Journal Logo


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


Author Information
Medicine & Science in Sports & Exercise: January 2010 - Volume 42 - Issue 1 - p 50-57
doi: 10.1249/MSS.0b013e3181b07d12
  • Free


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.


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.


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).

Anabolic signaling pathways in skeletal muscle. One of the critical processes involved with the progression of the cell cycle is the removal of the inhibition of E2F family transcription factors. A, Hypophosphorylated Rb protein inhibits the transcriptional activity of E2F. Phosphorylation of Rb releases E2F inhibition and promotes the progression from G1- to S-phase of the cell cycle (21,28). B, Increased signaling via Ras and PI3K promotes a complex system of downstream effects leading to the phosphorylation of Rb and thereby promotion of entry into the cell cycle. Key components of these pathways are often used to assess changes in signaling flux. The phosphorylation state of intermediates such as theERK and S6K are often used as surrogates for the measurement of activity. AKT/pkB, a serine/threonine kinase; cdk, cyclin-dependent kinase; c-myc, transcription factor; DAG, diacylglycerol; E2F, transcription factor family (regulates genes associated with proliferation); ERK, extracellular signal-regulated kinase, also known as mitogen-activated protein kinase (MAPK); GSK, gylcogen synthase kinase; IRS, insulin receptor substrate; MEK, MAPK/ERK kinase; p21, p27, p53, cyclin-dependent kinase inhibitors; p90RSK, 90-kDa ribosomal S6 kinase; PA, phosphatidic acid; PDK, PI3K-dependent kinase; PIP, phosphoinositol phosphate; PPA, phosphoprotein phosphatase; Raf, a serine/threonine kinase; Ras, guanosine 5c-triphosphatase; Rheb, Ras homolog enriched in brain protein; S6K1, 70-kDa ribosomal S6 kinase; Shc, SH2-containing collagen-related proteins; TSC, tuberous sclerosis complex.

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.

Anabolic signaling increases ribosomal RNA transcription. Hyperphosphorylation of Rb protein reduces the sequestration of UBF, thereby promoting rDNA transcription (36). In addition to its effects via Rb, mTOR-dependent phosphorylation of UBF by S6K1 also promotes rDNA transcription (35).

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.


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.


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).

TNFα signaling via NF-κB may inhibit IGF-I signaling. Research suggests that IκK complexes may directly interact with IRS-1 to inhibit receptor-mediated signaling (29). NEMO, NFκB essential modulator; NFκB, nuclear factor κB. TRADD, TNF receptor-1-associated death domain protein; TRAF6, TNF receptor-associated factor 6.
TNFα signaling via JNK may inhibit IGF-I signaling. Research indicates that TNFα-activated JNK may associate with IRS-1 and subsequently initiate serine phosphorylation of IRS-1 leading to inhibition of its interaction with receptors (5).

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.


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.


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.

IL-6 signaling may inhibit IGF-I signaling via increased SOCS. IL-6 treatment has been reported to reduce the interaction between IRS-1 and PI3K in skeletal muscle (42). In addition, IL-6-induced increase in the expression of SOCS1 or SOCS3 can result in ubiquitin-mediated degradation of IRS-1 (58).

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).

IL-6 signaling may inhibit IGF-I signaling via activation of AMPK. The activity of AMPK suppresses protein synthesis by down-regulating mTOR signaling (13). IL-6 has been shown to activate AMPK in several tissues including skeletal muscle cells (17,30,57).


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.


