HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Free All Versions of this Article: 103/1/378    most recent 00089.2007v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (17) Citing Articles via Google Scholar Google Scholar Articles by Frost, R. A. Articles by Lang, C. H. Search for Related Content PubMed PubMed Citation Articles by Frost, R. A. Articles by Lang, C. H.

INVITED REVIEW

HIGHLIGHTED TOPIC
Exercise and Inflammation

Protein kinase B/Akt: a nexus of growth factor and cytokine signaling in determining muscle mass

Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania

	ABSTRACT

TOP ABSTRACT AKT SHARES ITS METABOLIC... PI3K SIGNALING REGULATES MUSCLE... AKT LOCALIZATION DETERMINES ITS... AKT ENERGIZES SKELETAL MUSCLE... AKT MEDIATES THE POSITIVE... NEGATIVE AFFECTS OF CYTOKINES... MUSCLE CYTOKINES AND MYOSTATIN... SUMMARY GRANTS REFERENCES

 
Although the boundaries of skeletal muscle size are fundamentally determined by genetics, this dynamic tissue also demonstrates great plasticity in response to environmental and hormonal factors. Recent work indicates that contractile activity, nutrients, growth factors, and cytokines all contribute to determining muscle mass. Muscle responds not only to endocrine hormones but also to the autocrine production of growth factors and cytokines. Skeletal muscle synthesizes anabolic growth factors such as insulin-like growth factor (IGF)-I and potentially inhibitory cytokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-, and myostatin. These self-regulating inputs in turn influence muscle metabolism, including the use of nutrients such as glucose and amino acids. These changes are principally achieved by altering the activity of the protein kinase known as protein kinase B or Akt. Akt plays a central role in integrating anabolic and catabolic responses by transducing growth factor and cytokine signals via changes in the phosphorylation of its numerous substrates. Activation of Akt stimulates muscle hypertrophy and antagonizes the loss of muscle protein. Here we review the many signals that funnel through Akt to alter muscle mass.

muscle metabolism; muscle cytokines; translation; hypertrophy; atrophy

The above environmental and hormonal cues impinge on muscle at the cellular level by forcing individual muscle fibers to either make or destroy protein. Anabolic factors such as nutrients, growth hormones, anabolic steroids, and muscle contraction in due course increase protein synthesis and inhibit protein degradation. In contrast, factors such as malnutrition, stress hormones, cytokines, and inactivity induce an atrophic phenotype (110). These same factors may also expand or contract the pool of stem cells in muscle by either stimulating satellite cell replication or augmenting apoptosis, respectively (12, 97).

Growth factor receptors, nutrients, and even muscle contraction all increase the activity of the protein kinase known as protein kinase B (PKB) or Akt (87, 90, 108). Akt is a serine(S)/threonine(T) kinase that signals via a wortmannin-sensitive pathway downstream of growth factor receptors by activating phosphoinositide-3 (PI3) kinase. Akt is activated by phospholipid binding to the plextrin-homology domain, which induces a conformational change allowing for phosphorylation of T308 by phosphoinositide-dependent kinase (PDK)-1. Akt is autophosphorylated on T72 and S246 and mutation of these sites dramatically inhibits the ability of insulin-like growth factor (IGF)-I to stimulate kinase activity (67). An additional site in the carboxy terminus (serine 473) is phosphorylated by the mammalian target of rapamycin (mTOR) and may provide substrate selectivity to the kinase (47).

Akt has the ability to phosphorylate and change the activity of many critical metabolic targets. Akt stimulates glucose uptake, glycogen synthesis, and protein synthesis by phosphorylating Akt substrate 160, glycogen synthase kinase-3/B, and the tuberous sclerosis (TSC)-2 proteins in that order (18, 50, 54). Akt also inhibits apoptosis and protein degradation in skeletal muscle by promoting the phosphorylation and inactivation of the pro-apoptotic protein Bad and FoxO transcription factors, respectively. Phosphorylation of FoxO by Akt alters its subcellular localization and prevents the expression of FoxO-dependent atrophy related genes such as atrogin-1 and muscle ring-finger (MuRF)-1 (95, 98).

Akt is therefore situated at a critical juncture in muscle signaling where it responds to diverse anabolic and catabolic stimuli. Akt has the dual potential to drive the formation of new protein while preventing the proteolytic degradation of existing protein. As a result, Akt is a key metabolic control point in a number of diseases that are characterized by changes in muscle mass (15, 55, 85, 87, 88). Hence, because of its central role, the purpose of this review is to summarize the molecular mechanisms by which Akt bidirectionally regulates signaling in muscle in response to growth factors, cytokines, and muscle contraction. Furthermore, the review will emphasize the factors that play a critical role in mediating muscle wasting in catabolic conditions.

	AKT SHARES ITS METABOLIC MISSION

TOP ABSTRACT AKT SHARES ITS METABOLIC... PI3K SIGNALING REGULATES MUSCLE... AKT LOCALIZATION DETERMINES ITS... AKT ENERGIZES SKELETAL MUSCLE... AKT MEDIATES THE POSITIVE... NEGATIVE AFFECTS OF CYTOKINES... MUSCLE CYTOKINES AND MYOSTATIN... SUMMARY GRANTS REFERENCES

 
Three separate genes code for Akt mRNAs and these mRNAs are translated into three distinct Akt proteins designated Akt1, -2, and -3. Akt1 and -2 are highly expressed in insulin-sensitive tissues, whereas the abundance of Akt3 is low in skeletal muscle (71). Constitutive expression of Akt1 in L6 myoblasts promotes glucose and amino acid transport into the cell as well as protein synthesis (42). In contrast, overexpression of Akt2, but not Akt1, in C2C12 cells stimulates this cell line to differentiate into myotubes, suggesting that both isoforms are necessary for attaining optimal muscle mass (100).

Mice lacking Akt1 show only a subtle decrease in muscle size compared with their wild-type littermates, whereas mice that lack Akt2 exhibit a diabetic phenotype (14, 37). Although whole body glucose disposal was impaired in Akt2 null mice, insulin-stimulated glucose uptake was reduced in the EDL but not the soleus muscle and therefore displayed fiber type selective insulin resistance (15). The data are consistent with muscle glycogen being reduced in type IIa but not type I fibers from patients with diabetes mellitus and the concept that the intracellular concentration of glucose in type II fibers is regulated predominantly at the level of glucose transport, whereas in the soleus it is regulated predominantly at the level of glucose phosphorylation (43, 44). A similar fiber type selective loss of signaling downstream of Akt occurs in sepsis, where the gastrocnemius but not the soleus exhibits reduced mTOR activity (59). Double knockout mice display multiple developmental defects including severe muscle atrophy, implying both isoforms of Akt contribute to the determination of muscle size.

