Cystathionine γ-lyase-deficient mice require dietary cysteine to protect against acute lethal myopathy and oxidative injury

Isao Ishii, Noriyuki Akahoshi, Hidenori Yamada, Shintaro Nakano, Takashi Izumi, Makoto Suematsu

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

Cysteine is considered a nonessential amino acid in mammals as it is synthesized from methionine via trans-sulfuration. However, premature infants or patients with hepatic failure may require dietary cysteine due to a lack of cystathionine γ-lyase (CTH), a key trans-sulfuration enzyme. Here, we generated CTH-deficient (Cth-/-) mice as an animal model of cystathioninemia/cystathioninuria. Cth-/- mice developed normally in general but displayed hypercystathioninemia/hyperhomocysteinemia though not hypermethioninemia. When fed a low cyst(e)ine diet, Cth-/- mice showed acute skeletal muscle atrophy (myopathy) accompanied by enhanced gene expression of asparagine synthetase and reduced contents of glutathione in livers and skeletal muscles, and intracellular accumulation of LC3 and p62 in skeletal myofibers; they finally died of severe paralysis of the extremities. Cth-/- hepatocytes required cystine in a culture medium and showed greater sensitivity to oxidative stress. Cth-/- mice exhibited systemic vulnerability to oxidative injury, which became more prominent when they were fed the low cyst(e)ine diet. These results reveal novel roles of trans-sulfuration previously unrecognized in mice lacking another trans-sulfuration enzyme cystathionine β-synthase (Cbs-/-). Because Cbs-/- mice display hyperhomocysteinemia and hypermethioninemia, our results raise questions against the homocysteine-based etiology of CBS deficiency and the current newborn screening for homocysteinemia using Guthrie's method, which detects hypermethioninemia.

Original languageEnglish
Pages (from-to)26358-26368
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number34
DOIs
Publication statusPublished - 2010 Aug 20

Fingerprint

Cystathionine
Lyases
Muscular Diseases
Cysteine
Nutrition
Muscle
Wounds and Injuries
Aspartate-Ammonia Ligase
Hyperhomocysteinemia
Mammals
Oxidative stress
Cystine
Homocysteine
Enzymes
Gene expression
Methionine
Liver
Glutathione
Culture Media
Cysts

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Cystathionine γ-lyase-deficient mice require dietary cysteine to protect against acute lethal myopathy and oxidative injury. / Ishii, Isao; Akahoshi, Noriyuki; Yamada, Hidenori; Nakano, Shintaro; Izumi, Takashi; Suematsu, Makoto.

In: Journal of Biological Chemistry, Vol. 285, No. 34, 20.08.2010, p. 26358-26368.

Research output: Contribution to journalArticle

Ishii, Isao ; Akahoshi, Noriyuki ; Yamada, Hidenori ; Nakano, Shintaro ; Izumi, Takashi ; Suematsu, Makoto. / Cystathionine γ-lyase-deficient mice require dietary cysteine to protect against acute lethal myopathy and oxidative injury. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 34. pp. 26358-26368.
@article{36985c0b0cf645a38d9e56d8e077b8f3,
title = "Cystathionine γ-lyase-deficient mice require dietary cysteine to protect against acute lethal myopathy and oxidative injury",
abstract = "Cysteine is considered a nonessential amino acid in mammals as it is synthesized from methionine via trans-sulfuration. However, premature infants or patients with hepatic failure may require dietary cysteine due to a lack of cystathionine γ-lyase (CTH), a key trans-sulfuration enzyme. Here, we generated CTH-deficient (Cth-/-) mice as an animal model of cystathioninemia/cystathioninuria. Cth-/- mice developed normally in general but displayed hypercystathioninemia/hyperhomocysteinemia though not hypermethioninemia. When fed a low cyst(e)ine diet, Cth-/- mice showed acute skeletal muscle atrophy (myopathy) accompanied by enhanced gene expression of asparagine synthetase and reduced contents of glutathione in livers and skeletal muscles, and intracellular accumulation of LC3 and p62 in skeletal myofibers; they finally died of severe paralysis of the extremities. Cth-/- hepatocytes required cystine in a culture medium and showed greater sensitivity to oxidative stress. Cth-/- mice exhibited systemic vulnerability to oxidative injury, which became more prominent when they were fed the low cyst(e)ine diet. These results reveal novel roles of trans-sulfuration previously unrecognized in mice lacking another trans-sulfuration enzyme cystathionine β-synthase (Cbs-/-). Because Cbs-/- mice display hyperhomocysteinemia and hypermethioninemia, our results raise questions against the homocysteine-based etiology of CBS deficiency and the current newborn screening for homocysteinemia using Guthrie's method, which detects hypermethioninemia.",
author = "Isao Ishii and Noriyuki Akahoshi and Hidenori Yamada and Shintaro Nakano and Takashi Izumi and Makoto Suematsu",
year = "2010",
month = "8",
day = "20",
doi = "10.1074/jbc.M110.147439",
language = "English",
volume = "285",
pages = "26358--26368",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "34",

