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Insulin-Like Growth Factor I Signaling in Skeletal Muscle and the Potential for Cytokine Interactions

ADAMS, GREGORY R.

Medicine & Science in Sports & Exercise: January 2010 - Volume 42 - Issue 1 - p 50-57
doi: 10.1249/MSS.0b013e3181b07d12
BASIC SCIENCES: Symposium

Recent research has demonstrated that intracellular signaling components associated with several proinflammatory cytokines have the potential to interact with signaling pathways that regulate anabolic processes in skeletal muscle. This presentation and the ensuing brief review are intended to present a selection of the potential interactions between these two critical processes.

Department of Physiology and Biophysics, University of California, Irvine, CA

Address for correspondence: Gregory R. Adams, Ph.D., Department of Physiology and Biophysics, Medical Sciences 1, Room D335, University of California, Irvine, CA 92697-4560; E-mail: gradams@uci.edu.

Submitted for publication December 2008.

Accepted for publication February 2009.

In recent years, the cellular and molecular mechanisms that contribute to loading-induced skeletal muscle hypertrophy have begun to be elucidated. As a part of this process, several intracellular signaling pathways that seem to be critical to the hypertrophy process have been identified. In parallel, the mechanisms and signaling pathways associated with proinflammatory cytokine activities have also been identified.

The aim of this brief review was to highlight some examples of potential interactions between the signaling pathways associated with these two systems. This synopsis should in no way be viewed as a comprehensive review of this area. Rather, this set of vignettes is intended to provoke interest in the area and suggests further investigation into the broader spectrum of potential interactions.

In the interest of brevity and focus, the presentation of this article is based on, and limited to, the presupposition that hypertrophic signaling cascades, which include mammalian target of rapamycin (mTOR) and extracellular response kinases (ERK), are critical in most physiologically relevant circumstances.

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INSULIN-LIKE GROWTH FACTOR I AND SKELETAL MUSCLE HYPERTROPHY

With respect to skeletal muscle, much of the original interests in these signaling pathways were generated in the context of their relationship to insulin and insulin-like growth factor 1 receptor (IGFR1) activity. We and others have demonstrated that increased muscle IGF-I levels can result in skeletal muscle hypertrophy (4,10,49). For many years, the working hypothesis of our research group has been that the primary mechanism of this response involves the autocrine/paracrine production of IGF for the promotion of satellite cell proliferation and differentiation and the subsequent fusion of the differentiated progeny with existing myofibers in support of loading-induced skeletal muscle hypertrophy (1,2). The context for this theoretical framework is rooted in the myonuclear domain (7) or DNA unit hypothesis (18). It has long been understood that there is a finite relationship between the number of myonuclei and the size of myofibers and that, above some threshold of expansion, the addition of myonuclei is necessary to maintain hypertrophic processes (7,53). In fact, Barton-Davis et al. (11) speculated that IGF-I-induced incorporation of myonuclei into myofibers precedes and drives subsequent hypertrophy. As would be expected, the relationship between myofiber size and myonuclear number would have a fairly wide range. For example, Kadi et al. (40) observed in human studies that moderate levels of muscle hypertrophy can occur in the absence of significant levels of myonuclear incorporation. This design seems logical in that there would be an appreciable metabolic and resource expense associated with the constant activation of satellite cell proliferation in response to moderate fluctuations in muscle loading. It also seems reasonable to expect that, after a period of rapid satellite cell or myoblast activity (i.e., proliferation, differentiation, and fusion), there would be a period of protein synthesis to reestablish the myonuclear-to-myofiber size ratio in the absence of further cell replication events (50,56).

