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Title: GROWTH HORMONE ALTERS METHIONINE AND GLUTATHIONE METABOLISM IN AMES DWARF MICE

Author
item BROWN-BORG, HOLLY - UNIV OF NORTH DAKOTA
item RAKOCZY, SHARLENE - UNIV OF NORTH DAKOTA
item Uthus, Eric

Submitted to: Mechanisms of Aging and Development
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/14/2004
Publication Date: 10/13/2004
Citation: Brown-Borg, H.M., Radoczy, S.G., Uthus, E.O. 2004. Growth hormone alters methionine and glutathione metabolism in Ames dwarf mice. Mechanisms of Ageing and Development 126:389-398.

Interpretive Summary: Animals that lack growth hormone (GH) and another growth factor called IGF-1, usually live longer than animals that have normal amounts of these compounds. One animal that lacks these compounds (because of a genetic mutation) is the Ames dwarf mouse. Because it lacks GH it is considerably smaller than its counterpart which has the hormone. Furthermore, the Ames dwarf lives 50-64% longer than its "normal" counterpart. One possible reason that the Ames dwarf mouse lives so long is that it appears to have an enhanced capacity to neutralize the effects of oxidative damage. We wanted to know whether the enhanced oxidative defense system in the Ames dwarf mouse was the result of its lack of GH. Thus, we injected GH into a group of the dwarf mice and compared their oxidative defense system to other dwarf mice that were injected with saline only. We found that the ability to defend against oxidative stress of those mice injected with GH was not as great as that found in the dwarf mice which lack GH. Our results suggest that GH can regulate the oxidative defense system and ultimately, the life span of these mice.

Technical Abstract: Reduced signaling of the growth hormone (GH)/insulin-like growth factor-1(IGF-1)/insulin pathway is associated with extended life span in several species. Ames dwarf mice are GH and IGF-1 deficient and live 50-64% longer than wild type littermates (males and females, respectively). Previously, we have shown that Ames mice exhibit elevated levels of antioxidant enzymes and lower oxidative damage. To further explore the relationship between GH and antioxidant expression, we administered GH or saline to dwarf mice and elevated components of the methionine and glutathione (GSH) metabolic pathways. Treatment of dwarf mice with GH significantly suppressed methionine adenosyltransferase (40 and 38%) and glycine-N-methyltransferase (44 and 43%) activities (in 3 and 12 month old mice, respectively). Growth hormone treatment elevated kidney gamma-glutamyl-cysteine synthetase protein levels in 3 and 12 month old dwarf mice. In contrast, the activity of the GSH degradation enzyme, gamma-glutamyl transpeptidase, was suppressed by GH administration in heart and liver. The activity of glutathione-S-transferase, an enzyme involved in detoxification, was also affected by GH treatment. Taken together, the current results along with data from previous studies support a role for growth hormone in the regulation of antioxidative defense and ultimately, life span in organisms with altered GH or IGF-1 signaling.