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

被引：143

作者：

Sato, Emiko ^{[1
,2
]}

Mori, Takefumi ^{[1
,3
,4
]}

Mishima, Eikan ^{[1
]}

Suzuki, Arisa ^{[1
]}

Sugawara, Sanae ^{[1
]}

Kurasawa, Naho ^{[1
]}

Saigusa, Daisuke ^{[5
]}

Miura, Daisuke ^{[6
]}

Morikawa-Ichinose, Tomomi ^{[6
]}

Saito, Ritsumi ^{[5
]}

Oba-Yabana, Ikuko ^{[1
,4
]}

Oe, Yuji ^{[1
]}

Kisu, Kiyomi ^{[1
]}

Naganuma, Eri ^{[1
]}

Koizumi, Kenji ^{[1
]}

Mokudai, Takayuki ^{[7
]}

Niwano, Yoshimi ^{[7
]}

Kudo, Tai ^{[8
]}

Suzuki, Chitose ^{[1
]}

Takahashi, Nobuyuki ^{[1
,2
]}

Sato, Hiroshi ^{[1
,2
]}

Abe, Takaaki ^{[1
]}

Niwa, Toshimitsu ^{[9
]}

Ito, Sadayoshi ^{[1
]}

机构：

[1] Tohoku Univ, Grad Sch Med, Div Nephrol Endocrinol & Vasc Med, Sendai, Miyagi 9808574, Japan

[2] Tohoku Univ, Grad Sch Pharmaceut Sci, Div Clin Pharmacol & Therapeut, Sendai, Miyagi 9808578, Japan

[3] Tohoku Univ, Grad Sch Med, Div Integrat Renal Replacement Therapy, Sendai, Miyagi 9808574, Japan

[4] Tohoku Med & Pharmaceut Univ, Div Nephrol & Endocrinol, Sendai, Miyagi 9818512, Japan

[5] Tohoku Univ, Tohoku Med Megabank Org, Dept Integrat Genom, Sendai, Miyagi 9808573, Japan

[6] Kyushu Univ, Innovat Ctr Med Redox Nav, Fukuoka 8128582, Japan

[7] Tohoku Univ, Grad Sch Dent, Lab Redox Regulat, Sendai, Miyagi 9808575, Japan

[8] Primetech Co Ltd, Tokyo 1120002, Japan

[9] Shubun Univ, Ichinomiya 4910938, Japan

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

关键词：

PROTEIN; EXPRESSION; KLOTHO; ACTIVATION; ACIDOSIS; TOXINS; TRANSCRIPTION; GLUCOSE; PLASMA; SIGNAL;

D O I：

10.1038/srep36618

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

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[11]

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[12] A potential role for Akt/FOXO signalling in both protein loss and the impairment of muscle carbohydrate oxidation during sepsis in rodent skeletal muscle [J].