In the context of the myonuclear domain hypothesis, it is important to note that this critical role for IGF-I in muscle hypertrophy would only be evident when the nuclear domain size within myofibers would be limiting (53). Myofiber size expansion in the presence of relatively smaller myonuclear domains could occur below this threshold. In contrast, myofiber hypertrophy in the presence of large domain sizes would encounter the threshold condition more rapidly, requiring the addition of myonuclei for continued hypertrophy. As an example of this, Spangenburg et al. (65) recently reported that a transgenic mouse that expresses a dominant-negative IGF-I receptor in skeletal muscle demonstrates significant muscle hypertrophy in response to increased loading. The phenotype of this specific transgenic mouse includes 20% more myonuclei per myofiber, for example, relatively small myonuclear domains (26). This suggests that significant hypertrophy could occur within the myofibers of this mutant mouse without approaching the limit for myonuclear domain size and, therefore, be independent of IGF-I.

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INTRACELLULAR SIGNALING AND SKELETAL MUSCLE HYPERTROPHY

A critical event in the mobilization of satellite cells to support loading-induced muscle hypertrophy involves exiting the G1 phase and entering the cell cycle. This process is tightly regulated, in part, via control of the phosphorylation status of retinoblastoma (Rb) protein (Fig. 1A). Hypophosphorylated Rb inhibits the transcriptional activity of E2F family transcription factors. Phosphorylation of Rb releases E2F inhibition and promotes the progression from G1- to S-phase of the cell cycle (21). Both ERK and mTOR are constituent members of signaling pathways that can regulate Rb phosphorylation (Fig. 1B).

FIGURE 1-A

FIGURE 1-A

Figure 1B places ERK and mTOR in the context of some of the known signaling components associated with their activity. This simplified diagram also demonstrates some of the potential interactions between the ERK and mTOR pathways.

In addition to their role in the regulation of E2F activity, signaling cascades including both ERK and mTOR regulate critical steps involved with the up-regulation of translational capacity via the upstream binding factor (UBF) and the transcriptional regulation of ribosomal RNA production (Fig. 2) (28,35,36,69). Signaling via mTOR also plays an important role in the regulation of mRNA translation (14). As such, these pathways represent critical components of the anabolic process in skeletal muscle.

FIGURE 2-A

FIGURE 2-A

It has become increasingly clear that components of these regulatory pathways, originally associated with insulin and IGF, also receive input from many sources such as availability of amino acid and state of mechanical load (14). As such, the ERK- and mTOR-containing signaling cascades provide useful and relevant examples for examining potential interactions.

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PROINFLAMMATORY CYTOKINES AND SKELETAL MUSCLE

Elevated circulating levels of proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) are often reported in conditions such as aging that involve muscle loss (e.g., 62). Numerous studies have clearly established a cause and effect relationship between proinflammatory cytokines and muscle atrophy (12,16,27,31,34,48,64). However, it is not entirely clear from such studies that proinflammatory cytokines induce atrophy by exerting direct effects on muscle, that is, via receptor-mediated events at the level of the myofibers, satellite cells, or ancillary cell types that constitute a skeletal muscle.

The elucidation of intracellular signaling pathways associated with cytokine receptor ligation now allows for the examination of potential mechanisms by which proinflammatory cytokines could directly impact skeletal muscle adaptation (e.g., 2,46,59). It has become increasing clear that some of these effects may be a result of interactions between cytokine-stimulated signaling and anabolic pathways in skeletal muscle.

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POTENTIAL INTERACTIONS BETWEEN TNFα AND ANABOLIC SIGNALING

TNFα has been reported to directly stimulate atrophy in various models used to study skeletal muscle (60). For example, Smith et al. (64) recently reported that exposure of myotubes to TNFα for 72 h resulted in a net loss of protein. This loss included a disproportionate decrease in myosin heavy chain protein, one of the key components of the contractile apparatus.

