Metabolic alterations by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease.
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.
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.|Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, 980-8578, Japan.
Emiko
E
Sato
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.|Division of Integrative Renal Replacement Therapy, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.|Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, Sendai, 981-8512, Japan.
Takefumi
T
Mori
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
Eikan
E
Mishima
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
Arisa
A
Suzuki
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
Sanae
S
Sugawara
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
Naho
N
Kurasawa
Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan.
Daisuke
D
Saigusa
Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, 812-8582, Japan.
Daisuke
D
Miura
Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, 812-8582, Japan.
Tomomi
T
Morikawa-Ichinose
Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan.
Ritsumi
R
Saito
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.|Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, Sendai, 981-8512, Japan.
Ikuko
I
Oba-Yabana
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
Yuji
Y
Oe
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
Kiyomi
K
Kisu
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
Eri
E
Naganuma
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
Kenji
K
Koizumi
Laboratory for Redox Regulation, Tohoku University Graduate School of Dentistry, Sendai, 980-8575, Japan.
Takayuki
T
Mokudai
Laboratory for Redox Regulation, Tohoku University Graduate School of Dentistry, Sendai, 980-8575, Japan.
Yoshimi
Y
Niwano
Primetech Co. Ltd., Tokyo, 112-0002, Japan.
Tai
T
Kudo
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
Chitose
C
Suzuki
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.|Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, 980-8578, Japan.
Nobuyuki
N
Takahashi
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.|Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, 980-8578, Japan.
Hiroshi
H
Sato
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
Takaaki
T
Abe
Shubun University, Ichinomiya, 491-0938, Japan.
Toshimitsu
T
Niwa
Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
Sadayoshi
S
Ito
D000818:Animals; D004195:Disease Models, Animal; D007200:Indican / Q000378:metabolism*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000473:pathology; D055948:Sarcopenia / Q000378:metabolism* / Q000473:pathology; D014511:Uremia / Q000378:metabolism* / Q000473:pathology
D007200:Indican