}

TY - JOUR

T1 - Cystathionine γ-lyase-deficient mice require dietary cysteine to protect against acute lethal myopathy and oxidative injury

AU - Ishii, Isao

AU - Akahoshi, Noriyuki

AU - Yamada, Hidenori

AU - Nakano, Shintaro

AU - Izumi, Takashi

AU - Suematsu, Makoto

PY - 2010/8/20

Y1 - 2010/8/20

N2 - Cysteine is considered a nonessential amino acid in mammals as it is synthesized from methionine via trans-sulfuration. However, premature infants or patients with hepatic failure may require dietary cysteine due to a lack of cystathionine γ-lyase (CTH), a key trans-sulfuration enzyme. Here, we generated CTH-deficient (Cth-/-) mice as an animal model of cystathioninemia/cystathioninuria. Cth-/- mice developed normally in general but displayed hypercystathioninemia/hyperhomocysteinemia though not hypermethioninemia. When fed a low cyst(e)ine diet, Cth-/- mice showed acute skeletal muscle atrophy (myopathy) accompanied by enhanced gene expression of asparagine synthetase and reduced contents of glutathione in livers and skeletal muscles, and intracellular accumulation of LC3 and p62 in skeletal myofibers; they finally died of severe paralysis of the extremities. Cth-/- hepatocytes required cystine in a culture medium and showed greater sensitivity to oxidative stress. Cth-/- mice exhibited systemic vulnerability to oxidative injury, which became more prominent when they were fed the low cyst(e)ine diet. These results reveal novel roles of trans-sulfuration previously unrecognized in mice lacking another trans-sulfuration enzyme cystathionine β-synthase (Cbs-/-). Because Cbs-/- mice display hyperhomocysteinemia and hypermethioninemia, our results raise questions against the homocysteine-based etiology of CBS deficiency and the current newborn screening for homocysteinemia using Guthrie's method, which detects hypermethioninemia.

AB - Cysteine is considered a nonessential amino acid in mammals as it is synthesized from methionine via trans-sulfuration. However, premature infants or patients with hepatic failure may require dietary cysteine due to a lack of cystathionine γ-lyase (CTH), a key trans-sulfuration enzyme. Here, we generated CTH-deficient (Cth-/-) mice as an animal model of cystathioninemia/cystathioninuria. Cth-/- mice developed normally in general but displayed hypercystathioninemia/hyperhomocysteinemia though not hypermethioninemia. When fed a low cyst(e)ine diet, Cth-/- mice showed acute skeletal muscle atrophy (myopathy) accompanied by enhanced gene expression of asparagine synthetase and reduced contents of glutathione in livers and skeletal muscles, and intracellular accumulation of LC3 and p62 in skeletal myofibers; they finally died of severe paralysis of the extremities. Cth-/- hepatocytes required cystine in a culture medium and showed greater sensitivity to oxidative stress. Cth-/- mice exhibited systemic vulnerability to oxidative injury, which became more prominent when they were fed the low cyst(e)ine diet. These results reveal novel roles of trans-sulfuration previously unrecognized in mice lacking another trans-sulfuration enzyme cystathionine β-synthase (Cbs-/-). Because Cbs-/- mice display hyperhomocysteinemia and hypermethioninemia, our results raise questions against the homocysteine-based etiology of CBS deficiency and the current newborn screening for homocysteinemia using Guthrie's method, which detects hypermethioninemia.

UR - http://www.scopus.com/inward/record.url?scp=77956194462&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77956194462&partnerID=8YFLogxK

U2 - 10.1074/jbc.M110.147439

DO - 10.1074/jbc.M110.147439

M3 - Article

C2 - 20566639

AN - SCOPUS:77956194462

VL - 285

SP - 26358

EP - 26368

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 34

ER -