Intramuscular injection of an adenovirus carrying constitutively active Akt1 induced myofiber hypertrophy in the gastrocnemius, which was associated with a greater recruitment of new blood vessels and perfusion of the muscle (103). Lai et al. (55) also demonstrated that expression of constitutively active Akt from a tamoxifen-inducible promoter increased the weight of the quadriceps by 73% in just 14 days. In addition, these mice exhibited a two- to threefold increase in the number of fibers in the tibialis anterior and gastrocnemius with cross-sectional areas greater than those of wild-type muscle. Because expression of Akt was induced postnataly rapid hypertrophy appears not to be due to changes in muscle development in utero and therefore Akt may be amenable to pharmacological manipulation in disease states. Akt activation in this model also increased the phosphorylation of S6K1 on T421/S424, suggesting muscle hypertrophy results from downstream activation of the mTOR/S6K1 pathway and an increase in muscle protein synthesis. Later studies by Latres et al. (64) also showed that Akt phosphorylates FoxO transcription factors to inhibit the expression of atrophy-related genes such as atrogin-1 and MuRF-1 and therefore Akt exerts its influence on both sides of the muscle protein balance equation (92).

	PI3K SIGNALING REGULATES MUSCLE MASS VIA AKT

TOP ABSTRACT AKT SHARES ITS METABOLIC... PI3K SIGNALING REGULATES MUSCLE... AKT LOCALIZATION DETERMINES ITS... AKT ENERGIZES SKELETAL MUSCLE... AKT MEDIATES THE POSITIVE... NEGATIVE AFFECTS OF CYTOKINES... MUSCLE CYTOKINES AND MYOSTATIN... SUMMARY GRANTS REFERENCES

 
One would predict that loss of PI3K, the upstream signal activating Akt in skeletal muscle, would significantly impair growth and alter the insulin responsiveness of this tissue. As the total loss of PI3K is embryonic lethal, Luo generated mice lacking the p85/B regulatory subunits of PI3K specifically in skeletal muscle. As expected, the knockout mice exhibited a 30% decrease in the weight of the gastrocnemius and a dramatic decrease in the cross-sectional area of muscle fibers (69). Elimination of the p85 subunit was also associated with a reduction in the phosphorylation of Akt, ribosomal protein S6, and 4EBP-1 in fed mice consistent with a decrease in translation initiation in these animals. The mRNAs for the atrophy-related ubiquitin ligases atrongin-1 and MuRF-1 were not increased in the knockout mice relative to their fasted wild-type littermates, making it unlikely that the decreased muscle size is due to an atrogene-induced muscle atrophy in the PI3K null mice.

The PI3 kinase/Akt signaling pathway is also negatively regulated by the phosphatase and tensin homolog deleted on chromosome 10 (PTEN). PTEN attenuates PI3K signaling by dephosphorylating the phosphatidylinositol 3,4,5-trisphosphate generated by PI3K. PTEN increases in rat muscle as they age and this has been proposed as one mechanism by which the protein synthetic response to insulin is blunted in more mature animals (101). Indeed, muscle specific deletion of PTEN protected mice from high fat diet-induced diabetes but the deletion of PTEN did not significantly alter the weight of either the soleus or EDL muscle (112). In addition, neither the basal level of Akt phosphorylation nor insulin-stimulated Akt phosphorylation was enhanced by the loss of PTEN in skeletal muscle. These data suggest muscle may have a redundant system to compensate for the loss of PTEN but not for the loss of PI3K.

	AKT LOCALIZATION DETERMINES ITS SUBSTRATES AND ACTIVITY

TOP ABSTRACT AKT SHARES ITS METABOLIC... PI3K SIGNALING REGULATES MUSCLE... AKT LOCALIZATION DETERMINES ITS... AKT ENERGIZES SKELETAL MUSCLE... AKT MEDIATES THE POSITIVE... NEGATIVE AFFECTS OF CYTOKINES... MUSCLE CYTOKINES AND MYOSTATIN... SUMMARY GRANTS REFERENCES

 
The subcellular localization of Akt greatly influences its ability to stimulate different pathways. For example, constitutively active Akt was sufficient to increase the phosphorylation of 4EBP-1, whereas S6K1 phosphorylation required Akt to be not only catalytically active but also to be targeted to the cell membrane (26). Akt also binds to a scaffold protein called periplakin and overexpression of the carboxy-terminal portion of periplakin localizes Akt to intermediate filaments while excluding Akt from the nucleus (107). Nuclear exclusion of Akt ameliorates its ability to phosphorylate FoxO proteins while concomitantly inhibiting FoxO-mediated transcription of atrophy-associated genes.

Nuclear bodies first described in promyelocytic leukemia and referred to as Pml bodies have also been shown to inactivate nuclear Akt and prevent FoxO3 phosphorylation. Pml brings protein phosphatase 2a (PP2a) subunits and Akt in close proximity in nuclear bodies to dephosphorylate T308, thereby inactivating the enzyme (104). Borgotti et al. (7) reported Akt binds strongly to the nuclear matrix protein nucleolin and PP2A. PP2A binding was strongest in nuclei with weak Akt activity. Dephosphorylation of Akt via PP2a would be expected to yet again activate FoxO3-dependent genes such as atrogin-1 and MuRF-1 as well as the proapoptotic protein Bim (106).

In a similar series of studies, Bernardi et al. (5) found Pml also binds to and favors the nuclear accumulation of mTOR. The physical interaction between mTOR and Pml in the nucleus negatively regulates the association of mTOR with the small GTPase Rheb and its ability to phosphorylate downstream substrates. Rheb is normally distributed to membranous structures in the cytoplasm with characteristics of the Golgi apparatus (9). Failure of mTOR and Rheb to attach to these membrane structures impedes Rheb signaling to S6K1. Thus Pml may orchestrate the loss of muscle mass at multiple levels including the inhibition of protein synthesis, enhanced ubiquitin ligase-dependent protein degradation, and the enhanced expression of the pro-apoptotic protein Bim that is normally repressed by Akt.

Although not specifically demonstrated in skeletal muscle, Akt also translocates from the cytosol to mitochondria in cardiac muscle. Activation of mitochondrial ATP-sensitive potassium channels with diazoxide provides cardioprotection and triggers the binding of Akt to mitochondria in a PI3K-dependent manner (1). Akt may therefore play an important role in energy and protein balance in skeletal muscle as outlined below.

