Muscle atrophy in experimental cancer cachexia: Is the IGF‐1 signaling pathway involved?

Abstract

Skeletal muscle wasting, one of the main features of cancer cachexia, is associated with marked protein hypercatabolism, and has suggested to depend also on impaired IGF-1 signal transduction pathway. To investigate this point, the state of activation of the IGF-1 system has been evaluated both in rats bearing the AH-130 hepatoma and in mice transplanted with the C26 colon adenocarcinoma. In the skeletal muscle of tumor hosts, the levels of phosphorylated (active) Akt, one of the most relevant kinases involved in the IGF-1 signaling pathway, were comparable to controls, or even increased. Accordingly, downstream targets such as GSK3b, p70 S6K and FoxO1 were hyperphosphorylated, while the levels of phosphorylated eIF2awere markedly reduced with respect to controls. In the attempt to force the metabolic balance toward anabolism, IGF-1 was hyperexpressed by gene transfer in the tibialis muscle of the C26 hosts. In healthy animals, IGF-1 overexpression markedly increased both fiber and muscle size. As a positive control, IGF-1 was also overexpressed in the muscle of aged mice. In IGF-1 hyperexpressing muscles the fiber cross-sectional area definitely increased in both young and aged animals, while, by contrast, loss of muscle mass or reduction of fiber size in mice bearing the C26 tumor were not modified. These results demonstrate that muscle wasting in tumor-bearing animals is not associated with downregulation of molecules involved in the anabolic response, and appears inconsistent, at least, with reduced activity of the IGF-1 signaling pathway.Cancer cachexia is a syndrome characterized by loss of body weight, skeletal muscle proteins, depletion of lipid stores, weakness, and perturbations of the hormonal homeostasis.

Habitual Myofibrillar Protein Synthesis Is Normal in Patients with Upper GI Cancer Cachexia

“…This protein complex, normally associated with the maintenance of muscle mass and muscle hypertrophy could be activated by the increase in amino acids released as a result of increased protein breakdown by the proteasome (41). In a murine model of cancer cachexia, increased levels of phosphorylated Akt and increased expression of IGFI in muscle of tumor-bearing AH-130 and C26 mice suggests that muscle wasting in tumor-bearing animals may not be associated with downregulation of molecules involved in the anabolic response (42). In further support of a counterregulatory response to compensate for muscle loss in cachexia, Op den Kamp and colleagues (43) have recently observed increased Akt phosphorylation in the muscle of patients with cachectic lung cancer.…”

Photobiomodulation-Mediated Pathway Diagnostics

“…33 The above PBM indicated that IGF-1 might promote the myoblast proliferation in hG to establish the hPlSH in which the FOXO3a is the same as in the nPlSH, and it might also promote myoblast proliferation in its nPlSH might be upgraded by IGF-1 upregulation and FOXO3a downregulation. Penna et al 34 have hyperexpressed IGF-1 by gene transfer in the tibialis muscle of the C26 hosts. In healthy animals, they found that IGF-1 overexpression markedly increased both¯ber and muscle size.…”

Mechanism-Based Therapeutic Approaches to Cachexia

“…The other way round, inhibition of this pathway was reported in conditions characterized by muscle wasting such as denervation, aging, disuse, or glucocorticoid treatment, and its restoration by means of IGF-1 administration or IGF-1 local hyperexpression is able to prevent or correct muscle depletion (reviewed in Glass, 2010). An exception, in this regard, is experimental cancer cachexia, where the PI3K/Akt/mTOR pathway is not down-regulated (Acharrya et al, 2005;Penna, Bonetto et al, 2010), and muscle atrophy cannot be prevented by both IGF-1 administration or its hyperexpression in the skeletal muscle (Costelli et al, 2006;Penna, Bonetto et al, 2010).…”

“…Such a strategy appears to work perfectly well in several experimental models of muscle wasting including denervation, amyotrophic lateral sclerosis, disuse (reviewed in Glass, 2010). However, it is useless in experimental cancer cachexia, where, despite high protein breadown rates occur, the insulin/IGF-1 pathway is not down-regulated, protein synthesis rates are only slightly reduced or even unchanged, and the protein synthetic signaling is poised into the activated state (Costelli et al, 1993;Penna, Bonetto, et al, 2010;Aversa et al, 2012).…”

“…AMPK may affect protein synthesis mainly in view of its ability to inhibit mTOR-dependent signaling (Mihaylova & Shaw, 2011), however it was also shown to modulate protein degradation rates, acting on atrogin-1 expression through a FoxO-dependent mechanism (Nakashima et al, 2007;Romanello et al, 2010). Of interest, increased AMPK activation is detectable in the skeletal muscle of tumor-bearing animals (Penna, Bonetto et al, 2010;White et al, 2011), where it is associated with marked alterations of mitochondrial morphology (Penna et al, unpublished observations).…”