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.
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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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).
Griffiths, R. D. Muscle mass, survival, and the elderly ICU patient. Nutrition 12, 456–458 (1996).
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).
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).
Moorthi, R. N. & Avin, K. G. Clinical relevance of sarcopenia in chronic kidney disease. Curr. Opin. Nephrol. Hyperten. 26, 219–228 (2017).
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).
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).
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).
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).
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).
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).
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).
Kovesdy, C. P. & Kalantar-Zadeh, K. Why is protein-energy wasting associated with mortality in chronic kidney disease? Sem. Nephrol. 29, 3–14 (2009).
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).
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).
Ikizler, T. A. et al. KDOQI clinical practice guideline for nutrition in CKD: 2020 update. Am. J. Kidney Dis. 76, S1–S107 (2020).
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).
Clark, A. S. & Mitch, W. E. Comparison of protein synthesis and degradation in incubated and perfused muscle. Biochem. J. 212, 649–653 (1983).
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).
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).
Deger, S. M. et al. Systemic inflammation is associated with exaggerated skeletal muscle protein catabolism in maintenance hemodialysis patients. JCI Insight 2, e95185 (2017).
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).
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).
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).
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).
Dumont, N. A., Bentzinger, C. F., Sincennes, M. C. & Rudnicki, M. A. Satellite cells and skeletal muscle regeneration. Comp. Physiol. 5, 1027–1059 (2015).
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).
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).
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).
Meyer-Schwesinger, C. The ubiquitin-proteasome system in kidney physiology and disease. Nat. Rev. Nephrol. 15, 393–411 (2019).
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).
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).
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).
Rom, O., Kaisari, S., Reznick, A. Z. & Aizenbud, D. in Oxidative Stress and Cardiorespiratory Function (ed. Pokorski M.) 1–8 (Springer, 2014).
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).
Schwerk, C. & Schulze-Osthoff, K. Non-apoptotic functions of caspases in cellular proliferation and differentiation. Biochem. Pharmacol. 66, 1453–1458 (2003).
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).
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).
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).
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).
Hu, J. et al. XIAP reduces muscle proteolysis induced by CKD. J. Am. Soc. Nephrol. 21, 1174–1183 (2010).
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).
Morel, E. et al. Autophagy: a druggable process. Ann. Rev. Pharmacol. Toxicol. 57, 375–398 (2017).
Levine, B. & Kroemer, G. Biological functions of autophagy genes: a disease perspective. Cell 176, 11–42 (2019).
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).
Jang, M. et al. AMPK contributes to autophagosome maturation and lysosomal fusion. Sci. Rep. 8, 12637 (2018).
Corona Velazquez, A. F. & Jackson, W. T. So many roads: the multifaceted regulation of autophagy induction. Mol. Cell Biol. 38, e00303–e00318 (2018).
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).
Gunta, S. S. & Mak, R. H. Ghrelin and leptin pathophysiology in chronic kidney disease. Pediatr. Nephrol. 28, 611–616 (2013).
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).
Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).
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).
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).
Bodine, S. C. et al. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294, 1704–1708 (2001).
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).
O’Neill, B. T. et al. FoxO transcription factors are critical regulators of diabetes-related muscle atrophy. Diabetes 68, 556–570 (2019).
von Walden, F. Ribosome biogenesis in skeletal muscle: coordination of transcription and translation. J. Appl. Physiol. 127, 591–598 (2019).
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).
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).
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).
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).
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).
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).
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).
Kraut, J. A. & Madias, N. E. Adverse deffects of the metabolic acidosis of chronic kidney disease. Adv. Chronic Kidney Dis. 24, 289–297 (2017).
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).
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).
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).
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).
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).
Garibotto, G. et al. Skeletal muscle protein synthesis and degradation in patients with chronic renal failure. Kidney Int. 45, 1432–1439 (1994).
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).
Mihai, S. et al. Inflammation-related mechanisms in chronic kidney disease prediction, progression, and outcome. J. Immunol. Res. 2018, 2180373 (2018).
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).
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).
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).
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).
Raj, D. S. et al. Interleukin-6 modulates hepatic and muscle protein synthesis during hemodialysis. Kidney Int. 73, 1054–1061 (2008).
Thoma, A. & Lightfoot, A. P. in Muscle Atrophy (ed. Xiao J.) 267–279 (Springer, 2018).
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).
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).
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).
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).
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).
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).
Lee, S. J. & McPherron, A. C. Regulation of myostatin activity and muscle growth. Proc. Natl Acad. Sci. USA 98, 9306–9311 (2001).
Kaji, H. Effects of myokines on bone. Bonekey Rep. 5, 826 (2016).
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).
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).
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).
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).
Yano, S. et al. Relationship between blood myostatin levels and kidney function: Shimane CoHRE Study. PLoS ONE 10, e0141035 (2015).
Mitch, W. E. Proteolytic mechanisms, not malnutrition, cause loss of muscle mass in kidney failure. J. Ren. Nutr. 16, 208–211 (2006).
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).
Butler, A. A. et al. Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nat. Neurosci. 4, 605–611 (2001).
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).
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).
Nishikawa, M. et al. Measurement of serum leptin in patients with chronic renal failure on hemodialysis. Clin. Nephrol. 51, 296–303 (1999).
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).
Canpolat, N. et al. Leptin and ghrelin in chronic kidney disease: their associations with protein-energy wasting. Pediatr. Nephrol. 33, 2113–2122 (2018).
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).
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).
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).
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).
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).
Mak, R. H. et al. Wasting in chronic kidney disease. J. Cachexia Sarcopenia Muscle 2, 9–25 (2011).
