Despite the sustained overexpression of IGF-1 in either skeletal muscle or the CNS of mice expressing a mutant form (G93A) of the human SOD-1 gene, these animals were indistinguishable from control SOD-1 mice in several measures of pathophysiology that characterize this mouse model of familial ALS. Deficits in motor performance, decreased life span, motor neuron atrophy and loss of motor neurons were all unaffected by IGF-1 overexpression. This failure to detect any effects of CNS or muscle overexpression of IGF-1 in the SOD-1 mouse model of ALS was surprising in that several previous studies have reported beneficial effects of IGF-1 in this same mouse model.
In one study intramuscular injection of an AAV construct expressing IGF-1 was retrogradely transported to the spinal cord of SOD-1 mice and shown to increase lifespan, improve motor performance and reduce motor neuron atrophy and degeneration (Kaspar et al., 2003
). In another study SOD-1 mice that overexpress IGF-1 in skeletal muscle were also reported to have enhanced motor performance, increased life-span and reduced degeneration of motor neurons (Dobrowolny et al., 2005
). Finally, continuous intrathecal delivery of exogenous IGF-1 to SOD-1 mice delayed deficits in motor performance, extended life-span and reduced motor neuron loss (Nagano et al., 2005
). However, despite the positive effects of IGF-1 in these studies, the benefits were transient and the IGF-1 treated SOD-1 mice in all three studies died prematurely compared to WT mice. Nonetheless, the positive effects observed in these three studies differ significantly from the uniformly lack of effect of IGF-1 in the present study.
Some possible differences between the present study and these three studies that could potentially account for the discrepant results include: genetic background; mode of IGF-1 administration; promoters used for muscle-specific overexpression; differential access of motor neurons to IGF-1 overexpression in muscle or CNS; and lower levels of IGF-1 overexpression in the present study.
Although the muscle IGF-1 mice used here were on a FVB background, the CNS IGF-1 mice were on a C57BL/6 background similar to the SOD-1 mice in the three studies cited above. Our mode of IGF-1 administration also may be a source for differences in that it is possible that continuous exposure to IGF-1 throughout development could alter receptor expression and hence dampen IGF-1's effect. However, muscle IGF-1 transgenic mice used by Dobrowolny et al. (2005)
were also exposed to IGF-1 from birth and showed a positive effect from IGF-1. In the study by Dobrowolny et al., (2005)
, a myosin light chain (mlc) promoter was used to drive skeletal muscle expression of IGF-1, whereas we used an alpha actin skeletal muscle promoter (Dobrowolny et al., 2005
). However, both promoters result in muscle-specific overexpression of IGF-1 in primarily fast twitch-muscles and both induce skeletal muscle hypertrophy. Although exogenous IGF-1 injected into skeletal muscle of the chick embryo (Rind and von Bartheld, 2002
) and adult rat (Caroni, 1993
) is retrogradely transported, the retrograde transport of IGF-1 wasn't specifically examined in our study or that of Dobrowolny and colleagues. In the present study, IGF-1 levels in the spinal cord as measured by RIA were similar in bSOD+/S1S2- and bSOD+/S1S2+ mice. Even in the absence of retrograde transport, however, target-derived neurotrophic factors can induce retrograde signaling cascades (Zweifel et al., 2005
). For example, IGF-1 receptors are expressed on motor axons and terminals (Caroni, 1993
) and in a previous study we demonstrated that muscle-specific overexpression of IGF-1 can affect motor terminals and innervation (Messi and Delbono, 2003
). Additionally, the application of exogenous IGF-1 at the site of peripheral axotomy in the sciatic and facial nerve of neonatal mice and rats also rescues motor neurons from injury induced cell death (Hughes et al., 1993
; Li et al., 1994
). Finally, intramuscular injection of IGF-1 binding proteins that sequester and reduce the biological activity of endogenous IGF-1 in muscle, perturbs neuromuscular innervation, consistent with a role for endogenous muscle derived IGF-1 on motor neurons (Caroni, 1993
; D'Costa et al., 1998
; Rind and von Bartheld, 2002
). Accordingly, it seems unlikely that our failure to observe any effect of IGF-1 overexpression in muscle on disease progression in SOD-1 mice is due to a total lack of motor neuron access to IGF-1. However, we cannot exclude the possibility that our use of the alpha actin promoter precluded the retrograde transport of IGF-1 and that retrograde transport may be critical for preventing motor neuron deficits in SOD-1 mice. For example, in a related study comparing muscles vs
CNS overexpression of GDNF, it was indicated that retrograde transport of GDNF may be critical for neuroprotection in SOD-1 mice (Li et al., 2007
); GDNF was neuroprotective following muscle but not CNS overexpression. Although this might also explain why CNS overexpression of IGF-1 was ineffective in the present study, it does not explain why CNS (intrathecal) infusion of IGF-1 was neuroprotective in SOD-1 mice (Nagano et al., 2005
) or why in our study, CNS overexpression of IGF-1 resulted in increased growth of brain and spinal cord, a clear index of biological activity in the CNS.
Although we are unable to provide a definitive explanation for our failure (in contrast to previous studies) to detect a neuroprotective effect of IGF-1 in a mouse model of ALS, these negative results, together with a negative results of one of two clinical trials using IGF-1 with ALS patients (Borasio et al., 1998
), indicate a note of caution in the future use of IGF-1 to treat motor neuron disease. However, since SOD+ mouse models do not always represent human disease, it is still possible that IGF-1 may have some beneficial effects in humans, the current clinical trial will be crucial to understanding how the route of IGF-1 effects the disease course in humans.