Effects of insulin-like growth factor 1 on glutathione S-transferases and thioredoxin in growth hormone receptor knockout mice.

ABSTRACT

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) have been shown to affect processes involved in cellular stress defense, aging, and longevity. This study was designed to identify possible mechanisms of a disrupted GH signaling pathway on stress resistance using growth hormone receptor knockout (GHRKO) mice. GHRKO mice are GH resistant due to the targeted disruption of the GH receptor/binding protein gene, thus preventing GH from binding and exerting its downstream effects. These mice have very low circulating IGF-1 levels and high GH levels, are obese yet insulin sensitive, and live longer than their wild-type controls. Wild-type or GHRKO mice were treated with saline or IGF-1 (WT saline, GHRKO saline, GHRKO IGF-1) two times daily for 7 days. Glutathione S-transferase (GST) activities, proteins, and gene expression were determined. Liver mitochondrial GSTA1, GSTA3, and GSTZ1 proteins were significantly higher in GHRKO when compared to those of WT mice. The 4-hydroxynonenal (4-HNE) GST activity was upregulated in GHRKO mice and was suppressed after IGF-1 administration. Interestingly, thioredoxin (Trx)1, Trx2, thioredoxin reductase (TrxR)1, and TrxR2 messenger RNA (mRNA) levels were significantly higher in the GHRKO as compared to WT mice, and IGF-1 treatment suppressed the expression of each. We also found that glutaredoxin (Grx)2 mRNA and cytosolic Grx activity were higher in GHRKO mice. These results suggest that the detoxification and stress response mechanisms in GHRKO mice are contributed in part by the circulating level of IGF-1.