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).
Zhang, L. et al. Mechanisms regulating muscle protein synthesis in chronic kidney disease. J. Am. Soc. Nephrol. 31, 2573–2587 (2020).
Wang, X. H. et al. Decreased miR-29 suppresses myogenesis in CKD. J. Am. Soc. Nephrol. 22, 2068–2076 (2011).
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).
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).
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).
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).
Gamboa, J. L. et al. Mitochondrial dysfunction and oxidative stress in patients with chronic kidney disease. Physiol. Rep. 4, e12780 (2016).
Roshanravan, B. et al. CKD and muscle mitochondrial energetics. Am. J. Kidney Dis. 68, 658–659 (2016).
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).
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).
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).
McFarlane, C. et al. Myostatin signals through Pax7 to regulate satellite cell self-renewal. Exp. Cell Res. 314, 317–329 (2008).
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).
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).
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).
Kalantar-Zadeh, K. & Fouque, D. Nutritional management of chronic kidney disease. N. Engl. J. Med. 377, 1765–1776 (2017).
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).
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).
Hara, H. et al. Protein energy wasting and sarcopenia in dialysis patients. Cont. Nephrol. 196, 243–249 (2018).
Graham, K. A. et al. Correction of acidosis in CAPD decreases whole body protein degradation. Kidney Int. 49, 1396–1400 (1996).
Mak, R. H. Effect of metabolic acidosis on insulin action and secretion in uremia. Kidney Int. 54, 603–607 (1998).
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).
Dobre, M., Rahman, M. & Hostetter, T. H. Current status of bicarbonate in CKD. J. Am. Soc. Nephrol. 26, 515–523 (2015).
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).
Loniewski, I. & Wesson, D. E. Bicarbonate therapy for prevention of chronic kidney disease progression. Kidney Int. 85, 529–535 (2014).
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).
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).
K/DOQI Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am. J. Kidney Dis. 45, S1–153 (2005).
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).
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).
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).
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).
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).
Su, Z. et al. Acupuncture plus low-frequency electrical stimulation (Acu-LFES) attenuates diabetic myopathy by enhancing muscle regeneration. PLoS ONE 10, e0134511 (2015).
Onda, A. et al. Acupuncture ameliorated skeletal muscle atrophy induced by hindlimb suspension in mice. Biochem. Biophys. Res. Commun. 410, 434–439 (2011).
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).
Sudhakaran, P. Amyotrophic lateral sclerosis: an acupuncture approach. Med. Acupunct. 29, 260–268 (2017).
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).
Su, Z. et al. Acupuncture plus low-frequency electrical stimulation (Acu-LFES) attenuates denervation-induced muscle atrophy. J. Appl. Physiol. 120, 426–436 (2016).
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).
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).
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).
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).
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).
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).
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).
Takaoka, Y. et al. Electroacupuncture suppresses myostatin gene expression: cell proliferative reaction in mouse skeletal muscle. Physiol. Genomics 30, 102–110 (2007).
Ashby, D. R. et al. Sustained appetite improvement in malnourished dialysis patients by daily ghrelin treatment. Kidney Int. 76, 199–206 (2009).
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).
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).
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).
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).
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).
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).
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).
Khal, J. & Tisdale, M. J. Downregulation of muscle protein degradation in sepsis by eicosapentaenoic acid (EPA). Biochem. Biophys. Res. Commun. 375, 238–240 (2008).
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).
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).
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).
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).
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).
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).
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).
Zhang, A. et al. Exogenous miR-26a suppresses muscle wasting and renal fibrosis in obstructive kidney disease. FASEB J. 33, 13590–13601 (2019).
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).
Wang, H. et al. Exosome-mediated miR-29 transfer reduces muscle atrophy and kidney fibrosis in mice. Mol. Ther. 27, 571–583 (2019).
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).
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).
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).
Peng, H. et al. Myokine mediated muscle-kidney crosstalk suppresses metabolic reprogramming and fibrosis in damaged kidneys. Nat. Commun. 8, 1493 (2017).
Chang, J. S. & Kong, I. D. Irisin prevents dexamethasone-induced atrophy in C2C12 myotubes. Pflug. Arch. 472, 495–502 (2020).
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).
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).
Chen, J. L. et al. Elevated expression of activins promotes muscle wasting and cachexia. FASEB J. 28, 1711–1723 (2014).
Latres, E. et al. Activin A more prominently regulates muscle mass in primates than does GDF8. Nat. Commun. 8, 15153 (2017).
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).
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).
Jean, G., Souberbielle, J. C. & Chazot, C. Vitamin D in chronic kidney disease and dialysis patients. Nutrients 9, 328 (2017).
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).
Girgis, C. M. Vitamin D and skeletal muscle: emerging roles in development, anabolism and repair. Calcif. Tissue Int. 106, 47–57 (2020).
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).
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).
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).
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).
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).
Chen, J. L. et al. Development of novel activin-targeted therapeutics. Mol. Ther. 23, 434–444 (2015).
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).
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).
The authors declare no competing interests.
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Muscle fibres composed of many multinucleated myotubes.
- Satellite cells
Undifferentiated multipotent cells with potential to form myoblasts; also known as muscle stem cells.
Immature muscle cells that are committed to fuse and form multinucleated myotubes.
Genes that encode proteins that are responsible for causing muscle protein loss.
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.
A region of the brain that helps regulate many homeostatic functions of the body including appetite and weight.
A cytokine-like protein produced by skeletal muscle fibres and myocytes. Myostatin is a myokine.
A recombinant immunological protein developed by fusing a bioactive peptide with the Fc region of an antibody.
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