1. Adams GR. Role of IGF-I in the regulation of skeletal muscle adaptation. Exerc Sport Sci Rev. 1998;26:31-60.
2. Adams GR. Invited review: autocrine/paracrine IGF-I and skeletal muscle adaptation. J Appl Physiol. 2002;93:1159-67.
3. Adams GR. Satellite cell proliferation and skeletal muscle hypertrophy. Appl Physiol Nutr Metab. 2006;31:782-90.
4. Adams GR, McCue SA. Localized infusion of IGF-I results in skeletal muscle hypertrophy in rats. J Appl Physiol. 1998;84:1716-22.
5. Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem. 2000;275:9047-54.
6. Alexander WS. Suppressors of cytokine signalling (SOCS) in the immune system. Nat Rev Immunol. 2002;2:410-6.
7. Allen DL, Roy RR, Edgerton VR. Myonuclear domains in muscle adaptation and disease. Muscle Nerve. 1999;22:1350-60.
8. Ballinger A. Fundamental mechanisms of growth failure in inflammatory bowel disease. Horm Res. 2002;58:7-10.
9. Bartoccioni E, Michaelis D, Hohlfeld R. Constitutive and cytokine-induced production of interleukin-6 by human myoblasts. Immunol Lett. 1994;42:135-8.
10. Barton-Davis ER, Shoturma DI, Musaro A, Rosenthal N, Sweeney HL. Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function. Proc Nat Acad Sci U S A. 1998;95:15603-7.
11. Barton-Davis ER, Shoturma DI, Sweeney HL. Contribution of satellite cells to IGF-I induced hypertrophy of skeletal muscle. Acta Physiol Scand. 1999;167:301-5.
12. Bodell PW, Kodesh E, Haddad F, Zaldivar FP, Cooper DM, Adams GR. Skeletal muscle growth in young rats is inhibited by chronic exposure to IL-6 but preserved by concurrent voluntary endurance exercise. J Appl Physiol. 106:443-530.
13. Bolster DR, Crozier SJ, Kimball SR, Jefferson LS. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J Biol Chem. 2002;277:23977-80.
14. Bolster DR, Jefferson LS, Kimball SR. Regulation of protein synthesis associated with skeletal muscle hypertrophy by insulin-, amino acid- and exercise-induced signalling. Proc Nutr Soc. 2004;63:351-6.
15. Broussard SR, McCusker RH, Novakofski JE, et al. IL-1β impairs insulin-like growth factor I-induced differentiation and downstream activation signals of the insulin-like growth factor I receptor in myoblasts. J Immunol. 2004;172:7713-20.
16. Cantini M, Massimino ML, Rapizzi E, et al. Human satellite cell proliferation in vitro is regulated by autocrine secretion of IL-6 stimulated by a soluble factor(s) released by activated monocytes. Biochem Biophys Res Commun. 1995;216:49-53.
17. Carey AL, Steinberg GR, Macaulay SL, et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes. 2006;55:2688-97.
18. Cheek DB, Holt AB, Hill DE, Talbert JL. Skeletal muscle mass and growth: the concept of the deoxyribonucleic acid unit. Pediatr Res. 1971;5:312-28.
19. Cohen T, Nahari D, Cerem LW, Neufeld G, Levi BZ. Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem. 1996;271:736-41.
20. de Alvaro C, Teruel T, Hernandez R, Lorenzo M. Tumor necrosis factor α produces insulin resistance in skeletal muscle by activation of inhibitor κB kinase in a p38 MAPK-dependent manner. J Biol Chem. 2004;279:17070-8.
21. de Falco G, Comes F, Simone C. pRb: master of differentiation. Coupling irreversible cell cycle withdrawal with induction of muscle-specific transcription. Oncogene. 2006;25:5244-9.
22. DeBenedetti F, Alonzi T, Moretta A, et al. Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-1. A model for stunted growth in children with chronic inflammation. J Clin Invest. 1997;99:643-50.
23. DeBenedetti F, Meazza C, Oliveri M, et al. Effect of IL-6 on IGF binding protein-3: a study in IL-6 transgenic mice and in patients with systemic juvenile idiopathic arthritis. Endocrinology. 2001;142:4818-26.
24. Dogan Y, Akarsu S, Ustundag B, Yilmaz E, Gurgoze MK. Serum IL-1β, IL-2, and IL-6 in insulin-dependent diabetic children. Mediators Inflamm. 2006;59206:1-6.
25. Dubbelhuis PF, Meijer AJ. Hepatic amino acid-dependent signaling is under the control of AMP-dependent protein kinase. FEBS Lett. 2002;521:39-42.
26. Fernández AM, Dupont J, Farrar RP, Lee S, Stannard B, LeRoith D. Muscle-specific inactivation of the IGF-I receptor induces compensatory hyperplasia in skeletal muscle. J Clin Invest. 2002;109:347-55.