	AKT ENERGIZES SKELETAL MUSCLE WITH ATP

TOP ABSTRACT AKT SHARES ITS METABOLIC... PI3K SIGNALING REGULATES MUSCLE... AKT LOCALIZATION DETERMINES ITS... AKT ENERGIZES SKELETAL MUSCLE... AKT MEDIATES THE POSITIVE... NEGATIVE AFFECTS OF CYTOKINES... MUSCLE CYTOKINES AND MYOSTATIN... SUMMARY GRANTS REFERENCES

 
Recently Akt was unexpectedly shown to regulate cellular ATP content. Addition of serum to control cells nearly doubles ATP levels, whereas Akt1/2 double knockout cells have reduced ATP and a marked increase in the AMP/ATP ratio (41). Because protein synthesis is a highly ATP-demanding process, eukaryotic organisms have developed exquisitely sensitive mechanisms to conserve ATP and restrain translation. ATP depletion increases AMP-activated protein kinase (AMPK) activity and attenuates the ability of activated Akt and growth factors to stimulate mTOR activity (41). These data are consistent with studies demonstrating AMPK activation with 5-aminoimidazole-4-carboxamide 1-beta-D-ribonucleoside decreases muscle protein synthesis by blocking mTOR activity (6, 113). Akt therefore functions at two levels: first it phosphorylates TSC2 on T1462 to inactivate the TSC1/2 complex and, second, Akt raises ATP levels to inhibit AMPK and relieve the negative effect of AMPK on mTOR.

TSC-1 and -2 appear to play a critical role in regulating basal mTOR activity in skeletal muscle because overexpression of TSC-1 leads to a reduction in muscle fiber cross-sectional area. Expression of the TSC1 transgene mediates its affect by stabilizing and increasing the level of TSC2. Despite the negative influence of excess TSC1/TSC2 on muscle mass, TSC1/TSC2 does not antagonize insulin-stimulated mTOR signaling (111). Therefore, pharmacological levels of insulin and/or IGF-I would be expected to restore muscle mass in pathophysiological conditions characterized by an excess of the TSC1/TSC2 complex. An exception to this rule may occur in patients that are treated chronically with the immunosuppressant rapamycin for 6 mo. Insulin fails to stimulate Akt phosphorylation on S473 under these conditions while increasing basal IRS-1 activation (24).

As noted above, mTOR not only phosphorylates downstream substrates such as S6K1 and 4EBP-1 but also phosphorylates the upstream kinase Akt on S473. As a result, mTOR participates in a positive feedback loop for the preservation of mTOR activity. The TORC2 complex binds to Rictor as well as a protein known as stress-activated protein kinase interacting protein (Sin)-1 (51). Knockdown of Sin1 in Drosophila and mammalian cells decreases Akt activity in vitro and Jacinto et al. (51) found Akt to be only singly phosphorylated on T308 in Sin1-negative cells (116). These studies defined mTOR as the kinase responsible for S473-Akt phosphorylation. Although Akt retained only minimal activity in Sin1-negative cells it continued to normally phosphorylate substrates such as GSK3 and TSC2. Moreover, phosphorylation of S6K1 and 4EBP-1 was normal. In contrast to most Akt substrates, Sin1 deficiency strongly inhibited the phosphorylation of FoxO3a at T24/T32, whereas S256 phosphorylation was normal. These data define an explicit linkage between mTOR, Akt, and FoxO3-dependent genes that does not affect other Akt substrates. Insufficient Sin1 may therefore accelerate muscle atrophy as activated FoxO3a upregulates the genetic program for atrophy-related atrogenes in skeletal muscle (91).

The mammalian target of rapamycin is also a classical nutrient sensor that responds to excursions in plasma amino acid levels. The amino acid leucine in particular strongly stimulates mTOR both in vitro and in vivo. In L6 muscle cells, leucine-stimulated mTOR activation is PI3 kinase dependent but Akt independent, whereas in vivo leucine fails to stimulate Akt phosphorylation on T308 in skeletal muscle (58, 83). Amino acids such as leucine may stimulate mTOR activity by promoting the binding of other proteins such as the Rheb GTPase to mTOR and its substrates, although these functions still remain largely unknown (3, 53).

Akt can also directly affect energy metabolism by binding to outer membrane sites on mitochondria. Here Akt interacts with the mitochondrial hexokinase and cooperates with the voltage-dependent anion channel (VDAC) and the inner mitochondrial membrane adenine nucleotide translocator. These two membrane complexes are critical for the passage of metabolites and adenine nucleotides in and out of the mitochondria. Hexokinase inhibitors such as 3-bromopyruvate inhibit mitochondrial adenine nucleotide transport (36). Majewski et al. (70) demonstrated activated Akt increases the association of hexokinase with mitochondria to facilitate energy homeostasis and prevent the release of cytochrome C and apoptosis. Akt is also important in insulin-mediated maintenance of mitochondrial oxidative phosphorylation enzymes, mitochondriogenesis, and maximizing the generation of ATP (80).

Like Akt, the mTOR-raptor complex can also be purified in the mitochondrial fraction, implying the mTOR pathway may mediate and/or facilitate some of the affects of Akt on energy production. Treatment of cells with rapamycin disrupts the interaction of mTOR and raptor and lowers mitochondrial membrane potential and their capacity to resynthesize ATP (94). Interestingly, rapamycin does not alter protein expression in mitochondria but has a dramatic affect on the mobility (and potential phosphorylation) of mitochondrial proteins, including pyruvate decarboxylase and VDAC (94). Given the functional ability of mTOR to assist in the selection of Akt substrates, it will be interesting to know whether the phosphorylation of mitochondrial proteins is altered by Akt, mTOR, or both kinases.

ATP and Akt may also have other positive affects on skeletal muscle. ATP stimulates mouse embryonic stem cell proliferation and this can be inhibited by the PI3K inhibitor wortmannin (46). It is possible that Akt-dependent elevations in ATP may expand the pool of satellite cells in skeletal muscle and aid in the restoration of muscle mass after injury. Therefore, Akt, mTOR, and the FoxO transcription factors may also affect the genesis of new muscle (48).

