Taurine deficiency, synthesis and transport in the mdx mouse model for Duchenne Muscular Dystrophy

Abstract

The amino acid taurine is essential for the function of skeletal muscle and administration is proposed as a treatment for Duchenne Muscular Dystrophy (DMD). Taurine homeostasis is dependent on multiple processes including absorption of taurine from food, endogenous synthesis from cysteine and reabsorption in the kidney. This study investigates the cause of reported taurine deficiency in the dystrophic mdx mouse model of DMD. Levels of metabolites (taurine, cysteine, cysteine sulfinate and hypotaurine) and proteins (taurine transporter [TauT], cysteine deoxygenase and cysteine sulfinate dehydrogenase) were quantified in juvenile control C57 and dystrophic mdx mice aged 18 days, 4 and 6 weeks. In C57 mice, taurine content was much higher in both liver and plasma at 18 days, and both cysteine and cysteine deoxygenase were increased. As taurine levels decreased in maturing C57 mice, there was increased transport (reabsorption) of taurine in the kidney and muscle. In mdx mice, taurine and cysteine levels were much lower in liver and plasma at 18 days, and in muscle cysteine was low at 18 days, whereas taurine was lower at 4: these changes were associated with perturbations in taurine transport in liver, kidney and muscle and altered metabolism in liver and kidney. These data suggest that the maintenance of adequate body taurine relies on sufficient dietary intake of taurine and cysteine availability and metabolism, as well as retention of taurine by the kidney. This research indicates dystrophin deficiency not only perturbs taurine metabolism in the muscle but also affects taurine metabolism in the liver and kidney, and supports targeting cysteine and taurine deficiency as a potential therapy for DMD.

Levels of inflammation and oxidative stress, and a role for taurine in dystropathology of the Golden Retriever Muscular Dystrophy dog model for Duchenne Muscular Dystrophy

“…This is reflected in the upregulation of TauT, cysteine deoxygenase and cysteine sulfinate decarboxylase we observed in GRMD muscle. Interestingly, this was not observed in mdx mice, where we have previously described downregulation of TauT in both young (18 day) and adult (6 week) mdx muscle, and a downregulation of cysteine deoxygenase at 4 weeks of age [31].…”

“…We and others have observed that taurine content of dystrophic mdx muscle is variable across the age (and stage of disease progression) [31], [34], [100]. Whilst the timing and muscles used in these different mdx studies is variable, early in the disease progression (before 6 weeks) mdx muscles have low taurine content, with taurine content increasing with age.…”

“…Investigating taurine homeostasis in GRMD muscle in conjunction with measuring protein oxidation and inflammation is of interest as we have previously shown taurine homeostasis is perturbed in mdx mice [31], and taurine treatment decreased protein thiol oxidation, neutrophil and MPO content in mdx muscle, and prevented myofibre necrosis [23]. The antioxidant and anti-inflammatory properties of taurine are attributed to its ability to interact with HOCl, which reacts with amino acids to form long-lived chloramines such as taurine chloramine; chloramines are much less reactive than HOCl [41].…”

“…Taurine is found in many tissues and is considered important for the function of skeletal muscle; the concentration of taurine in tissues is regulated by interactions between dietary intake, biosynthetic rate (mainly in the liver) tissue uptake and elimination via the kidney [31]. We recently showed in mdx mice that systemic taurine homeostasis is perturbed and may correlate with the onset of pathology [31], and treatment of adult mdx mice with taurine improves both in vivo and ex vivo muscle strength [23], [32], [33]. Importantly, in young mdx mice aged 22 days, taurine treatment (from day 14) prevents the acute onset of myofibre necrosis [34].…”

“…Taurine can accumulate in cells through two mechanisms; by uptake from the extracellular space by the sodium dependent transporter TauT, and by endogenous local synthesis from cysteine by two enzymes, cysteine deoxygenase and cysteine sulfinate decarboxylase [29], [53]. Since we have previously shown that both mechanisms are perturbed in mdx muscle [31], we measured TauT, cysteine deoxygenase and cysteine sulfinate decarboxylase in GRMD muscle, as well as taurine content of the muscle and plasma (to establish extracellular taurine concentrations). We show that GRMD muscle has an increased content of neutrophils and macrophages with resultant high levels of MPO and HOCl, associated with high levels of protein thiol oxidation and irreversible oxidative damage of both intracellular and extracellular proteins; we also show perturbations of taurine homeostasis in GRMD dogs.…”