IL-13 mediates the recruitment of reserve cells for fusion during IGF-1-induced hypertrophy of human myotubes

Abstract

Insulin-like growth factor-1 (IGF-1) has been shown to induce skeletal muscle hypertrophy, to prevent the loss of muscle mass with ageing and to improve the muscle phenotype of dystrophic mice. We previously developed a model of IGF-1-induced hypertrophy of human myotubes, in which hypertrophy was not only characterized by an increase in myotube size and myosin content but also by an increased recruitment of reserve cells for fusion. Here, we describe a new mechanism of IGF-1-induced hypertrophy by demonstrating that IGF-1 signals exclusively to myotubes but not to reserve cells, leading, under the control of the transcription factor NFATc2, to the secretion of IL-13 that will secondly recruit reserve cells for differentiation and fusion. In addition, we show that IGF-1 also signals to myotubes to stimulate protein metabolism via Akt by (1) activating the mTOR-p70S6K-S6 pathway and inhibiting GSK-3␤, both involved in the control of protein translation, and (2) inhibiting the Foxo1-atrogin-1 protein degradation pathway. Journal of Cell Science 671 IL-13-mediated reserve cell recruitment (Abbott et al., 1998;Horsley et al., 2001), the data in the literature concerning the role of calcineurin in skeletal muscle hypertrophy are again often contradictory since some studies in rodent models show that IGF-1-induced hypertrophy can be suppressed using the calcineurin inhibitors cyclosporine A or FK506 Semsarian et al., 1999b), whereas other groups see no effect of these inhibitors on hypertrophy and no increase in calcineurin activity in the presence of IGF-1 (Bodine et al., 2001b;Rommel et al., 2001).The ability of IGF-1 to act as an anabolic factor on skeletal muscle and to counterbalance the signalling pathways of muscle atrophy has led to the proposition that IGF-1 could be used as a therapeutic agent to combat muscle atrophy related to age (sarcopenia) or to various diseases. However all data available until now describing the mechanisms of IGF-1-induced hypertrophy have been obtained in rodent models, and very little is known about the effects and the signalling pathways of IGF-1 in human skeletal muscle. It is becoming increasingly evident that the results obtained in rodent models cannot always be directly transposed to man. For example, whereas a twofold increase was observed in the lifespan of myoblasts from transgenic mice overexpressing IGF-1 in muscle (Chakravarthy et al., 2000), we recently showed in human myoblasts that IGF-1 has no effect on the proliferative lifespan, suggesting a different mechanism of regulation in these two species (Jacquemin et al., 2004).We previously developed an in vitro model of human myotube hypertrophy induced by IGF-1 where cultures were exposed to IGF-1 only 3 days after the induction of differentiation, a time when most of the myoblasts have already fused into myotubes and no more proliferation is observed. This model allows us to distinguish between the different effects of IGF-1 on proliferation, differentiation and hypertrophy (Jacquemin et al., 2004). In these condition...

During post-natal human myogenesis, normal myotube size requires TRPC1 and TRPC4 mediated Ca2+ entry

“…In human myoblast, it was shown that interleukin 13 (IL-13) had positive effect on myoblast fusion as it stimulates the recruitment of reserve cells to increase myotube size (Jacquemin et al, 2007). We first confirmed that exogenous IL-13 increased dosedependently the number of nuclei per myotube (Fig.…”

“…The role of IL-4 in the fusion of myoblasts to nascent myotubes was confirmed in human, and further extended to a role of promoting myoblast migration (Lafreniere et al, 2006). Using a model of IGF-1-mediated human myotube hypertrophy, the group of Mouly showed that IL-13, but not IL-4, favors reserve cells activation, and their subsequent recruitment and fusion to myotubes (Jacquemin et al, 2007). An in vivo study further pointed to a role of IL-4 and IL-13 in exercise-induced human muscle hypertrophy (Prokopchuk et al, 2007).…”

Expression of muscle anabolic and metabolic factors in mechanically loaded MLO-Y4 osteocytes

“…In muscle, IGF-I Ea is a potent growth factor that stimulates both the rate of mRNA transcription of contractile proteins (53) and their rate of translation via phosphatidylinositol-3 kinase/ Akt/mTOR pathway (32). The splice variant of IGF-I, MGF, seems to be involved in satellite cell activation and migration of myoblasts and satellite cells, resulting in an increased myonuclear density in the muscle fiber (44,65).…”

Creatine supplementation prevents the inhibition of myogenic differentiation in oxidatively injured C2C12 murine myoblasts

“…Besides Akt, IGF-1 acts on the mTOR/p70S6K and GSK-3 pathways, both of which are involved in the control of protein translocation. IGF-1 also potentiates the recruitment of reserve cells for fusion via the secretion of IL-13 by myotubes under the control of NFATc2 [16].…”