	AKT MEDIATES THE POSITIVE EFFECTS OF IGF-I IN MUSCLE

TOP ABSTRACT AKT SHARES ITS METABOLIC... PI3K SIGNALING REGULATES MUSCLE... AKT LOCALIZATION DETERMINES ITS... AKT ENERGIZES SKELETAL MUSCLE... AKT MEDIATES THE POSITIVE... NEGATIVE AFFECTS OF CYTOKINES... MUSCLE CYTOKINES AND MYOSTATIN... SUMMARY GRANTS REFERENCES

 
Growth hormone and IGF-I are potent regulators of muscle mass as evidenced by the dramatic enlargement of muscle in transgenic mice overexpressing these proteins (16, 78, 79). In general, this increase is characterized by a hypertrophic response due to cell volume expansion in existing myocytes similar to that described above for Akt overexpression (55). Indeed cells from Akt1/2 double knockout mice are resistant to the stimulatory effect of serum growth factors on Akt and 4EBP-1 phosphorylation and, conversely, dominant negative forms of Akt negate the positive effects of IGF-I on cell survival (81, 109).

It is likely that insulin receptor substrate (IRS)-1 transmits the insulin/IGF-I anabolic signal in skeletal muscle because IRS-1-deficient mice exhibit reduced insulin-stimulated Akt phosphorylation, S6K1 activity, and protein synthesis (89, 115). Huang et al. (49) demonstrated that IRS-1 signals to both Akt1 and -2 in myotubes, whereas IRS2 only signals to Akt2. This selectivity in signaling translates into major differences in physiological endpoints where siRNA against IRS-1 but not IRS-2 decreased insulin-stimulated glucose uptake in muscle cells. Therefore, it is likely IRS-1 mediates the majority of signaling to Akt and mTOR to elicit muscle hypertrophy.

Classical IGF-I signaling via the above pathways may not be the sole means by which IGF-I increases muscle mass. In response to growth hormone, muscle damage, and muscle contraction, IGF-I mRNA can also be alternatively spliced to generate a protein referred to as mechano-growth factor (MGF) (40). Exon 5 of MGF codes for an E-domain, which precludes MGF from binding to IGF binding proteins, and it has been speculated that MGF may be more potent than IGF-I derived from the circulation (40). Yang and Goldspink (115a) observed that MGF expands the pool of satellite/stem cells and, whereas an IGF-I receptor antibody could block the affects of recombinant IGF-I, the antibody could not block the affect of MGF. These data suggest MGF may interact with a unique receptor in muscle where it stimulates the proliferation and migration of myogenic precursor cells to restore muscle mass (73). Although the findings on MGF are provocative, more progress needs to be made in identifying the MGF receptor and how it integrates with known signaling pathways.

Malnutrition, critical illness, and sepsis are all associated with a dramatic reduction in the overall pool of IGF-I contributed from the circulation as an endocrine hormone as well as autocrine IGF-I produced by the muscle itself. The fall in muscle IGF-I content in these conditions is associated with muscle atrophy. Consequently, growth hormone has been used clinically to increase lean body mass in patients with muscle wasting (8, 32). The development of growth hormone resistance in disease states has limited the use of growth hormone clinically, whereas the risk of hypoglycemia has restricted the use of IGF-I (61). IGF-I complexed to insulin-like growth factor binding protein-3 (IPLEX, Insmed Therapeutic Proteins, Boulder, CO), which is now approved for the treatment of children with primary IGF-I deficiency, reverses muscle wasting in animal models of sepsis and alcoholic myopathy with little evidence of side effects (60, 102). The IGF-I/IGF binding protein-3 complex has also been reported to be more efficacious than IGF-I alone at stimulating Akt phosphorylation in nonobese diabetic mice, suggesting this complex may be useful in both growth hormone and insulin-resistant conditions (13).

Although the effects of sepsis, critical illness, and endotoxin on the systemic growth hormone/IGF axis are profound, we focused our attention on the local synthesis of IGF-I in skeletal muscle per se. The rationale for this decision was threefold: 1) growth hormone stimulates IGF-I expression not only in the liver but also in muscle (105), 2) specific deletion of the IGF-I gene from the liver decreases circulating IGF-I levels by 80% but does not decrease muscle size (114), and 3) the local production of IGF-I is likely to contribute substantially to the biologically active pool of IGF-I in the local milieu of the myofiber as evidenced by mice that specifically overexpress IGF-I in skeletal muscle (78).

LPS, a Toll-like receptor-4 ligand, tumor necrosis factor (TNF)-, and interleukin (IL)-1 all decrease the local content of IGF-I in skeletal muscle (28, 29, 56). The decrease in IGF-I peptide is paralleled by a concomitant decrease in IGF-I mRNA. Furthermore, the LPS-induced decrease in muscle IGF-I mRNA only occurs in mice with a functional LPS receptor. Intraperitoneal injection of LPS into Toll-like receptor-4 signaling-deficient C3H/HeJ mice maintained muscle IGF-I mRNA levels similar to those seen in wild-type mice injected with saline (31). The decrease in skeletal muscle IGF-I expression after LPS is likely mediated by cytokines such as TNF- and IL-1 because LPS failed to decrease IGF-I mRNA in skeletal muscle of rats that were pretreated with either a TNF neutralizing antibody or an IL-1 receptor antagonist (56).

Dehoux et al. (20) found that fasting and diabetes increased the expression of atrogin-1 in skeletal muscle and that normalization of plasma IGF-I levels blunted its expression. Yet these investigators recently found that, although IGF-I could inhibit the induction of atrogin-1 by a mixture of TNF- and interferon (IFN)-, IGF-I could not protect C2C12 myotubes from a TNF-/IFN--induced loss of myosin heavy chain, MyoD, and a decrease in myotube diameter (21). Therefore, muscle atrophy can occur independently of atrogin-1 expression. It should also be noted that although atrogin-1 mRNA is elevated in a number of studies, very few investigations reported whether there is a concomitant rise in atrogin-1 protein.

	NEGATIVE AFFECTS OF CYTOKINES AND NF-B ACTIVATION ON MUSCLE PROTEIN

TOP ABSTRACT AKT SHARES ITS METABOLIC... PI3K SIGNALING REGULATES MUSCLE... AKT LOCALIZATION DETERMINES ITS... AKT ENERGIZES SKELETAL MUSCLE... AKT MEDIATES THE POSITIVE... NEGATIVE AFFECTS OF CYTOKINES... MUSCLE CYTOKINES AND MYOSTATIN... SUMMARY GRANTS REFERENCES

 
Muscle damage due to eccentric exercise induces TNF- and this cytokine dramatically impairs insulin stimulation of IRS-1, PI3-kinase, and Akt (22). TNF- is thought to produce insulin resistance in skeletal muscle by activation of the inhibitor of B kinase (IKK). In this regard, IKK phosphorylates IRS-1 on S307 and thereby precludes subsequent tyrosine phosphorylation of IRS-1 and activation of PI3 kinase and Akt (19, 25). In agreement with this hypothesis, targeted ablation of IKK2 increased skeletal muscle strength and protected against atrophy by increasing signaling by means of protein synthetic pathways and decreasing activation of protein degradative pathways (77). Deletion of IKK2 dramatically upregulated the phosphorylation of Akt and S6K1 and this was maintained even after muscle denervation, suggesting that inhibition of this kinase provides protection from muscle atrophy. IKK2 deletion also blunted the rise in MuRF-1 but not atrogin-1 mRNA in response to denervation.

