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Urotensin II can Induce Skeletal Muscle Atrophy Associated with Upregulating Ubiquitin–Proteasome System and Inhibiting the Differentiation of Satellite Cells in CRF Mice

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Abstract

Skeletal muscle wasting and atrophy is highly prevalent in chronic renal failure (CRF) and increases the risk of mortality. According to our previous study, we speculate that urotensin II (UII) can induce skeletal muscle atrophy by upregulating ubiquitin–proteasome system(UPS) in CRF. C2C12 mouse myoblast cells were differentiated into myotubes, and myotubes were exposed to different concentrations of UII. Myotube diameters, myosin heavy chain(MHC), p-Fxo03A, skeletal muscle-specific E3 ubiquitin ligases such as muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx/atrogin1) were detected. Three animal models (the sham operation mice as normal control (NC) group, wild-type C57BL/6 mice with 5/6 nephrectomy (WT CRF) group, UII receptor gene knock out (UT KO) mice with 5/6 nephrectomy (UT KO CRF) group) were designed. Cross-sectional area (CSA) of skeletal muscle tissues in three animal models were measured, and western blot detected protein of UII, p-Fxo03A, MAFbx and MuRF1, and immunofluorescence assays explored the satellite cell marker of Myod1 and Pax7, and PCR arrays detected the muscle protein degradation genes, protein synthesis genes and the genes which were involved in muscle components. UII could decrease mouse myotube diameters, and upregulate dephosphorylated Fxo03A protein. MAFbx and MuRF1 were higher in WT CRF group than that in NC group, but after UII receptor gene was knocked out (UT KO CRF), their expressions were downregulated. UII could inhibit the expression of Myod1 but not Pax7 in animal study. We first demonstrate that skeletal muscle atrophy induced by UII associated with upregulating ubiquitin–proteasome system and inhibiting the differentiation of satellite cells in CRF mice.

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Acknowledgements

This study was supported by Ministry of Education & National Natural Science Foundation of Beijing (Grant No. KZ 202110025038), National Natural Science Foundation of China (Grant No 81570663), the Xuanwu Hospital Huizhi talent leader training program to Aihua zhang

Funding

National Natural Science Foundation of China, Grant No. 81570663, Aihua Zhang,Ministry of Education & National Natural Science Foundation of Beijing, Grant No. KZ 202110025038, Aihua Zhang, Xuanwu Hospital Huizhi talent leader training program

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Authors and Affiliations

  1. Department of Nephrology, Xuan Wu Hospital, Capital Medical University, No. 45, Chang-Chun Street, Xicheng District, Beijing, People’s Republic of China

    Yajing Pan, Ting Zhou, Xingtong Dong, Leiyun Wu, Peiwen Wang, Shiyuan Wang & Aihua Zhang

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  1. Yajing Pan
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  2. Ting Zhou
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Contributions

AZ and YP: designed the study and prepared the first draft of the paper. TZ, XD and LW: contributed to the experimental work. PW and SW: was responsible for statistical analysis of the data. All authors revised the paper critically for intellectual content and approved the final version. All authors agree to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the paper are investigated and properly resolved.

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Correspondence to Aihua Zhang.

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Yajing Pan, Ting Zhou, Xingtong Dong, Leiyun Wu, Peiwen Wang, Shiyuan Wang and Aihua Zhang declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

The experimental protocols were approved by the Biological Medical Ethics Committee of the Xuan Wu Hospital, Capital Medical University (AEE-2020–185).

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Pan, Y., Zhou, T., Dong, X. et al. Urotensin II can Induce Skeletal Muscle Atrophy Associated with Upregulating Ubiquitin–Proteasome System and Inhibiting the Differentiation of Satellite Cells in CRF Mice. Calcif Tissue Int 112, 603–612 (2023). https://doi.org/10.1007/s00223-023-01073-4

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