoing dialysis. J. Ren. Nutr. 23, 132–140 (2013).

    Article  CAS  PubMed  Google Scholar 

  141. Su, Z. et al. Acupuncture plus low-frequency electrical stimulation (Acu-LFES) attenuates diabetic myopathy by enhancing muscle regeneration. PLoS ONE 10, e0134511 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Onda, A. et al. Acupuncture ameliorated skeletal muscle atrophy induced by hindlimb suspension in mice. Biochem. Biophys. Res. Commun. 410, 434–439 (2011).

    Article  CAS  PubMed  Google Scholar 

  143. Liu, Y., Xiao, F. & Liang, X. Acupuncture improves the facial muscular function in a case of facioscapulohumeral muscular dystrophy. J. Acupunct. Meridian Stud. 12, 73–76 (2019).

    Article  PubMed  Google Scholar 

  144. Sudhakaran, P. Amyotrophic lateral sclerosis: an acupuncture approach. Med. Acupunct. 29, 260–268 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Yu, J., Wang, M., Liu, J., Zhang, X. & Yang, S. Effect of electroacupuncture on the expression of agrin and acetylcholine receptor subtypes in rats with tibialis anterior muscular atrophy induced by sciatic nerve injection injury. Acupunct. Med. 35, 268–275 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Su, Z. et al. Acupuncture plus low-frequency electrical stimulation (Acu-LFES) attenuates denervation-induced muscle atrophy. J. Appl. Physiol. 120, 426–436 (2016).

    Article  CAS  PubMed  Google Scholar 

  147. Che-Yi, C., Wen, C. Y., Min-Tsung, K. & Chiu-Ching, H. Acupuncture in haemodialysis patients at the Quchi (LI11) acupoint for refractory uraemic pruritus. Nephrol. Dial. Transpl. 20, 1912–1915 (2005).

    Article  Google Scholar 

  148. Kim, K. H. et al. Acupuncture for symptom management in hemodialysis patients: a prospective, observational pilot study. J. Altern. Complement. Med. 17, 741–748 (2011).

    Article  PubMed  Google Scholar 

  149. Su, L. H., Wu, K. D., Lee, L. S., Wang, H. & Liu, C. F. Effects of far infrared acupoint stimulation on autonomic activity and quality of life in hemodialysis patients. Am. J. Chin. Med. 37, 215–226 (2009).

    Article  PubMed  Google Scholar 

  150. Munoz-Canoves, P., Scheele, C., Pedersen, B. K. & Serrano, A. L. Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? FEBS J. 280, 4131–4148 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Kharraz, Y., Guerra, J., Mann, C. J., Serrano, A. L. & Munoz-Canoves, P. Macrophage plasticity and the role of inflammation in skeletal muscle repair. Med. Inflamm. 2013, 491497 (2013).

    Article  Google Scholar 

  152. Morton, R. W. et al. Neither load nor systemic hormones determine resistance training-mediated hypertrophy or strength gains in resistance-trained young men. J. Appl. Physiol. 121, 129–138 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Mounier, R. et al. AMPKα1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration. Cell Metab. 18, 251–264 (2013).

    Article  CAS  PubMed  Google Scholar 

  154. Takaoka, Y. et al. Electroacupuncture suppresses myostatin gene expression: cell proliferative reaction in mouse skeletal muscle. Physiol. Genomics 30, 102–110 (2007).

    Article  CAS  PubMed  Google Scholar 

  155. Ashby, D. R. et al. Sustained appetite improvement in malnourished dialysis patients by daily ghrelin treatment. Kidney Int. 76, 199–206 (2009).

    Article  CAS  PubMed  Google Scholar 

  156. Wynne, K. et al. Subcutaneous ghrelin enhances acute food intake in malnourished patients who receive maintenance peritoneal dialysis: a randomized, placebo-controlled trial. J. Am. Soc. Nephrol. 16, 2111–2118 (2005).

    Article  CAS  PubMed  Google Scholar 

  157. Campbell, G. A., Patrie, J. T., Gaylinn, B. D., Thorner, M. O. & Bolton, W. K. Oral ghrelin receptor agonist MK-0677 increases serum insulin-like growth factor 1 in hemodialysis patients: a randomized blinded study. Nephrol. Dial. Transpl. 33, 523–530 (2018).

    Article  CAS  Google Scholar 

  158. Han, H. Q., Zhou, X., Mitch, W. E. & Goldberg, A. L. Myostatin/activin pathway antagonism: molecular basis and therapeutic potential. Int. J. Biochem. Cell Biol. 45, 2333–2347 (2013).

    Article  CAS  PubMed  Google Scholar 

  159. Campbell, C. et al. Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: results of a randomized, placebo-controlled clinical trial. Muscle Nerve 55, 458–464 (2017).