Sepsis is often associated with muscle atrophy (e.g., 75). Using a sepsis model, Lang and Frost (45) demonstrated that administration of a TNFα binding protein could prevent the down-regulation of mTOR-related signaling. In their study, one of the primary effects of TNFα was an increase in the binding of the inhibitory eukaryotic initiation factor 4E binding protein (4E-BP1) to eukaryotic initiation factor 4E (eIF4E), indicating that the mTOR pathway was inhibited. Treatment with the anti-TNFα binding protein prevented this increase in 4E-BP1 inhibitory binding. When 4E-BP1 is hyperphosphorylated, the inhibition of eIF4E is removed and translational initiation can proceed. These results highlight the interactions between TNFα and mTOR signaling.

There is evidence that one of the mechanisms of the antianabolic mechanisms of TNFα in skeletal muscle may be via interactions with IGF-I signaling. Signaling initiated by TNFα has the potential to result in phosphorylation of insulin receptor substrate 1 (IRS-1) at serine residues preventing its interaction with the IGF-I (or insulin) receptor (20,29,41). Serine phosphorylation of IRS-1 is a common component of regulatory feedback in skeletal muscle. Phosphorylation of IRS-1 on Serine307/312 (rodent/human) prevents its association with the IGF-I receptor and is also known to result in targeting IRS-1 for degradation (52). One mechanism by which TNFα can down-regulate insulin/IGF-I-related signaling is via direct interaction between the inhibitor of κB kinase (IκK) complexes and IRS-1 (29) (Fig. 3). A second potential mechanism involves the activation of c-Jun NH2-terminal kinase (JNK) downstream of the TNF receptor. For example, Strle et al. (67) found that TNFα prevented IGF-I-induced activation of IRS-1 via tyrosine phosphorylation in myoblasts and that a peptide inhibitor of JNK restored the effects of IGF-I. In support of this model, TNFα-activated JNK has been shown to directly associate with, and induce subsequent serine phosphorylation of, IRS-1, thereby interfering with IGFR1-IRS-1 interactions (5) (Fig. 4).

FIGURE 3

FIGURE 3

FIGURE 4

FIGURE 4

Taken together, interactions between TNFα-induced signaling components and IRS-1 have the potential to induce a state of IGF-I resistance in affected cells. Interference with the ability of IRS-1 to transduce IGF-I receptor activity to downstream elements such as phosphoinositide-3 kinase (PI3K) would clearly have negative effects on this highly anabolic pathway.

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POTENTIAL INTERACTIONS BETWEEN IL-1 AND ANABOLIC SIGNALING

IL-1 has been shown to decrease skeletal muscle protein synthesis via the down-regulation of translational initiation and capacity (e.g., 74,75). Processes responsible for the regulation of both protein initiation and capacity are known to include signaling pathways associated with IGF-I (3).

IL-1 shares many intracellular signaling components with TNFα. As such, the activity of this proinflammatory cytokine could be expected to generate similar interactions with anabolic signaling cascades. There is some experimental evidence to suggest that this is the case. For example, several studies have reported that the treatment of an adipocyte cell line with IL-1β or IL-1α resulted in a decrease in the levels of IRS-1 present in these cells (39,72). In the same cell line, He et al. (37) reported that IL-1α treatment reduced the activation of IRS-1 and that this activity was recovered in the presence of an IκK inhibitor or a JNK inhibitor.

Similar to the effects of TNFα, IL-1β interferes with IGF-1 signaling in a skeletal muscle cell line via a reduction in the activation of IRS-1 (15). In skeletal muscle, Strle et al. (66,68) demonstrated that either TNFα or IL-1β prevents IGF-I-induced increases in myogenin, a member of the myogenic regulatory factor family. These authors found that the anti-inflammatory cytokine IL-10 prevented IL-1β-induced interference with IGF-I actions (68).

Taken together, the results to date suggest that IL-1 has similar anti-IGF-I signaling effects that result from similar mechanisms to those previously outlined for TNFα.

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POTENTIAL INTERACTIONS BETWEEN IL-6 AND ANABOLIC SIGNALING

Circulating levels of IL-6 are often reported to be elevated in conditions accompanied by chronic inflammation (24,63). However, IL-6 can play either a proinflammatory or an anti-inflammatory role (e.g., 51,63).