NF-B plays an essential role mediating muscle atrophy produced by unloading. Judge et al. (52) found overexpression of an IKB super-repressor in the soleus inhibited unloading-induced atrophy by 40%. The super-repressor also blunted the expression of atrophy-related genes (52).

We and others found that sepsis, LPS, inflammatory cytokines as well as the over production of glucocorticoids all increase the expression of the muscle atrophy genes atrogin-1 and MuRF-1 (34). Although sepsis increases both atrogenes, only atrogin-1 expression is sustained up to 72 h. In addition, only atrogin-1 expression was suppressed in septic rats treated with a binary complex of IGF-I and IGF binding protein-3, a combination we previously showed to reverse sepsis-induced changes in the weight and protein content of the gastrocnemius and the efficiency of protein to be synthesized from a given amount of RNA (102). It is particularly noteworthy that the IGF-I/IGF binding protein-3 complex was efficacious when given after the initial septic insult, a time point at which anti-cytokine therapies have failed (74).

The most direct evidence for a role of NF-B in the etiology of muscle wasting comes from studies of transgenic mice engineered to express a constitutively active IKK2 exclusively in skeletal muscle. IKK2-overexpressing mice displayed greater activation of NF-B than control animals and severe muscle wasting was confirmed by a 50% decrease in fiber diameter (10). This resulted in a 75% decrease in the maximal force generated by single muscle fibers from the IKK-overexpressing mice. Because the wasting phenotype was blocked by cross breeding these mice with mice overexpressing the IB super-repressor, it is highly likely the wasting phenotype is due to NF-B activation and not activation of other pathways.

Muscle from the IKK-overexpressing mice released 2.5-fold more tyrosine than wild-type muscle when incubated ex vivo, suggesting that the muscle wasting is largely due to muscle protein breakdown. At least 50% of the change in muscle mass could be attributed to NF-B activation of the ubiquitin ligase MuRF-1, because mating the IKK2-overexpressing mice and MuRF-1 knockout mice generated offspring in which the IKK-induced drop in muscle mass was ameliorated (10). The above findings are consistent with the ability of salicylate (an IKK inhibitor) to block atrophy in IKK-overexpressing mice and an IKK2 inhibitor to ameliorate muscle wasting in a murine model of human acquired immune deficiency syndrome (45).

Sandri et al. (91) recently showed the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 protects skeletal muscle from atrophy due to denervation and fasting. PGC-1 strongly inhibited the expression of atrogin-1, MuRF-1, and cathepsin L, consistent with its ability to prevent a loss in muscle fiber cross-sectional area and mass. PGC-1 was also a strong inhibitor of both a FoxO reporter plasmid and the atrogin-1 promoter in vivo. Muscle PGC-1 is downregulated in diabetic and uremic mice as well as mice with cancer cachexia, and this response may explain the propensity of these animals to lose muscle mass (91). Loss of PGC-1 may also explain the muscle atrophy in mice overexpressing IKK because compounds that stimulate NF-B (e.g., LPS and palmitate) decrease PGC-1 (17, 84). Yet rats injected with LPS exhibit a rapid but transient increase (not decrease) in PGC-1 mRNA (118). Collectively, these data suggest the ability of NF-B to decrease PGC-1 mRNA and induce muscle wasting is dependent on a more sustained activation of NF-B as would be delivered by constitutively active IKK or a protracted septic insult.

In contrast to the findings of Sandri et al., Miura et al. (75) found that overexpression of PGC-1 increased the oxidative capacity of skeletal muscle by increasing mitochondrial biogenesis in 13- to 15-wk-old mice. Although mitochondria from PGC-1-overexpressing mice exhibited a two- to threefold increase in oxygen consumption, respiration was uncoupled from ATP synthesis and ATP content was markedly decreased in PGC-1 transgenic mice (76). When PGC-1-overexpressing mice were followed for longer periods of time (25 wk) the mice developed selective atrophy of the quadriceps and gastrocnemius (fast glycolytic type-2B fibers) but not in the soleus, and these muscles exhibited increased infiltration of adipocytes (76). The dramatically different conclusion that can be reached by both studies may be due to differences in the age at which the mice were studied, differences in the promoters used to drive PGC-1 expression (muscle creatine kinase vs. the human -skeletal actin), or even the particular strain that was chosen for the studies. In the original work of Lin et al. (68), for example, strain 23 expressed very high levels of PGC-1 and showed distinct weight loss (68).

Southgate et al. (96) also provided evidence that PGC-1 is downregulated by Akt-mediated phosphorylation of FoxO1 in insulin-stimulated skeletal muscle. The PGC-1 promoter contains FoxO1 binding sites and insulin-stimulated phosphorylation of Akt and phosphorylation of FoxO1 restricts the transcription factor to the cytoplasm limiting PGC-1 promoter activity. This accounts for the negative regulation of PGC-1 mRNA by insulin in control subjects. In contrast, in Type II diabetics, insulin failed to phosphorylate Akt and FoxO1 as efficiently and did not diminish PGC-1 mRNA levels (96). Akt2 null mice were also insulin resistant at the level of FoxO1 phosphorylation and insulin failed to repress PGC-1 mRNA expression. It is not known whether the loss of adipose tissue described in Akt2 null mice is redistributed to skeletal muscle or if these changes contribute to muscle wasting (37, 96).

Interestingly, endurance training induces a fast-to-slow twitch phenotype that can be mimicked by low-frequency stimulation of isolated rat muscles. Atherton et al. (2) demonstrated that low-frequency stimulation increases PGC-1 in the soleus. These authors proposed that low-frequency stimulation increases the AMP/ATP ratio in skeletal muscle and as a result activates AMPK. Indeed, Lee et al. (66) demonstrated that activation of AMPK with 5-aminoimidazole-4-carboxamide 1-beta-D-ribonucleoside increased PGC-1 in C2C12 cells in vitro and C57BL/J6 mice in vivo. Endurance exercise may therefore mediate its anti-inflammatory and anti-atrophy effects by many routes, including upregulating PGC-1 in muscle, reduced NF-B binding to DNA, downregulation of Toll-like receptors, and enhanced release of IL-6 resulting in inhibition of TNF production (27, 39, 82). It should also be noted that although muscle contraction limits atrophy, this occurs despite elevated circulating concentrations of glucocorticoids, which would normally be expected to promote protein breakdown. Atherton's studies suggest short bursts of exercise and high-frequency electrical stimulation compliment the abovementioned effects by robustly increasing Akt phosphorylation, markers of translation initiation, and protein synthesis in skeletal muscle (2).

