Saikosaponin A and D attenuate skeletal muscle atrophy in chronic kidney disease by reducing oxidative stress through activation of PI3K/AKT/Nrf2 pathway

Minna Huang; Yan Yan; Zihao Deng; Lingli Zhou; Meiling She; Yajun Yang; Meng Zhang; Dongtao Wang

doi:10.1016/j.phymed.2023.154766

Saikosaponin A and D attenuate skeletal muscle atrophy in chronic kidney disease by reducing oxidative stress through activation of PI3K/AKT/Nrf2 pathway

Phytomedicine. 2023 Jun:114:154766. doi: 10.1016/j.phymed.2023.154766. Epub 2023 Mar 21.

Authors

Minna Huang¹, Yan Yan¹, Zihao Deng², Lingli Zhou², Meiling She¹, Yajun Yang³, Meng Zhang¹, Dongtao Wang⁴

Affiliations

¹ Department of Traditional Chinese Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, 518000, China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510000, China.
² The First Clinical Medical College, Southern Medical University, Guangzhou, 510000, China.
³ Department of Pharmacology, Guangdong Key Laboratory for R&D of Natural Drug, Guangdong Medical University, Zhanjiang,524000, China.
⁴ Department of Traditional Chinese Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, 518000, China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510000, China. Electronic address: 95401864@qq.com.

PMID: 37002971
DOI: 10.1016/j.phymed.2023.154766

Abstract

Background: Skeletal muscle atrophy in chronic kidney disease (CKD) leads to a decline in quality of life and increased risk of morbidity and mortality. We have obtained evidence that oxidative stress is essential in the progression of CKD-related muscle atrophy. Whether Saikosaponin A and D, two emerging antioxidants extracted from Bupleurum chinense DC, alleviate muscle atrophy remains to be further studied. The purpose of this study was to investigate the effects and mechanisms of these two components on CKD complicated with muscle atrophy.

Methods: In this research, muscle dystrophy model was established using 5/6 nephrectomized mice in vivo and in vitro with Dexamethasone (Dex)-managed C2C12 myotubes.

Results: The results of RNA-sequencing showed that exposure to Dex affected the antioxidant activity, catalytic activity and enzyme regulator activity of C2C12 cells. According to KEGG analysis, the largest numbers of differentially expressed genes detected were enriched in the PI3K/AKT pathway. In vivo, Saikosaponin A and D remain renal function, cross-section size, fiber-type composition and anti-inflammatory ability. These two components suppressed the expression of MuRF-1 and enhanced the expression of MyoD and Dystrophin. In addition, Saikosaponin A and D maintained redox balance by increasing the activities of antioxidant enzymes while inhibiting the excessive accumulation of reactive oxygen species. Furthermore, Saikosaponin A and D stimulated PI3K/AKT and its downstream Nrf2 pathway in CKD mice. The effects of Saikosaponin A and D on increasing the inner diameter of C2C12 myotube, reducing oxidative stress and enhancing expression of p-AKT, p-mTOR, p70S6K, Nrf2 and HO-1 proteins were observed in vitro. Importantly, we verified that these protective effects could be significantly reversed by inhibiting PI3K and knocking out Nrf2.

Conclusions: In summary, Saikosaponin A and D improve CKD-induced muscle atrophy by reducing oxidative stress through the PI3K/AKT/Nrf2 pathway.

Keywords: Chronic kidney disease; Oxidative stress; PI3K/AKT/Nrf2 pathway; Saikosaponin; Skeletal muscle atrophy.

MeSH terms

Animals
Antioxidants / pharmacology
Mice
Muscle Fibers, Skeletal
Muscle, Skeletal
Muscular Atrophy / etiology
NF-E2-Related Factor 2 / metabolism
Oxidation-Reduction
Oxidative Stress
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt* / metabolism
Quality of Life
Renal Insufficiency, Chronic*

Substances

Proto-Oncogene Proteins c-akt
Phosphatidylinositol 3-Kinases
NF-E2-Related Factor 2
saikosaponin D
Antioxidants

Supplementary concepts

Bupleurum falcatum