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 ␥-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 ␤-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.

Plasma Cystathionine and Risk of Incident Stroke in Patients With Suspected Stable Angina Pectoris

“…It is therefore interesting that plasma cystathionine demonstrated a positive association with asymmetric dimethylarginine in our study, given that asymmetric dimethylarginine may induce vascular dysfunction through suppression of endothelial nitric oxide synthase 31. In addition, systemic cystathionine elevation has previously been related to impaired downstream catabolism to cysteine, rather than increased production per se 7, 32. Reduced cystathionine‐transsulfuration may impair glutathione production and thereby lead to oxidative stress 7.…”

“…Oxidative stress can, in turn, further impair endothelial morphology by inactivating nitric oxide,9 in addition to mediating several other biological processes such as lipid peroxidation and induction of vascular lesions 1. Notably, a previous study from a subsample of the current cohort showed that higher plasma cystathionine concentration are related to low levels of reduced glutathione,33 indicating impaired antioxidant defence 7…”

“…Met, Hcy, and Cys are important metabolites of 1‐carbon cycle and are closely associated with cystathionine metabolism 2, 7. Hence, we also studied the potential influence by adjusting for these parameters on the cystathionine‐stroke risk associations.…”

“…In addition, systemic cystathionine elevation has previously been related to impaired downstream catabolism to cysteine, rather than increased production per se 7, 32. Reduced cystathionine‐transsulfuration may impair glutathione production and thereby lead to oxidative stress 7. Oxidative stress can, in turn, further impair endothelial morphology by inactivating nitric oxide,9 in addition to mediating several other biological processes such as lipid peroxidation and induction of vascular lesions 1.…”

“…Increased flux through cystathionine β‐synthase has also been suggested to worsen outcome of ischemic stroke in experimental studies 5. Notably, elevated circulating cystathionine concentrations were observed in patients with cardiovascular disease (CVD),6 and increased levels were associated with oxidative damage7 and endothelial dysfunction 4, 8. Both these processes play a critical role in the pathogenesis of atherosclerotic disease9 and hence to clinical manifestations such as ischemic stroke 1, 10.…”