The role of IL-6 and skeletal muscle also presents a paradox. Muscle cells are known to produce IL-6 in culture and in vivo (9,32), and intense exercise has been shown to increase muscle IL-6 production (51). In contrast, IL-6 expression is often found to be elevated when muscle wasting is occurring (31,34,55,62).

Exercise-induced IL-6 production is thought to be involved with the regulation of glucose metabolism (51). However, IL-6 also has the potential to stimulate myoblast or satellite cell proliferation (16,54) and to promote angiogenesis; all features are indicative of anabolic processes (19). This would seem to be at odds with studies that have established that long-term IL-6 exposure can have catabolic effects on skeletal muscle (31,34,55). It seems most likely that some of the seemingly paradoxical effects of IL-6 exposure may be related to temporal factors. For example, long-term exposure, as seen during chronic inflammation, may have very different effects from acute effects such as those seen with exercise.

One of the more troubling aspects of chronic inflammation during childhood is the evidence suggesting that the growth defects that are associated with childhood diseases involving chronic inflammation may be mediated by increased circulating IL-6 (e.g., 22,47). Recent studies indicate that elevated levels of IL-6 per se may negatively impact growth. For example, transgenic mice that overexpress IL-6 have decreased growth that can be mitigated by IL-6-neutralizing antibodies (22,23). Similarly, in animal models of inflammatory bowel disease, treatment with IL-6-neutralizing antibodies restores growth (8,61).

Recently, the therapeutic use of an antibody that prevents formation of the IL-6-IL-6 receptor complex has also shown great promise for the treatment of systemic juvenile idiopathic arthritis in children (77). Taken together, these results suggest that long-term elevation in IL-6 mediates an antianabolic state in skeletal muscle.

There are several potential mechanisms by which long-term exposure of skeletal muscle to elevated levels of IL-6 might interfere with anabolic signaling pathways (Fig. 5). For example, Kim et al. (42) demonstrated that IL-6 treatment reduced the interaction between IRS-1 and PI3K in skeletal muscle and that this effect could be prevented via concurrent treatment with the anti-inflammatory cytokine IL-10. In contrast to this report, Weigert et al. (76) found that acute treatment of mice with IL-6 increased insulin-stimulated signaling downstream of IRS-1 in skeletal muscle.

FIGURE 5-I

FIGURE 5-I

One potential mechanism for IL-6-IGF-I signaling interactions centers on recent work indicating that there is a convergence of elements associated both with IL-6 and with IGF-I axis signaling (6,70,78). These common elements include signaling via the Janus kinase (JAK)/signal transducer activator of transcription (STAT) pathway (70) (Fig. 5). A critical outcome of JAK/STAT activity is the phosphorylation of STAT proteins resulting in dimerization and subsequent translocation of STAT to the nucleus (71). In the nucleus, STAT dimers function as transcription factors leading to alterations in the expression of several proteins important to the inflammatory response (71). In the context of cytokine-growth factor interactions, one of the more significant changes may be alterations in the expression of members of the suppressors of cytokine signaling (SOCS) family (6,71). SOCS family proteins can act as the negative regulators of JAK/STAT signaling, thereby regulating STAT activity. It is important to consider that, in the absence of compartmentalization, SOCS proteins produced in response to one stimulus would be expected to provide a feedback on any and all receptors using the JAK/STAT signaling mechanism. As an example, in the current scenario, SOCS produced in response to IL-6 would also have the potential to provide a feedback on anabolic signaling pathways subserving IGF-I and growth hormone (34).

In the study by Weigert et al. (76), acute treatment with IL-6 failed to stimulate an increase in SOCS3 mRNA. In contrast, we have reported that long-term exposure to locally elevated IL-6 in rat muscle results in significant increases in the levels of SOCS3 mRNA (12,34). These differences may speak to the issue of short- versus long-term exposure to IL-6 in this tissue.