    Article  CAS  PubMed  Google Scholar 

  160. Perry, B. D. et al. Palmitate-induced ER stress and inhibition of protein synthesis in cultured myotubes does not require Toll-like receptor 4. PLoS ONE 13, e0191313 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Woodworth-Hobbs, M. E. et al. Docosahexaenoic acid counteracts palmitate-induced endoplasmic reticulum stress in C2C12 myotubes: impact on muscle atrophy. Physiol. Rep. 5, e13530 (2017).

    Article  PubMed Central  Google Scholar 

  162. Woodworth-Hobbs, M. E. et al. Docosahexaenoic acid prevents palmitate-induced activation of proteolytic systems in C2C12 myotubes. J. Nutr. Biochem. 25, 868–874 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Khal, J. & Tisdale, M. J. Downregulation of muscle protein degradation in sepsis by eicosapentaenoic acid (EPA). Biochem. Biophys. Res. Commun. 375, 238–240 (2008).

    Article  CAS  PubMed  Google Scholar 

  164. Hung, A. M. et al. Omega-3 fatty acids inhibit the up-regulation of endothelial chemokines in maintenance hemodialysis patients. Nephrol. Dial. Transplant. 30, 266–274 (2015).

    Article  CAS  PubMed  Google Scholar 

  165. Deger, S. M. et al. High dose omega-3 fatty acid administration and skeletal muscle protein turnover in maintenance hemodialysis patients. Clin. J. Am. Soc. Nephrol. 11, 1227–1235 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Ishikawa, Y. et al. Effect of exercise on kidney function, oxidative stress, and inflammation in type 2 diabetic KK-A(y) mice. Exp. Diabetes Res. 2012, 702948 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Ghosh, S. et al. Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice. Am. J. Physiol. Ren. Physiol. 296, F700–F708 (2009).

    Article  CAS  Google Scholar 

  168. Hanatani, S. et al. Akt1-mediated fast/glycolytic skeletal muscle growth attenuates renal damage in experimental kidney disease. J. Am. Soc. Nephrol. 25, 2800–2811 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Wang, B. et al. Exogenous miR-29a attenuates muscle atrophy and kidney fibrosis in unilateral ureteral obstruction in mice. Hum. Gene Ther. 31, 367–375 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Wang, B. et al. miR-26a limits muscle wasting and cardiac fibrosis through exosome-mediated microRNA transfer in chronic kidney disease. Theranostics 9, 1864–1877 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Zhang, A. et al. Exogenous miR-26a suppresses muscle wasting and renal fibrosis in obstructive kidney disease. FASEB J. 33, 13590–13601 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Zhang, A. et al. miRNA-23a/27a attenuates muscle atrophy and renal fibrosis through muscle-kidney crosstalk. J. Cachexia Sarcopenia Muscle 9, 755–770 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Wang, H. et al. Exosome-mediated miR-29 transfer reduces muscle atrophy and kidney fibrosis in mice. Mol. Ther. 27, 571–583 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Mootha, V. K. et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).

    Article  CAS  PubMed  Google Scholar 

  175. Rahnert, J. A., Zheng, B., Hudson, M. B., Woodworth-Hobbs, M. E. & Price, S. R. Glucocorticoids alter CRTC-CREB signaling in muscle cells: impact on PGC-1α expression and atrophy markers. PLoS ONE 11, e0159181 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Roberts-Wilson, T. K. et al. Calcineurin signaling and PGC-1α expression are suppressed during muscle atrophy due to diabetes. Biochim. Biophys. Acta 1803, 960–967 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Peng, H. et al. Myokine mediated muscle-kidney crosstalk suppresses metabolic reprogramming and fibrosis in damaged kidneys. Nat. Commun. 8, 1493 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Chang, J. S. & Kong, I. D. Irisin prevents dexamethasone-induced atrophy in C2C12 myotubes. Pflug. Arch. 472, 495–502 (2020).

    Article  CAS  Google Scholar 

  179. Walton, K. L. et al. Activin A-induced cachectic wasting Is attenuated by systemic delivery of Its cognate propeptide in male mice. Endocrinology 160, 2417–2426 (2019).

    Article  CAS  PubMed  Google Scholar 

  180. Lee, S. J. et al. Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight. Proc. Natl Acad. Sci. USA 117, 23942–23951 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Chen, J. L. et al. Elevated expression of activins promotes muscle wasting and cachexia. FASEB J. 28, 1711–1723 (2014).

    Article  CAS  PubMed  Google Scholar 

  182. Latres, E. et al. Activin A more prominently regulates muscle mass in primates than does GDF8. Nat. Commun. 8, 15153 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Solagna, F. et al. Pro-cachectic factors link experimental and human chronic kidney disease to skeletal muscle wasting programs. J. Clin. Invest. 131, e135821 (2021).