	MUSCLE CYTOKINES AND MYOSTATIN NEGATIVELY REGULATE AKT

TOP ABSTRACT AKT SHARES ITS METABOLIC... PI3K SIGNALING REGULATES MUSCLE... AKT LOCALIZATION DETERMINES ITS... AKT ENERGIZES SKELETAL MUSCLE... AKT MEDIATES THE POSITIVE... NEGATIVE AFFECTS OF CYTOKINES... MUSCLE CYTOKINES AND MYOSTATIN... SUMMARY GRANTS REFERENCES

 
Accumulating evidence from rodent studies suggests LPS and sepsis alter translation initiation in skeletal muscle by disrupting mTOR signaling (57, 58). Recently we examined the affects of LPS and IFN- on mTOR signaling in C2C12 skeletal muscle cells in culture. The combination of LPS and IFN- decreased the autophosphorylation of mTOR and its substrates S6K1 and 4EBP-1. A comparable reduction in the phosphorylation of ribosomal protein S6 and protein synthesis was also observed, suggesting S6K1 activity is decreased in the presence of LPS and IFN-. LPS alone could not in and by itself diminish mTOR signaling or protein synthesis in this cell type but it did induce the expression of IL-6 and nitric oxide synthase (NOS)-2 (35). A combination of LPS and IFN- is necessary to produce the decline in mTOR phosphorylation and protein synthesis. We speculate that the dependency of this decrease on IFN- may be due to the ability of this cytokine to dramatically enhance the magnitude and duration of LPS-stimulated NOS2 expression by stabilizing NOS2 mRNA (23). Hence, the elevated levels of NO expressed for a protracted period of time causes a greater damage to regulatory proteins in growth signaling pathways via nitrosylation. Indeed we observed that NOS inhibitors prevented both the LPS/IFN--induced decrease in protein synthesis and changes in mTOR signaling (Frost and Lang, unpublished observations).

Akt is a confirmed target for NO action. NO donors rapidly inactivate Akt by S-nitrosylation and mutation of cysteine 224 to serine restores Akt activity (117). Although originally described as a mechanism of insulin resistance in diabetes, it is likely nitrosylation and inactivation of Akt decreases mTOR signaling in myotubes exposed to LPS and IFN-. Indeed, LPS increases the nitrosylation of the insulin receptor beta subunit, IRS-1, and Akt in skeletal muscle of wild-type mice but not NOS-2-negative mice. Consequently, NOS-2 knockout mice fail to develop LPS-induced insulin resistance (11).

Myostatin, an endogenous inhibitor of muscle mass is also highly expressed in select models of muscle atrophy. Gilson et al. (38) delineated the importance of myostatin in glucocorticoid-induced atrophy by showing myostatin knockout mice fail to lose muscle mass in response to the synthetic glucocorticoid dexamethasone. The myostatin knockout mice are also resistant to dexamethasone-induced atrogin-1 and MuRF-1 expression, suggesting one or more of the atrogenes mediate the negative affects of myostatin on muscle mass. Burn injury increased myostatin expression fourfold and this was inhibited by RU-486 (63). Notwithstanding, Lang et al. (62) found that the rise in atrogin-1 and MuRF-1 after thermal injury was glucocorticoid independent but inhibitable by IGF-I. These data suggest burn injury may induce two signals to stimulate atrogene expression and muscle atrophy: one mediated by glucocorticoids and myostatin and a second signal that alters basal but not IGF-I-responsive Akt activity toward FoxO-dependent genes (30, 99).

McFarlane et al. (72) recently demonstrated myostatin induces cachexia by activating the ubiquitin proteolytic system through a FoxO1-dependent mechanism. Addition of myostatin to C2C12 cells decreased the phosphorylation of Akt on S473 and FoxO1 on S256 consistent with reduced mTOR signaling. The enhanced translocation of FoxO1 into the nucleus and the stimulation of FoxO1-inducible genes and muscle wasting by myostatin is consistent with the muscle wasting phenotype of FoxO1-overexpressing mice (72).

	SUMMARY

TOP ABSTRACT AKT SHARES ITS METABOLIC... PI3K SIGNALING REGULATES MUSCLE... AKT LOCALIZATION DETERMINES ITS... AKT ENERGIZES SKELETAL MUSCLE... AKT MEDIATES THE POSITIVE... NEGATIVE AFFECTS OF CYTOKINES... MUSCLE CYTOKINES AND MYOSTATIN... SUMMARY GRANTS REFERENCES

 
A plethora of studies in recent years have eloquently examined the mechanisms by which muscle grows or atrophies. Indeed muscle is largely self-sufficient in its ability to respond to varied inputs. The protein kinase Akt has emerged as a key intermediary in the response of muscle to activity, nutrients growth factors, and cytokines (Fig. 1). Akt sits at a nexus of intracellular signaling in which it phosphorylates substrates such as TSC2 to increase protein synthesis and FoxO transcription factors to inhibit protein degradation. Akt monitors and responds to the flow of energy in the cell via its ability to interact with mitochondria and AMPK. Cytokines dramatically decrease the magnitude of growth factor signals such as IGF-I and attenuate the ability of nutrients to signal via mTOR. The generation of excess cytokine-induced NO decreases translational signaling and protein synthesis in vitro. Myostatin also decreases Akt phosphorylation and signals through FoxO transcription factors to induce atrophy. Muscle contraction, via signaling through many of these same pathways provides beneficial anti-inflammatory affects that limit atrophy and provide a strong stimulus to increase muscle mass.

View larger version (10K): [in this window] [in a new window]   Fig. 1. Numerous environmental and hormonal cues impinge on skeletal muscle to stimulate its growth or bring about its atrophy. These cues include positive inputs such as exercise, insulin-like growth factors (IGFs), and nutrients and negative inputs such as cytokines, glucocorticoids, and myostatin. Many of these signals are self-regulating in that they are made in an autocrine fashion by muscle itself. The protein kinase Akt acts at a nexus of intracellular signaling by translating these signals into changes in the phosphorylation and activity of other metabolically important enzymes [mammalian target of rapamycin (mTOR)] and transcription factors (FoxO). In a simplistic account mTOR activates protein translation and protein synthesis via S6K1 and 4EBP-1 phosphorylation to stimulate hypertrophy. In contrast, a reduction in Akt signaling allows for the nuclear accumulation of FoxO transcription factors and the transcription of atrogenes such as atrogin-1 and other components of the proteasome to degrade muscle protein and stimulate atrophy. Cytokines dramatically reduce mTOR signaling via a nitric oxide synthase (NOS)-dependent mechanism, whereas myostatin signals through FoxO transcription factors. Reduced Akt signaling appears to be a hallmark of both of these responses.

