Effects on Neural Function of Repleting Vitamin E–Deficient Rats With α-Tocopherol

Hayton, Samantha; Kriss, Tony; Wade, Angie; Muller, D. P. R.

doi:10.1152/jn.00842.2005

Cited by 13 publications

(4 citation statements)

References 32 publications

(34 reference statements)

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“…2, 86). Interestingly, a previous study showed a similar, age‐related effect on body weights of rats fed an αT‐depleted diet 38. Autopsy of the old αTTP‐KO mice was remarkable for decreased amount of abdominal white adipose tissue.…”

Section: Future Directionsmentioning

confidence: 65%

“…Equally noteworthy is that 1 mg of αT/Kg of diet is sufficient to prevent the deficiency symptoms. It seems that larger amounts of dietary αT supplements, 36 mg/Kg diet, are necessary to reverse the symptoms caused by dietary αT deficiency 38. The effects of the differences in micronutrient composition on “stability” of other labile dietary constituents, such as vitamin A, essential aminoacids and unsaturated fatty acids, remain uncharacterized.…”

Section: Nutritional Myopathy and Ataxia In Animal Models Of Dietarmentioning

confidence: 99%

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Dietary α‐tocopherol and neuromuscular health: Search for optimal dose and molecular mechanisms continues!

Gohil

Vasu

Cross

2010

Molecular Nutrition Food Res

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Rodents fed alpha-tocopherol (alphaT)-depleted diets develop neuromuscular deficits. Unequivocal role of alphaT in the prevention of these deficits is confounded by possible neurotoxic oxidant products generated, ex vivo in alphaT-depleted diets. The discovery that large doses of alphaT could ameliorate neuromuscular deficits, attributed to very low serum alphaT caused by mutations in either the microsomal triglyceride transfer protein or the alphaT-transfer protein (alphaTTP), underscores the necessity of alphaT for neuromuscular health in humans. The discovery of human alphaTTP provided physiological relevance to biochemical data from rodents documenting alphaT-binding transfer protein, expressed exclusively in liver. The cloning of alphaTTP gene and the creation of alphaTTP-knockout mice allowed to achieve severe systemic alphaT deficiency in brain and muscles, possibly at birth, eliminating the possible confounding effects of ex vivo-generated oxidant products in vitamin E-stripped diets. alphaTTP-knockout mice have proven useful models to discover alphaT-regulated phenotypes and molecular actions of alphaT in vivo. The results suggest that antioxidant and non-antioxidant actions of alphaT in vivo may not be mutually exclusive. These studies also suggest that low levels of dietary alphaT can achieve in excess of nanomolar alphaT levels in tissues and maintain normal neuromuscular functions. This is consistent with biochemical and crystallographic data of alpha-TTP and of other alphaT-binding proteins that have dissociation constants in nanomolar range. Molecular mechanisms that cause a long delay for the development of deficiency symptoms remain enigmatic. It is likely that alphaT is metabolically stable in post-mitotic neurons and myocytes and, if it undergoes redox-cycling in vivo, a large repertoire of alphaT-regenerating systems maintains its biological activity before it is totally depleted.

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Section: Future Directionsmentioning

confidence: 65%

Section: Nutritional Myopathy and Ataxia In Animal Models Of Dietarmentioning

confidence: 99%

Dietary α‐tocopherol and neuromuscular health: Search for optimal dose and molecular mechanisms continues!

Gohil

Vasu

Cross

2010

Molecular Nutrition Food Res

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“…A hierarchical cluster analysis further suggested that α-TTP might be required for normal functioning of glial cells and oligodendrocytes (Gohil et al 2004). A more detailed investigation of α-tocopherol-regulated genes in the brain will finally provide a molecular basis for neurological disorders that develop in vitamin E deficiency (Hayton et al 2006).…”

Section: Functions Of Vitamin Ementioning

confidence: 99%

Bioactivity of vitamin E

Brigelius‐Flohé

2006

Nutr. Res. Rev.