Rui et al. (58) reported that increased expression of SOCS1 or SOCS3 targeted IRS-1 and IRS-2 for ubiquitin-mediated degradation in several cell lines as well as in hepatic tissue in vivo. Unfortunately, the effects of SOCS3 were not investigated in skeletal muscle. In a study using direct, local, long-term infusion of IL-6 into a single skeletal muscle in vivo, we found that there was a strong negative correlation between increased SOCS3 mRNA levels and decreases in myofibrillar protein (34). We also found that relative to young adults, the muscles of old rats had elevated levels of STAT3 phosphorylation, high levels of SOCS3 mRNA, and markedly depressed levels of IRS-1 protein, suggesting a mechanism for the sarcopenia seen in these animals (33). More recently, we reported that locally elevated IL-6 inhibited the growth of skeletal muscles in young rats (12). In that study, IL-6 infusion markedly increased the levels of SOCS3 mRNA resulting in an apparent resistance to IGF-I.

The results of these studies indicate that increased expression of SOCS3 in the context of IL-6 signaling has the potential to provide a feedback on IGF-I-induced signaling, enacting a negative feedback function, possibly at the level of IRS-1, resulting in a down-regulation of signaling elements downstream such as mTOR.

A second potential mechanism by which IL-6 might interact with anabolic signaling in skeletal muscle seems to involve 5′-AMP-activated protein kinase (AMPK; Fig. 6). Recently, van Hall et al. (73) reported that acute systemic infusion of IL-6 into healthy human subjects, at levels that stimulate an intense exercise response, caused a small net muscle protein breakdown. These authors speculated that this effect was due to an IL-6-induced decrease in circulating amino acid pools rather than a direct effect of IL-6 on muscle. Alternatively, there is substantial evidence that IL-6 can activate AMPK in several tissues including skeletal muscle cells (17,30,57). Bolster et al. (13) reported that, in skeletal muscle, AMPK activity suppresses protein synthesis in the rat by down-regulating mTOR signaling. Several subsequent studies have verified that AMPK can down-regulate protein synthesis via its effects on the mTOR pathway (25,44). This mechanism can explain the observation that IL-6 decreases the activity of p70 S6 kinase (S6K) (30), a substrate of mTOR and a critical regulator of translation (38,43) (Fig. 1).

FIGURE 6-I

FIGURE 6-I

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CONCLUSIONS

From an evolutionary standpoint, cross talk between inflammatory mediators and anabolic processes represents a useful design. At a time when an organism is mounting a response to injury and/or infection and is most likely unable to obtain food, conservation and mobilization of endogenous resources are paramount. Growth and anabolism would be competitive with regard to these resources. In this context, the ability of intracellular signaling mechanisms to promote both a primary inflammatory response while at the same time dampening competing anabolic processes represents an elegant solution. However, in humans, injury and/or infection generally no longer result in a scarcity of resources, for example, amino acids and calories. As a result, this previously highly adaptive mechanism is no longer desirable.

This review highlighted a few of the possible mechanisms by which this previously adaptive process may be functioning. Many additional regulatory pathways that have a role in muscle adaptation have been identified. As research goes forward, it will be important to determine which of the cytokine-anabolic interactions described herein actually take place in vivo and to discover which additional anabolic pathways are subject to such regulatory interactions.

The author's research is supported by the National Institutes of Health (P01HD048721-Project 1) and the National Space Biomedical Research Institute (Project No. MA01601).

The results of the present study do not constitute endorsement by the American College of Sports Medicine.

The author thanks Dr. Nindl for the opportunity to contribute to this symposium and proceedings. The author thanks Dr. Ken Baldwin for his thoughtful critique of the paper.

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Keywords:

TNFα; IL-1β; IL-6; IRS-1; MTOR; ERK; ANABOLISM

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