	GRANTS

TOP ABSTRACT AKT SHARES ITS METABOLIC... PI3K SIGNALING REGULATES MUSCLE... AKT LOCALIZATION DETERMINES ITS... AKT ENERGIZES SKELETAL MUSCLE... AKT MEDIATES THE POSITIVE... NEGATIVE AFFECTS OF CYTOKINES... MUSCLE CYTOKINES AND MYOSTATIN... SUMMARY GRANTS REFERENCES

	FOOTNOTES

 

Address for reprint requests and other correspondence: Dr. Robert A. Frost, Dept. of Cellular and Molecular Physiology, Penn State Univ. College of Medicine, 500 Univ. Drive, Hershey, PA 17033 (e-mail: rfrost{at}psu.edu)

	REFERENCES

TOP ABSTRACT AKT SHARES ITS METABOLIC... PI3K SIGNALING REGULATES MUSCLE... AKT LOCALIZATION DETERMINES ITS... AKT ENERGIZES SKELETAL MUSCLE... AKT MEDIATES THE POSITIVE... NEGATIVE AFFECTS OF CYTOKINES... MUSCLE CYTOKINES AND MYOSTATIN... SUMMARY GRANTS REFERENCES

 

1. Ahmad N, Wang Y, Haider KH, Wang B, Pasha Z, Uzun O, Ashraf M. Cardiac protection by mitoKATP channels is dependent on Akt translocation from cytosol to mitochondria during late preconditioning. Am J Physiol Heart Circ Physiol 290: H2402–H2408, 2006.[Abstract/Free Full Text]
2. Atherton PJ, Babraj J, Smith K, Singh J, Rennie MJ, Wackerhage H. Selective activation of AMPK-PGC-1alpha or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation. FASEB J 19: 786–788, 2005.[Abstract/Free Full Text]
3. Avruch J, Hara K, Lin Y, Liu M, Long X, Ortiz-Vega S, Yonezawa K. Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. Oncogene 25: 6361–6372, 2006.[CrossRef][Web of Science][Medline]
4. Bassel-Duby R, Olson EN. Signaling pathways in skeletal muscle remodeling. Annu Rev Biochem 75: 19–37, 2006.[CrossRef][Web of Science][Medline]
5. Bernardi R, Guernah I, Jin D, Grisendi S, Alimonti A, Teruya-Feldstein J, Cordon-Cardo C, Simon MC, Rafii S, Pandolfi PP. PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature 442: 779–785, 2006.[CrossRef][Medline]
6. 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 277: 23977–23980, 2002.[Abstract/Free Full Text]
7. Borgatti P, Martelli AM, Tabellini G, Bellacosa A, Capitani S, Neri LM. Threonine 308 phosphorylated form of Akt translocates to the nucleus of PC12 cells under nerve growth factor stimulation and associates with the nuclear matrix protein nucleolin. J Cell Physiol 196: 79–88, 2003.[CrossRef][Web of Science][Medline]
8. Botfield C, Ross RJ, Hinds CJ. The role of IGFs in catabolism. Baillieres Clin Endocrinol Metab 11: 679–697, 1997.[CrossRef][Web of Science][Medline]
9. Buerger C, DeVries B, Stambolic V. Localization of Rheb to the endomembrane is critical for its signaling function. Biochem Biophys Res Commun 344: 869–880, 2006.[CrossRef][Web of Science][Medline]
10. Cai D, Frantz JD, Tawa NE Jr, Melendez PA, Oh BC, Lidov HG, Hasselgren PO, Frontera WR, Lee J, Glass DJ, Shoelson SE. IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell 119: 285–298, 2004.[CrossRef][Web of Science][Medline]
11. Carvalho-Filho MA, Ueno M, Carvalheira JB, Velloso LA, Saad MJ. Targeted disruption of iNOS prevents LPS-induced S-nitrosation of IRbeta/IRS-1 and Akt and insulin resistance in muscle of mice. Am J Physiol Endocrinol Metab 291: E476–E482, 2006.[Abstract/Free Full Text]
12. Chakravarthy MV, Abraha TW, Schwartz RJ, Fiorotto ML, Booth FW. Insulin-like growth factor-I extends in vitro replicative life span of skeletal muscle satellite cells by enhancing G1/S cell cycle progression via the activation of phosphatidylinositol 3'-kinase/Akt signaling pathway. J Biol Chem 275: 35942–35952, 2000.[Abstract/Free Full Text]
13. Chen W, Salojin KV, Mi QS, Grattan M, Meagher TC, Zucker P, Delovitch TL. Insulin-like growth factor (IGF)-I/IGF-binding protein-3 complex: therapeutic efficacy and mechanism of protection against type 1 diabetes. Endocrinology 145: 627–638, 2004.[Abstract/Free Full Text]
14. Chen WS, Xu PZ, Gottlob K, Chen ML, Sokol K, Shiyanova T, Roninson I, Weng W, Suzuki R, Tobe K, Kadowaki T, Hay N. Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev 15: 2203–2208, 2001.[Abstract/Free Full Text]
15. Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB, Kaestner KH 3rd, Bartolomei MS, Shulman GI, Birnbaum MJ. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292: 1728–1731, 2001.[Abstract/Free Full Text]
16. Coleman ME, DeMayo F, Yin KC, Lee HM, Geske R, Montgomery C, Schwartz RJ. Myogenic vector expression of insulin-like growth factor I stimulates muscle cell differentiation and myofiber hypertrophy in transgenic mice. J Biol Chem 270: 12109–12116, 1995.[Abstract/Free Full Text]
17. Coll T, Jove M, Rodriguez-Calvo R, Eyre E, Palomer X, Sanchez RM, Merlos M, Laguna JC, Vazquez-Carrera M. Palmitate-mediated downregulation of peroxisome proliferator-activated receptor-gamma coactivator 1alpha in skeletal muscle cells involves MEK1/2 and nuclear factor-kappaB activation. Diabetes 55: 2779–2787, 2006.[Abstract/Free Full Text]
18. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378: 785–789, 1995.[CrossRef][Medline]
19. de Alvaro C, Teruel T, Hernandez R, Lorenzo M. Tumor necrosis factor alpha produces insulin resistance in skeletal muscle by activation of inhibitor kappaB kinase in a p38 MAPK-dependent manner. J Biol Chem 279: 17070–17078, 2004.[Abstract/Free Full Text]
