Metabolic alterations by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease

Emiko Sato, Takefumi Mori, Eikan Mishima, Arisa Suzuki, Sanae Sugawara, Naho Kurasawa, Daisuke Saigusa, Daisuke Miura, Tomomi Morikawa-Ichinose, Ritsumi Saito, Ikuko Oba-Yabana, Yuji Oe, Kiyomi Kisu, Eri Naganuma, Kenji Koizumi, Takayuki Mokudai, Yoshimi Niwano, Tai Kudo, Chitose Suzuki, Nobuyuki TakahashiHiroshi Sato, Takaaki Abe, Toshimitsu Niwa, Sadayoshi Ito

Research output: Contribution to journalArticlepeer-review

64 Citations (Scopus)

Abstract

Sarcopenia is associated with increased morbidity and mortality in chronic kidney disease (CKD). Pathogenic mechanism of skeletal muscle loss in CKD, which is defined as uremic sarcopenia, remains unclear. We found that causative pathological mechanism of uremic sarcopenia is metabolic alterations by uremic toxin indoxyl sulfate. Imaging mass spectrometry revealed indoxyl sulfate accumulated in muscle tissue of a mouse model of CKD. Comprehensive metabolomics revealed that indoxyl sulfate induces metabolic alterations such as upregulation of glycolysis, including pentose phosphate pathway acceleration as antioxidative stress response, via nuclear factor (erythroid-2-related factor)-2. The altered metabolic flow to excess antioxidative response resulted in downregulation of TCA cycle and its effected mitochondrial dysfunction and ATP shortage in muscle cells. In clinical research, a significant inverse association between plasma indoxyl sulfate and skeletal muscle mass in CKD patients was observed. Our results indicate that indoxyl sulfate is a pathogenic factor for sarcopenia in CKD.

Original languageEnglish
Article number36618
JournalScientific reports
Volume6
DOIs
Publication statusPublished - Nov 10 2016

All Science Journal Classification (ASJC) codes

  • General

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