Role of the GH/IGF-I axis in the growth retardation of weaver mice

Abstract

IGF-I is a well-established anabolic growth factor essential for growth and development. Although the role of the GH/IGF-I axis is established for normal postnatal growth, its functional state in neurodegenerative diseases is not fully characterized. The weaver mutant mouse is a commonly used model for studying hereditary cerebellar ataxia and provides an opportunity to investigate the function of IGF-I in postnatal growth following neurodegeneration. Previously, we reported that weaver mice are growth retarded and their body weights correlate with a decrease in circulating IGF-I levels. Because weaver mice have the same food intake/body weight ratios as their wild type littermates, our observation suggests that an impairment of the GH/IGF-I axis, rather than poor nutrition, likely contributes to their growth retardation. This study further investigated the etiology of reduced circulating IGF-I levels. We found that GH levels in weaver mice were reduced following acute insulin injection, but the hepatic GH receptor transduction pathway signaled normally as evidenced by increased STAT5b phosphorylation and IGF-I mRNA levels in response to acute GH administration. In addition, 2-week GH treatment induced a significant increase in body weight and circulating IGF-I levels in homozygous weaver mice but not in wild type littermates. In summary, a deficiency in the GH/IGF-I axis may be partially responsible for postnatal growth retardation in weaver mutant mice. This deficiency may occur at the level of the pituitary and/or hypothalamus and can be improved with GH administration.

Distinctive Phenotypic Abnormalities Associated with Submicroscopic 21q22 Deletion Including DYRK1A

“…Heterozygous weaver mice have a decreased number of surviving granule cells and suffer sporadically from tonic-clonic seizures [Patil et al, 1995]. Also, homozygous weaver mice have decreased levels of circulating IGF1 and responded to GH-treatment [Yao et al, 2007]. The postnatal growth retardation in our patients might be partially explained by a deficient GH/IGF1 axis, as seen in mutant weaver mice.…”

IGF-I improved bone mineral density and body composition of weaver mutant mice

“…Regardless, malnutrition due to lower food intake is unlikely the cause of low IGF-I circulating levels, because homozygous weaver mice consumed the same amount of food as their wild-type littermates (Yao et al, 2007). On the other hand, decreased circulating IGF-I in weaver mice likely results from their lower circulating GH levels (50% lower) (Yao et al, 2007).…”

“…Regardless, malnutrition due to lower food intake is unlikely the cause of low IGF-I circulating levels, because homozygous weaver mice consumed the same amount of food as their wild-type littermates (Yao et al, 2007). On the other hand, decreased circulating IGF-I in weaver mice likely results from their lower circulating GH levels (50% lower) (Yao et al, 2007). Since GH also has positive effects on bone mass and BMD (Johansson et al, 1992), it is likely that the decrease in bone growth results from a combined deficiency of the GH/IGF-I axis.…”

“…Therefore, decreases in GH levels and/or GH activities likely attenuate its lipolytic action and lead to fat accumulation, as we see in homozygous weaver mice. Since both IGF-I (Yao et al, 2005) and GH hormone (Yao et al, 2007) are decreased in homozygous weaver mice, their poor body composition is most likely the result of the combined deficiency of the GH/IGF-I axis.…”