27. Fong Y, Moldawer LL, Marano M, et al. Cachectin/TNF or IL-1α induces cachexia with redistribution of body proteins. Am J Physiol. 1989;256:R659-65.
28. Frame S, Balmain A. Integration of positive and negative growth signals during ras pathway activation in vivo. Curr Opin Genet Dev. 2000;10:106-13.
29. Gao Z, Hwang D, Bataille F, et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kB kinase complex. J Biol Chem. 2002;277:48115-21.
30. Glund S, Deshmukh A, Long YC, et al. Interleukin-6 directly increases glucose metabolism in resting human skeletal muscle. Diabetes. 2007;56:1630-7.
31. Goodman MN. Interleukin-6 induces skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med. 1994;205:182-5.
32. Hacham M, Cristal N, White RM, Segal S, Apte RN. Complementary organ expression of IL-1 vs. IL-6 and CSF-1 activities in normal and LPS-injected mice. Cytokine. 1996;8:21-31.
33. Haddad F, Adams GR. Aging sensitive cellular and molecular mechanisms associated with skeletal muscle hypertrophy. J Appl Physiol. 2006;100:1188-203.
34. Haddad F, Zaldivar FP, Cooper DM, Adams GR. IL-6 induced skeletal muscle atrophy. J Appl Physiol. 2005;98:911-7.
35. Hannan KM, Brandenburger Y, Jenkins A, et al. mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Mol Cell Biol. 2003;23:8862-77.
36. Hannan KM, Hannan RD, Rothblum LI. Transcription by RNA polymerase I. Front Biosci. 1998;3:376-98.
37. He J, Usui I, Ishizuka K, et al. Interleukin-1α inhibits insulin signaling with phosphorylating insulin receptor substrate-1 on serine residues in 3T3-L1 adipocytes. Mol Endocrinol. 2006;20:114-24.
38. Holz MK, Ballif BA, Gygi SP, Blenis J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell. 2005;123:569-80.
39. Jager J, Grémeaux T, Cormont M, LeMarchand-Brustel Y, Tanti JF. Interleukin-1β-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology. 2007;148:241-51.
40. Kadi F, Schjerling P, Andersen LL, et al. The effects of heavy resistance training and detraining on satellite cells in human skeletal muscles. J Physiol. 2004;558:1005-12.
41. Kanety H, Feinstein R, Papa MZ, Hemi R, Karasik A. Tumor necrosis factor α-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1. J Biol Chem. 1995;270:23780-4.
42. Kim HJ, Higashimori T, Park SY, et al. Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes. 2004;53:1060-7.
43. Kimball SR. Interaction between the AMP-activated protein kinase and mTOR signaling pathways. Med Sci Sports Exerc. 2006;38(11):1958-64.
44. Krause U, Bertrand L, Hue L. Control of p70 ribosomal protein S6 kinase and acetyl-CoA carboxylase by AMP-activated protein kinase and protein phosphatases in isolated hepatocytes. Eur J Biochem. 2002;269:3751-9.
45. Lang CH, Frost RA. Sepsis-induced suppression of skeletal muscle translation initiation mediated by tumor necrosis factor α. Metabolism. 2007;56:49-57.
46. Lang CH, Frost RA, Nairn AC, MacLean DA, Vary TC. TNF-α impairs heart and skeletal muscle protein synthesis by altering translation initiation. Am J Physiol. 2002;282:E336-47.
47. Lieskovska J, Guo D, Derman E. IL-6-overexpression brings about growth impairment potentially through a GH receptor defect. Growth Horm IGF Res. 2002;12:388-98.
48. Ling PR, Schwartz JH, Bistrian BR. Mechanisms of host wasting induced by administration of cytokines in rats. Am J Physiol. 1997;272:E333-9.
49. Musarò A, McCullagh K, Paul A, et al. Localized IGF-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet. 2001;27:195-200.
50. Nader GA, McLoughlin TJ, Esser KA. mTOR function in skeletal muscle hypertrophy: increased ribosomal RNA via cell cycle regulators. Am J Physiol. 2005;289:C1457-65.
51. Pedersen BK. IL-6 signalling in exercise and disease. Biochem Soc Trans. 2007;35:1295-7.
52. Pederson TM, Kramer DL, Rondinone CM. Serine/threonine phosphorylation of IRS-1 triggers its degradation: possible regulation by tyrosine phosphorylation. Diabetes. 2001;50:24-31.
53. Petrella JK, Kim JS, Mayhew DL, Cross JM, Bamman MM. Potent myofiber hypertrophy during resistance training in humans is associated with satellite cell-mediated myonuclear addition: a cluster analysis. J Appl Physiol. 2008;104:1736-42.
