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.

Triheptanoin Protects Motor Neurons and Delays the Onset of Motor Symptoms in a Mouse Model of Amyotrophic Lateral Sclerosis

“…At 25 weeks of age, the end-stage of disease [67,74], and relative to untreated wild-type mice, hSOD1 G93A mice showed reduced gene expression for succinate dehydrogenase ( Sdha , 70%), Gpt2 (84%) and the β subunit of propionyl carboxylase ( Pccb , 64%) (all p<0.05 in post test, Figs 4–6). Triheptanoin prevented the reduction in the expression of these genes, indicating that it can preserve muscle energy metabolism.…”

Association of Insulin-like Growth Factor 1 Concentrations with Risk for and Prognosis of Amyotrophic Lateral Sclerosis – Results from the ALS Registry Swabia

“…Indirectly, increased circulating IGF-1 could be a fingerprint of higher GH-IGF1 axis activity, and GH is able to modulate oligodendroglial cell survival and myelination in the CNS 27 . Interestingly growth hormone secretion was dysregulated in both patients and mouse models of ALS 28 . Results from experimental studies indicate a circadian control of IGF-I production 29,30 .…”

hmSOD1 gene mutation‐induced disturbance in iron metabolism is mediated by impairment of Akt signalling pathway

“…It is important to note that tissue iron accumulation is associated with several morbidities; however, it is still not clear if the phenomenon is a cause or effect of the disease process . There is evidence that insulin and insulin‐like growth factor 1 signalling is impaired in the skeletal muscle of transgenic animals, as well as in the animal model of ALS, and also in patients presenting with ALS or cancer patients with cachexia . In other experimental models, it has been demonstrated that excess tissue iron accumulation is associated with impaired insulin signalling .…”

“…7 There is evidence that insulin and insulin-like growth factor 1 signalling is impaired in the skeletal muscle of transgenic animals, as well as in the animal model of ALS, and also in patients presenting with ALS or cancer patients with cachexia. 8,9 In other experimental models, it has been demonstrated that excess tissue iron accumulation is associated with impaired insulin signalling. 10 Phlebotomy is known to decrease body iron stores and improve insulin sensitivity.…”