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Potential mechanisms of uremic muscle wasting and the protective role of the mitochondria-targeted antioxidant Mito-TEMPO

  • Nephrology - Original Paper
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Abstract

Background

Muscle wasting is common in patients with chronic kidney disease (CKD). Many studies report that mitochondrial dysfunction and endoplasmic reticulum (ER) stress are involved in the development of muscle wasting. However, treatment approaches to protect against muscle wasting are limited. In this study, we investigated the benefits and potential mechanism of Mito-TEMPO, a mitochondria-targeted antioxidant on uremic-induced muscle wasting.

Methods

Mice were randomly divided into four groups as follows: control group, CKD group, CKD + Mito-TEMPO group, and Mito-TEMPO group. Renal injury was assessed by measurement of serum creatinine and BUN along with PAS and Masson’s staining. Bodyweight, gastrocnemius muscle mass, grip strength, and myofiber cross-sectional areas were investigated to evaluate muscle atrophy. Muscle protein synthesis and proteolysis were evaluated by Western blot and real-time PCR. Inflammatory cytokines including TNF-α, IL-6, IL-1β, and MCP-1 were measured by ELISA kits. Oxidative stress markers such as SOD2 activity and MDA level in gastrocnemius muscle tissue were measured by colorimetric assay. Mitochondrial dysfunction was evaluated by transmission electron microscopy and real-time PCR. ER stress was evaluated by Western blot.

Results

Impaired renal function was significantly restored by Mito-TEMPO treatment. Severe muscle atrophy was observed in muscle tissues of CKD mice along with increased inflammatory factors, oxidative stress markers, mitochondrial dysfunction, and ER stress. However, these effects were significantly attenuated with Mito-TEMPO treatment.

Conclusions

Mito-TEMPO improved muscle wasting in CKD mice possibly through alleviating mitochondrial dysfunction and endoplasmic reticulum stress, providing a potential new therapeutic approach for preventing muscle wasting in chronic kidney disease.

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Funding

This study was funded by “The Belt and Road international cooperation project”(18410741500), “interdisciplinary program of Shanghai Jiao Tong University” (YG2017MS07), and “the distinguished Young Scholar of Ninth people’s hospital” (jyyq09201701).

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Authors and Affiliations

  1. Division of Nephrology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University, 639 zhizaoju Road, Shanghai, 200011, China

    Yuqing Liu, Elangovan Perumal, Xiao Bi, Yingdeng Wang & Wei Ding

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  1. Yuqing Liu
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  2. Elangovan Perumal
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  3. Xiao Bi
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  4. Yingdeng Wang
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  5. Wei Ding
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Correspondence to Yingdeng Wang or Wei Ding.

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The authors declare that there are no conflicts of interest.

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All animal experiments were approved by the Animal Care Committee at Shanghai Jiao Tong University and carried out in accordance with institutional guidelines.

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Liu, Y., Perumal, E., Bi, X. et al. Potential mechanisms of uremic muscle wasting and the protective role of the mitochondria-targeted antioxidant Mito-TEMPO. Int Urol Nephrol 52, 1551–1561 (2020). https://doi.org/10.1007/s11255-020-02508-9

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  • DOI: https://doi.org/10.1007/s11255-020-02508-9

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