54. Quinn LS, Haugk KL, Grabstein KH. Interleukin-15: a novel anabolic cytokine for skeletal muscle. Endocrinology. 1995;136:3669-72.
55. Raj DS, Shah H, Shah VO, et al. Markers of inflammation, proteolysis, and apoptosis in ESRD. Am J Kidney Dis. 2003;42:1212-20.
56. Rommel C, Bodine SC, Clarke BA, et al. Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat Cell Biol. 2001;3:1009-13.
57. Ruderman NB, Keller C, Richard AM, et al. Interleukin-6 regulation of AMP-activated protein kinase. Potential role in the systemic response to exercise and prevention of the metabolic syndrome. Diabetes. 2006;55:S48-54.
58. Rui L, Yuan M, Frantz D, Shoelson S, White MF. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem. 2002;277:42394-8.
59. Saini A, Al-Shanti N, Faulkner SH, Stewart CE. Pro- and anti-apoptotic roles for IGF-I in TNF-α-induced apoptosis: a MAP kinase mediated mechanism. Growth Factors. 2008;26:239-53.
60. Saini A, Al-Shanti N, Stewart CE. Waste management-cytokines, growth factors and cachexia. Cytokine Growth Factor Rev. 2006;17:475-86.
61. Sawczenko A, Azooz O, Paraszczuk J, et al. Intestinal inflammation-induced growth retardation acts through IL-6 in rats and depends on the −174 IL-6 G/C polymorphism in children. Proc Natl Acad Sci U S A. 2005;102:13260-5.
62. Schaap LA, Pluijm SM, Deeg DJ, Visser M. Inflammatory markers and loss of muscle mass (sarcopenia) and strength. Am J Med. 2006;119:e9-17.
63. Sjöholm A, Nyström T. Inflammation and the etiology of type 2 diabetes. Diabetes Metab Res Rev. 2006;22:4-10.
64. Smith MA, Moylan JS, Smith JD, Li W, Reid MB. IFN-γ does not mimic the catabolic effects of TNF-α. Am J Physiol Cell Physiol. 2007;293:C1947-52.
65. Spangenburg EE, Le Roith D, Ward CW, Bodine SC. A functional insulin-like growth factor receptor is not necessary for load-induced skeletal muscle hypertrophy. J Physiol. 2008;586:283-91.
66. Strle K, Broussard SR, McCusker RH, et al. Proinflammatory cytokine impairment of insulin-like growth factor I-induced protein synthesis in skeletal muscle myoblasts requires ceramide. Endocrinology. 2004;145:4592-602.
67. Strle K, Broussard SR, McCusker RH, et al. C-jun N-terminal kinase mediates tumor necrosis factor-α suppression of differentiation in myoblasts. Endocrinology. 2006;147:4363-73.
68. Strle K, McCusker RH, Johnson RW, Zunich SM, Dantzer R, Kelley KW. Prototypical anti-inflammatory cytokine IL-10 prevents loss of IGF-I-induced myogenin protein expression caused by IL-1β. Am J Physiol. 2008;294:E709-18.
69. Sun H, Tu X, Liu M, Baserga R. Dual regulation of upstream binding factor 1 levels by IRS-1 and ERKs in IGF-1-receptor signaling. J Cell Physiol. 2007;212:780-6.
70. Takahashi T, Fukuda K, Pan J, et al. Characterization of insulin-like growth factor-I-induced activation of the JAK/STAT pathway in rat cardiomyocytes. Circ Res. 1999;85:884-91.
71. Tan JC, Rabkin R. Suppressors of cytokine signaling in health and disease. Pediatr Nephrol. 2005;20:567-75.
72. Uno T, He J, Usui I, et al. Long-term interleukin-1α treatment inhibits insulin signaling via IL-6 production and SOCS3 expression in 3T3-L1 adipocytes. Horm Metab Res. 2008;40:8-12.
73. van Hall G, Steensberg A, Fischer C, et al. Interleukin-6 markedly decreases skeletal muscle protein turnover and increases non-muscle amino acid utilization in healthy individuals. J Clin Endocrinol Metab. 2008;93:2851-8.
74. Vary TC, Deiter G, Lang CH. Cytokine-triggered decreases in levels of phosphorylated eukaryotic initiation factor 4G in skeletal muscle during sepsis. Shock. 2006;26:631-6.
75. Vary TC, Kimball SR. Sepsis-induced changes in protein synthesis: differential effects on fast- and slow-twitch muscles. Am J Physiol. 1992;262:C1513-9.
76. Weigert C, Hennige AM, Lehmann R, et al. Direct cross-talk of interleukin-6 and insulin signal transduction via insulin receptor substrate-1 in skeletal muscle cells. J Biol Chem. 2006;281:7060-7.
77. Yokota S, Miyamae T, Imagawa T, et al. Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2005;52:818-25.
78. Zong C, Chan J, Levy DE, Horvath C, Sadowski HB, Wang L. Mechanism of STAT3 activation by insulin-like growth factor I receptor. J Biol Chem. 2000;275:15099-105.


©2010The American College of Sports Medicine