IGF-1 is a trophic factor for different tissues, including nervous system and skeletal muscle. In particular, it is a survival factor for motoneurons, both in vitro
and in vivo
It is also a potent myogenic factor that promotes myoblast proliferation, myogenic differentiation, and myotube hypertrophy.2–6
In this study, in which IF and WB analyses were utilized, some IGF-1 system components, represented by IGF-1 and three binding proteins (BP3, BP4, and BP5), were less expressed in skeletal muscle in sALS patients than in normal and pathological controls. On the contrary, the muscle expression of IGF-1Rβ was increased in sALS patients compared with controls. These data might reflect a worrisome inhibition of the action of the IGF-1 system in skeletal muscles of sALS patients that could influence the course of the disease.
Wilczak et al. investigated the components of the IGF-1 system in spinal cord sections of patients with ALS.29
They reported that free IGF-1 concentrations were lower in ventral horn homogenates from ALS patients than in those from controls; in addition, IGF-1R immunoreactivity was enhanced in ALS spinal MNs. Indeed, our study disclosed a similar dysfunction of the IGF-1 system in another compartment of sALS patients that could play an important role in both MN degeneration and muscle atrophy. On the other hand, Millino et al. found that patients with spinal muscular atrophy type I, a neurodegenerative disorder associated with mutations of the survival MN gene and characterized by muscle weakness and atrophy caused by degeneration of spinal MNs, showed reduced expression of the genes involved in the IGF/PI3K/Akt pathway with an overexpression of the IGF-1R gene.33
Several hypotheses on the cause of this reduced activation of the IGF-1 system should be considered. First, nutrition is one of the main regulators of circulating IGF-1, so low nutrient intake downregulates IGF-1 gene transcription34
and reduces serum IGF-1 concentrations. The exquisite sensitivity of circulating IGF-1 to nutrients, the nycthemeral stability of its concentrations, and its relatively short half-life constitute the basis for its use as a marker of both nutritional status and adequacy of nutritional rehabilitation. Mazzini et al. reported that, at the onset of medical attendance, 53% of their ALS patients had a BMI <20 kg/m2
, and 55% had a weight loss of >15% of their usual weight. These data indicate a high occurrence of malnutrition in ALS patients that leads to an impairment of muscle function eventually mediated by reduced IGF-1 availability.35
This was not the case for the patients we studied, because they did not show any alteration of parameters of nutritional status.
A second hypothesis may be related to the role of cytokines in ALS. Accumulating evidence from studies in both cell cultures and ALS animal models suggests that the pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), may participate in the death of MNs, even from the early pathogenic events of the neurodegenerative process.36, 37
Both serum TNF-α and its soluble receptors have been reported to be significantly higher in ALS patients compared with healthy controls.38
Moreover, TNF-α impairs skeletal muscle trophism. In this context, activation of TNF-α signaling via the c-Jun N-terminal kinase can decrease IGF-1 RNA expression and inhibit IGF-1 signaling by phosphorylation and conformational changes in insulin receptor substrate-1 downstream of the IGF-1R.39
A third possible reason that may influence the IGF-1 system is related to growth hormone (GH). This important anabolic hormone has direct and indirect actions on protein synthesis of different tissues, including skeletal muscle.40, 41
Importantly, the indirect effects of GH are mediated mainly through the production of IGF-1.42, 43
Morselli et al. found that the majority (73%) of ALS patients have a GH deficiency, and thus this condition could induce a reduction of tissue IGF-1 synthesis.44
Finally, we considered that the initial response of the IGF-1 receptor to its ligand is related to an autophosphorylation on specific tyrosine residues. The intrinsic tyrosine kinase activity of IGF-1R phosphorylates multiple substrates that determine the activation of several downstream molecules, such as the serine–threonine kinase Akt. Thus, Leger et al. observed reduced active Akt in skeletal muscle of ALS patients and G93A SOD1 transgenic mice, which may be the “tip of the iceberg.”45
In other words, the reduction of Akt coincides with the decreased expression of IGF-1 and the increased expression of IGF-1R that we observed.
According to morphological criteria and results of histometrical analysis the degrees of denervation were similar between sALS and PC patients. These data support the idea that the augmented expression of IGF-1R in ALS skeletal muscles is not an effect of denervation but could be a specific phenomenon in sALS patients.
In this scenario it is also worth considering the relevant role of BPs in the balance of effects caused by the IGF-1 system components. IGF-BP3 is the most abundant circulating BP and exerts a complex array of functions at the cellular level. Primarily, IGF-BP3 inhibits IGF-1–mediated effects via high-affinity sequestration of the ligand, presumably leading to prevention of IGF-1R autophosphorylation and signaling.18
It has also been reported, based on competitive ligand-binding studies, that IGF-BP3 can interact with IGF-1R, causing inhibition of IGF-1 binding to its receptor.46
However, the recombinant human (rh)IGF-1/IGF-BP3 complex, which improves the safety and efficacy profile of rhIGF-1 alone,47
has an anabolic potential demonstrated in catabolic conditions such as burn injuries.48
In an ad hoc
animal study, the IGF-1/IGF-BP3 complex, but not IGF-1 alone, was able to support muscle protein synthesis in rats during semi-starvation.49
IGF-BP5 is considered a stimulatory BP because it seems to counteract the inhibitory actions of other BPs, such as IGF-BP4, in systems such as bone50
and cultured vascular smooth muscle cells.51
It is noteworthy that, in this study, we observed a reduced expression of IGF-1 and IGF-BP3 and -BP5, which could suggest a negative interference of muscle anabolism in ALS patients, even when considering the unchanged IGF-BP4 content in their muscle.
Previously, we demonstrated a high level of the active fraction of IGF-1 (free IGF-1) in the cerebrospinal fluid (CSF) of sALS patients without any change in serum and CSF levels of total IGF-1.52
In the present study we found a distinctive expression of IGF-1 and IGF-BP3 and -BP5 according to muscle fiber types, with a higher expression level of slow-twitch (ST) or type I fibers compared with fast-twitch (FT) or type II fibers (checkboard pattern). In light of this distribution, which was previously shown only in rat skeletal muscle fibers for the two BPs,53
the different resistance to denervation by the two types of muscle fibers should be considered. Pun et al. showed that in two mouse models of motoneuron disease (G93A SOD1 and G85R SOD1), axons of fast-fatigable motoneurons are affected synchronously, long before symptoms appear.54
Thus, fast-fatigue–resistant motoneuron axons are affected at symptom onset, whereas axons of slow motoneurons are resistant.
In conclusion, ALS is emerging as a “multisystemic” disease in which structural, physiological, and metabolic alterations in different tissues or cell types (motoneurons, glia, and muscle fibers) may act synergistically to induce and/or exacerbate the disease.55, 56
The cell interaction represents a functional cross-talk between neuronal and non-neuronal cells, whose derangement could make some therapeutic strategies ineffective. Therefore, although dysfunctions in the IGF-1 system emphasize the potential therapeutic role of IGF-1 in sALS, we should be aware that some disease-related tissue abnormalities can interfere with the potential therapeutic properties of this neurotrophic factor.