    Article  CAS  PubMed Central  Google Scholar 

  184. Kummer, S., von Gersdorff, G., Kemper, M. J. & Oh, J. The influence of gender and sexual hormones on incidence and outcome of chronic kidney disease. Pediatr. Nephrol. 27, 1213–1219 (2012).

    Article  PubMed  Google Scholar 

  185. Jean, G., Souberbielle, J. C. & Chazot, C. Vitamin D in chronic kidney disease and dialysis patients. Nutrients 9, 328 (2017).

    Article  PubMed Central  Google Scholar 

  186. Franca Gois, P. H., Wolley, M., Ranganathan, D. & Seguro, A. C. Vitamin D deficiency in chronic kidney disease: recent evidence and controversies. Int. J. Env. Res. Pub. Health 15, 1773 (2018).

    Article  Google Scholar 

  187. Girgis, C. M. Vitamin D and skeletal muscle: emerging roles in development, anabolism and repair. Calcif. Tissue Int. 106, 47–57 (2020).

    Article  CAS  PubMed  Google Scholar 

  188. Gordon, P. L., Doyle, J. W. & Johansen, K. L. Association of 1,25-dihydroxyvitamin D levels with physical performance and thigh muscle cross-sectional area in chronic kidney disease stage 3 and 4. J. Ren. Nutr. 22, 423–433 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Gordon, P. L., Sakka, G. K., Doyle, J. W., Shubert, T. & Johansen, K. L. Relationship between vitamin D and muscle size and strength in patients on hemodialysis. J. Ren. Nutr. 17, 397–407 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Hewitt, N. A., O’Connor, A. A., O’Shaughnessy, D. V. & Elder, G. J. Effects of cholecalciferol on functional, biochemical, vascular, and quality of life outcomes in hemodialysis patients. Clin. J. Am. Soc. Nephrol. 8, 1143–1149 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Mager, D. R., Jackson, S. T., Hoffman, M. R., Jindal, K. & Senior, P. A. Vitamin D supplementation, bone health and quality of life in adults with diabetes and chronic kideney disease: results of an open label randomized clinical trial. Clin. Nutr. 36, 686–696 (2017).

    Article  CAS  PubMed  Google Scholar 

  192. Morvan, F. et al. Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy. Proc. Natl Acad. Sci. USA 114, 12448–12453 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Chen, J. L. et al. Development of novel activin-targeted therapeutics. Mol. Ther. 23, 434–444 (2015).

    Article  CAS  PubMed  Google Scholar 

  194. Zhang, L. et al. Stat3 activation links a C/EBPdelta to myostatin pathway to stimulate loss of muscle mass. Cell Metab. 18, 368–379 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Ruiz-Ortega, M., Rayego-Mateos, S., Lamas, S., Ortiz, A. & Rodrigues-Diez, R. R. Targeting the progression of chronic kidney disease. Nat. Rev. Nephrol. 16, 269–288 (2020).

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Renal Division, Department of Medicine, Emory University, Atlanta, GA, USA

    Xiaonan H. Wang

  2. Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    William E. Mitch

  3. Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC, USA

    S. Russ Price

  4. Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA

    S. Russ Price

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Nature Reviews Nephrology thanks C. Kovesdy, who co-reviewed with W. Hassan; K. Wilund, who co-reviewed with S. Fang; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work

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Glossary

Myofibres

Muscle fibres composed of many multinucleated myotubes.

Satellite cells

Undifferentiated multipotent cells with potential to form myoblasts; also known as muscle stem cells.

Myoblasts

Immature muscle cells that are committed to fuse and form multinucleated myotubes.

Atrogenes

Genes that encode proteins that are responsible for causing muscle protein loss.

Ubiquitinylation

Covalent conjugation of a ubiquitin protein moiety to itself or another protein. The process is a post-translational modification required to target proteins for degradation by the proteasome. Polyubiquitinylation is when the conjugation process forms ubiquitin chains that are covalently linked to target proteins.

Hypothalamus

A region of the brain that helps regulate many homeostatic functions of the body including appetite and weight.

Myokine

A cytokine-like protein produced by skeletal muscle fibres and myocytes. Myostatin is a myokine.

Peptibody

A recombinant immunological protein developed by fusing a bioactive peptide with the Fc region of an antibody.

Exosomes

Extracellular vesicles that encapsulate proteins, lipids, portions of DNA, and RNAs and non-coding RNAs.

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Wang, X.H., Mitch, W.E. & Price, S.R. Pathophysiological mechanisms leading to muscle loss in chronic kidney disease. Nat Rev Nephrol 18, 138–152 (2022). https://doi.org/10.1038/s41581-021-00498-0

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