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More than 80 years after the discovery of the essentiality of vitamin E for mammals, the molecular basis of its action is still an enigma. From the eight different forms of vitamin E, only alpha-tocopherol is retained in the body. This is in part due to the specific selection of RRR-alpha-tocopherol by the alpha-tocopherol transfer protein and in part by its low rate of degradation and elimination compared with the other vitamers. Since the tocopherols have comparable antioxidant properties and some tocotrienols are even more effective in scavenging radicals, the antioxidant capacity cannot be the explanation for its essentiality, at least not the only one. In the last decade, a high number of so-called novel functions of almost all forms of vitamin E have been described, including regulation of cellular signalling and gene expression. alpha-Tocopherol appears to be most involved in gene regulation, whereas gamma-tocopherol appears to be highly effective in preventing cancer-related processes. Tocotrienols appear to be effective in amelioration of neurodegeneration. Most of the novel functions of individual forms of vitamin E have been demonstrated in vitro only and require in vivo confirmation. The distinct bioactivities of the various vitamers are discussed, considering their metabolism and the potential functions of metabolites.

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“…Previous studies in rodents [49] and humans [50] have suggested that chronic AT-deficiency results in initial loss of neural functions. Hence, the transcriptomic responses of skeletal muscles of ATTP-KO mice described here may be in addition to neural deficits.…”

Section: Discussionmentioning

confidence: 99%

Sarcolipin and ubiquitin carboxy-terminal hydrolase 1 mRNAs are over-expressed in skeletal muscles ofα-tocopherol deficient mice

Vasu

Ott

Hobson

et al. 2009

Free Radical Research

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The transcriptome of ataxic muscles from α-tocopherol transfer protein deficient (ATTP-KO), 23-month old, mice was compared with that of their normal littermates. Genes encoding sarcolipin (sln) and ubiquitin carboxyl-terminal hydrolase (uchl1) were over-expressed (≥ 10-fold) in ataxic muscles. SLN is a 3.2 kDa membrane protein that binds to sarcoplasmic reticulum calcium ATPase, regulates Ca ++ transport and muscle relaxation-contraction cycles. UCHL1 is a 24.8 kDa member of proteosome proteins; it is over-expressed in myofibrillar myopathy and is associated with neurodegenerative diseases. Furthermore, six additional transcripts, three encoding thin-filament proteins and three encoding Ca ++ sensing proteins that participate in contraction-relaxation cycle, and eight transcripts that encode members of lysosomal proteins were also over-expressed in ataxic muscles. These observations suggest that chronic α-tocopherol (AT) deficiency activates critical genes of muscle contractility and protein degradation pathways, simultaneously. The magnitude of induction of sln and uchl1 was lower in asymptomatic, 8-month old, ATTP-KO mice and in 8-month old mice fed an AT-depleted diet. These studies suggest sln and uchl1 genes as novel targets of AT deficiency and may offer molecular correlates of well documented descriptions of neuromuscular dysfunctions in AT-deficient rodents. Since the neuromuscular deficits of ATTP-KO mice appear to be similar to those of patients with ATTP mutations, it is suggested that over-expression of sln and uchl1 may also contribute to AT-sensitive ataxia in humans.

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Effects on Neural Function of Repleting Vitamin E–Deficient Rats With α-Tocopherol

Abstract: Effects on neural function of repleting vitamin E-deficient rats with ␣-tocopherol.

Cited by 13 publications

References 32 publications

Dietary α‐tocopherol and neuromuscular health: Search for optimal dose and molecular mechanisms continues!

Dietary α‐tocopherol and neuromuscular health: Search for optimal dose and molecular mechanisms continues!

Bioactivity of vitamin E

Sarcolipin and ubiquitin carboxy-terminal hydrolase 1 mRNAs are over-expressed in skeletal muscles ofα-tocopherol deficient mice

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