title: Cystathionine gamma-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 gamma-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 beta-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.
authors.affiliation: Department of Biochemistry and Integrative Medical Biology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan. isao-ishii@umin.ac.jp
authors.forename: Isao
authors.initials: I
authors.lastname: Ishii
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Akahoshi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Yamada
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nakano
authors.forename: Takashi
authors.initials: T
authors.lastname: Izumi
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
mesh_terms: D000818:Animals; D003542:Cystathionine gamma-Lyase / Q000172:deficiency*; D003545:Cysteine / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006712:Homocystinuria / Q000175:diagnosis / Q000209:etiology; D020138:Hyperhomocysteinemia / Q000188:drug therapy; D051379:Mice; D018345:Mice, Knockout; D009135:Muscular Diseases / Q000209:etiology / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects*; D020011:Protective Agents
chemical_list: D020011:Protective Agents; D003542:Cystathionine gamma-Lyase; D003545:Cysteine