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

Kishorchandra Gohil, Vihas T. Vasu, Carroll E Cross

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)693-709
Number of pages17
JournalMolecular Nutrition and Food Research
Volume54
Issue number5
DOIs
StatePublished - May 2010

Keywords

  • Antioxidant
  • Ataxia
  • Sarcolipin
  • TTP-KO
  • Vitamin E

ASJC Scopus subject areas

  • Food Science
  • Biotechnology

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