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Mechanisms of muscle wasting in chronic kidney disease

Nature Reviews Nephrology volume 10, pages 504–516 (2014)Cite this article

Subjects

Key Points

  • Muscle atrophy frequently complicates the course of chronic kidney disease (CKD) and is associated with excess morbidity and mortality

  • CKD-induced mechanisms that cause muscle atrophy include activation of the ubiquitin–proteasome system, caspase-3 and myostatin

  • Triggers that activate proteolysis in CKD include metabolic acidosis, defects in insulin/insulin-like growth factor 1 (IGF-1) intracellular signalling, inflammation and catabolic responses to microRNAs

  • Current strategies aimed at preventing muscle atrophy include correction of acidosis plus exercise; specific therapies that inhibit myostatin or signal transducer and activator of transcription 3 (Stat3) are being developed

Abstract

In patients with chronic kidney disease (CKD), loss of cellular proteins increases the risks of morbidity and mortality. Persistence of muscle protein catabolism in CKD results in striking losses of muscle proteins as whole-body protein turnover is great; even small but persistent imbalances between protein synthesis and degradation cause substantial protein loss. No reliable methods to prevent CKD-induced muscle wasting currently exist, but mechanisms that control cellular protein turnover have been identified, suggesting that therapeutic strategies will be developed to suppress or block protein loss. Catabolic pathways that cause protein wasting include activation of the ubiquitin–proteasome system (UPS), caspase-3, lysosomes and myostatin (a negative regulator of skeletal muscle growth). These pathways can be initiated by complications associated with CKD, such as metabolic acidosis, defective insulin signalling, inflammation, increased angiotensin II levels, abnormal appetite regulation and impaired microRNA responses. Inflammation stimulates cellular signalling pathways that activate myostatin, which accelerates UPS-mediated catabolism. Blocking this pathway can prevent loss of muscle proteins. Myostatin inhibition could yield new therapeutic directions for blocking muscle protein wasting in CKD or disorders associated with its complications.

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Figure 1: Stages of skeletal muscle regeneration.
Figure 2: Chronic kidney disease-induced protein degradation by the UPS.
Figure 3: Insulin/IGF-1 signalling stimulates protein synthesis and suppresses protein degradation.
Figure 4: A simplified mechanism of myostatin-induced muscle atrophy.

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Acknowledgements

This work was supported by NIAMS R01 AR060268 (X.H.W.) and NIDDK R37 DK037175 (W.E.M.).

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Authors and Affiliations

  1. Renal Division, Department of Medicine, Emory University, 1639 Pierce Drive, WMB 338, Atlanta, 30322, GA, USA

    Xiaonan H. Wang

  2. Nephrology Division, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, ABBR R705, Houston, 77030, TX, USA

    William E. Mitch

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  1. Xiaonan H. Wang
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Both authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and edited the manuscript before submission.

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Correspondence to Xiaonan H. Wang.

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Wang, X., Mitch, W. Mechanisms of muscle wasting in chronic kidney disease. Nat Rev Nephrol 10, 504–516 (2014). https://doi.org/10.1038/nrneph.2014.112

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