title: Impairments to the GH-IGF-I axis in hSOD1G93A mice give insight into possible mechanisms of GH dysregulation in patients with amyotrophic lateral sclerosis.
abstract: GH deficiency has been found in subjects with amyotrophic lateral sclerosis (ALS). Disrupted endocrine function could contribute to the progressive muscle loss and hypermetabolism seen in ALS. It is not possible to study all the elements of the GH-IGF-I axis in ALS patients. Consequently, it remains unclear whether dysfunctional GH secretion contributes to disease pathogenesis and why GH and IGF-I directed treatment strategies are ineffective in human ALS. The hSOD1(G93A) transgenic mouse model is useful for the detailed investigation of the pathogenesis of ALS. We report that symptomatic male hSOD1(G93A) transgenic mice exhibit a deficiency in GH secretion similar to that seen in human ALS. Further characterization of the GH-IGF-I axis in hSOD1(G93A) mice reveals central and peripheral abnormalities that are not found in wild-type age-matched controls. Specifically, we observe aberrant endogenous pulsatile GH secretion, reduced pituitary GH content, and decreased circulating levels of IGF-I, indicating global GH deficiency in hSOD1(G93A) mice. Furthermore, a reduction in the expression of the IGF-I receptor α-subunit in skeletal muscle and lumbar spinal cords of hSOD1(G93A) mice suggests impaired IGF-I signaling within these tissues. This is the first account of disrupted GH secretion in a transgenic mouse model of ALS. These observations are essential for the development of effective GH and IGF-I targeted therapies in ALS.
authors.affiliation: School of Biomedical Sciences, University of Queensland, St. Lucia 4072, Australia. f.steyn@uq.edu.au
authors.forename: F J
authors.initials: FJ
authors.lastname: Steyn
authors.forename: S T
authors.initials: ST
authors.lastname: Ngo
authors.forename: J D
authors.initials: JD
authors.lastname: Lee
authors.forename: J W
authors.initials: JW
authors.lastname: Leong
authors.forename: A J
authors.initials: AJ
authors.lastname: Buckley
authors.forename: J D
authors.initials: JD
authors.lastname: Veldhuis
authors.forename: P A
authors.initials: PA
authors.lastname: McCombe
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.forename: M C
authors.initials: MC
authors.lastname: Bellingham
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D005455:Fluorescent Antibody Technique; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism; D013002:Somatomedins / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D011986:Receptors, Somatotropin; C000606290:SOD1 protein, human; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D017526:Receptor, IGF Type 1