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Butyrate ameliorate skeletal muscle atrophy in Diabetic Nephropathy via enhancing gut barrier function and GPR43 mediated PI3K/AKT/mTOR signals
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  • Gang Tang,
  • Yi Du,
  • Haochen Guan,
  • Jieshuang Jia,
  • Nan Zhu,
  • Yuping Shi,
  • Shu Rong,
  • Weijie Yuan
Gang Tang
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
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Yi Du
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
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Haochen Guan
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
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Jieshuang Jia
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
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Nan Zhu
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
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Yuping Shi
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
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Shu Rong
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
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Weijie Yuan
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
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Abstract

Muscle protein catabolism in patients with diabetic nephropathy (DN) results in striking losses of muscle proteins, which increases morbidity and mortality risks. Emerging evidence shows that short-chain fatty acids (SCFAs) play an important role in the maintenance of health and disease development. Recently, the connection between butyrate (a SCFA) and DN has been revealed, although the relationship between butyrate and muscle atrophy is still not clear. In our study, we found a significant decrease in butyrate in DN using metabolomics analyses. The addition of butyrate remarkably intestinal barrier function. Concurrently, butyrate could alleviate muscle atrophy and promote PI3K/AKT/mTOR signals, and suppress oxidative stress and autophagy in the skeletal muscle of db/db mice as well as high glucose/lipopolysaccharide (HG/LPS)-induced C2C12 cells. To further explore the mechanism, we found that GPR43, the key SCFAs signaling molecule, was significantly decreased in the skeletal muscle of db/db mice and HG/LPS-induced C2C12 cells. Overexpression of GPR43 could activate PI3K/AKT/mTOR signals and inhibit oxidative stress and autophagy in HG/LPS-induced C2C12 cells. Silencing of GPR43 blocked PI3K/AKT/mTOR signals improved by butyrate, as well as suppression of oxidative stress and reduction of autophagy. Ultimately, butyrate alleviated muscle atrophy in DN via GPR43-mediated PI3K/AKT/mTOR pathway

Peer review status:IN REVISION

01 Dec 2020Submitted to British Journal of Pharmacology
02 Dec 2020Submission Checks Completed
02 Dec 2020Assigned to Editor
13 Dec 2020Reviewer(s) Assigned
28 Feb 2021Review(s) Completed, Editorial Evaluation Pending
10 Mar 2021Editorial Decision: Revise Minor
15 Apr 20211st Revision Received
16 Apr 2021Assigned to Editor
16 Apr 2021Submission Checks Completed