Disrupted GH-IGF-1 throughout disease progression in the hSOD1G93A mouse model of Amyotrophic Lateral Sclerosis (ALS) (#93)
Growth hormone (GH) deficiency has been described in ALS patients1 , and the hSOD1G93A mouse model of ALS2 . As a first step to characterizing the impact of altered GH on disease, we analysed pulsatile GH secretion, total circulating and muscle insulin-like growth factor 1 (IGF-1), and conducted histopathological assessment in wild-type and hSOD1G93A mice. Male wild-type and hSOD1G93A transgenic mice were studied at the pre-symptomatic (30-36 days), onset (63-75 days) and end-stage of disease (150-175 days). Tail-tip whole blood samples (2 or 4μl) were collected over a 6hr period at 10min intervals starting at 0700h and assayed for GH3. Pulsatile GH secretion was analysed by deconvolution analysis.
Pre-symptomatic hSOD1G93A mice have similar pulsatile GH secretion profiles when compared to wild-type age-matched controls. When compared to age-matched wild-type mice, hSOD1G93A mice at the onset of disease have a dramatic increase in GH secreted per burst, pulsatile GH secretion rate, and total GH secretion rate (p<0.05, n=9 wild-type, n=7 hSOD1G93A, t-test). As observed previously2 , hSOD1G93A mice at the end-stage of disease present with a significant decrease in the amount of GH secreted per burst, pulsatile GH secretion rate, and total GH secretion rate (p<0.05, n=11 wild-type, n=8 hSOD1G93A, t-test). Increased GH at the onset of disease in hSOD1G93A mice coincided with an increase in muscle IGF-1 (p=0.0171, n=6, t-test), and neuromuscular denervation (p=0.0002, n=6, t-test). Diminished GH at the end-stage of disease in hSOD1G93A mice occurred alongside a decrease in circulating IGF-1 (p=0.0407, n=6, t-test) and extensive neuromuscular denervation (p<0.0001, n=6, t-test). Analysis of IGF-1R in skeletal muscle reveals a significant decrease in IGF-1R in hSOD1G93A mice at the end-stage of disease (p=0.0082, n=6, t-test). Disruptions to GH and IGF-1 occur throughout ALS disease progression in hSOD1G93A mice. Whether these disruptions contribute to, or exacerbate the disease process remains to be determined.
This work was supported by the NHMRC, UQ, SBMS and UQCCR. Dr Shyuan Ngo is a Motor Neurone Disease Research Institute of Australia (MNDRIA) Bill Gole Postdoctoral Fellow.
- L.L. Morselli et al. (2006) Growth hormone secretion is impaired in amyotrophic lateral sclerosis. Clinical Endocrinology. 65 (3): 385-8.
- F.J. Steyn, S.T. Ngo et al. (2012) Impairments to the GH-IGF1 axis in hSOD1G93A mice give insight into possible mechanisms of GH dysregulation in patients with Amyotrophic Lateral Sclerosis. Endocrinology. doi:10.1210/en.2011-2171.
- F.J. Steyn, L. Huang et al. (2011) Development of a method for the determination of pulsatile growth hormone secretion in mice. Endocrinology. 152 (8): 3165-71.