20. Dehoux M, Gobier C, Lause P, Bertrand L, Ketelslegers JM, Thissen JP. IGF-I does not prevent myotube atrophy caused by proinflammatory cytokines despite activation of Akt/Foxo and GSK3 pathways and inhibition of Atrogin-1 mRNA. Am J Physiol Endocrinol Metab 292: E145–E150, 2007.[Abstract/Free Full Text]
21. Dehoux M, Van Beneden R, Pasko N, Lause P, Verniers J, Underwood L, Ketelslegers JM, Thissen JP. Role of the insulin-like growth factor I decline in the induction of atrogin-1/MAFbx during fasting and diabetes. Endocrinology 145: 4806–4812, 2004.[CrossRef][Web of Science][Medline]
22. Del Aguila LF, Krishnan RK, Ulbrecht JS, Farrell PA, Correll PH, Lang CH, Zierath JR, Kirwan JP. Muscle damage impairs insulin stimulation of IRS-1, PI 3-kinase, and Akt-kinase in human skeletal muscle. Am J Physiol Endocrinol Metab 279: E206–E212, 2000.[Abstract/Free Full Text]
23. Di Marco S, Mazroui R, Dallaire P, Chittur S, Tenenbaum SA, Radzioch D, Marette A, Gallouzi IE. NF-kappa B-mediated MyoD decay during muscle wasting requires nitric oxide synthase mRNA stabilization, HuR protein, and nitric oxide release. Mol Cell Biol 25: 6533–6545, 2005.[Abstract/Free Full Text]
24. Di Paolo S, Teutonico A, Leogrande D, Capobianco C, Schena PF. Chronic inhibition of mammalian target of rapamycin signaling downregulates insulin receptor substrates 1 and 2 and AKT activation: a crossroad between cancer and diabetes? J Am Soc Nephrol 17: 2236–2244, 2006.[Abstract/Free Full Text]
25. Dietze D, Koenen M, Rohrig K, Horikoshi H, Hauner H, Eckel J. Impairment of insulin signaling in human skeletal muscle cells by co-culture with human adipocytes. Diabetes 51: 2369–2376, 2002.[Abstract/Free Full Text]
26. Dufner A, Andjelkovic M, Burgering BM, Hemmings BA, Thomas G. Protein kinase B localization and activation differentially affect S6 kinase 1 activity and eukaryotic translation initiation factor 4E-binding protein 1 phosphorylation. Mol Cell Biol 19: 4525–4534, 1999.[Abstract/Free Full Text]
27. Durham WJ, Li YP, Gerken E, Farid M, Arbogast S, Wolfe RR, Reid MB. Fatiguing exercise reduces DNA binding activity of NF-kappaB in skeletal muscle nuclei. J Appl Physiol 97: 1740–1745, 2004.[Abstract/Free Full Text]
28. Fan J, Char D, Bagby GJ, Gelato MC, Lang CH. Regulation of insulin-like growth factor-I (IGF-I) and IGF-binding proteins by tumor necrosis factor. Am J Physiol Regul Integr Comp Physiol 269: R1204–R1212, 1995.[Abstract/Free Full Text]
29. Fan J, Molina PE, Gelato MC, Lang CH. Differential tissue regulation of insulin-like growth factor-I content and binding proteins after endotoxin. Endocrinology 134: 1685–1692, 1994.[Abstract/Free Full Text]
30. Fang CH, Li BG, James JH, King JK, Evenson AR, Warden GD, Hasselgren PO. Protein breakdown in muscle from burned rats is blocked by insulin-like growth factor I and glycogen synthase kinase-3beta inhibitors. Endocrinology 146: 3141–3149, 2005.[Abstract/Free Full Text]
31. Frost RA, Lang CH. Alteration of somatotropic function by proinflammatory cytokines. J Anim Sci 82, Suppl: E100–E109, 2004.[Abstract/Free Full Text]
32. Frost RA, Lang CH. Regulation of insulin-like growth factor-I in skeletal muscle and muscle cells. Minerva Endocrinol 28: 53–73, 2003.[Medline]
33. Frost RA, Lang CH. Skeletal muscle cytokines: regulation by pathogen-associated molecules and catabolic hormones. Curr Opin Clin Nutr Metab Care 8: 255–263, 2005.[Web of Science][Medline]
34. Frost RA, Nystrom GJ, Jefferson LS, Lang CH. Hormone, cytokine, and nutritional regulation of sepsis-induced increases in atrogin-1 and MuRF1 in skeletal muscle. Am J Physiol Endocrinol Metab 292: E501–E512, 2007.[Abstract/Free Full Text]
35. Frost RA, Nystrom GJ, Lang CH. Lipopolysaccharide stimulates nitric oxide synthase-2 expression in murine skeletal muscle and C₂C₁₂ myoblasts via Toll-like receptor-4 and c-Jun NH₂-terminal kinase pathways. Am J Physiol Cell Physiol 287: C1605–C1615, 2004.[Abstract/Free Full Text]
36. Garber K. Energy deregulation: licensing tumors to grow. Science 312: 1158–1159, 2006.[Abstract/Free Full Text]
37. Garofalo RS, Orena SJ, Rafidi K, Torchia AJ, Stock JL, Hildebrandt AL, Coskran T, Black SC, Brees DJ, Wicks JR, McNeish JD, Coleman KG. Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest 112: 197–208, 2003.[CrossRef][Web of Science][Medline]
38. Gilson H, Schakman O, Combaret L, Lause P, Grobet L, Attaix D, Ketelslegers JM, Thissen JP. Myostatin gene deletion prevents glucocorticoid-induced muscle atrophy. Endocrinology 148: 452–460, 2007.[Abstract/Free Full Text]
39. Gleeson M, McFarlin B, Flynn M. Exercise and Toll-like receptors. Exerc Immunol Rev 12: 34–53, 2006.[Web of Science][Medline]
40. Goldspink G. Impairment of IGF-I gene splicing and MGF expression associated with muscle wasting. Int J Biochem Cell Biol 38: 481–489, 2006.[CrossRef][Medline]
41. Hahn-Windgassen A, Nogueira V, Chen CC, Skeen JE, Sonenberg N, Hay N. Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J Biol Chem 280: 32081–32089, 2005.[Abstract/Free Full Text]
42. Hajduch E, Alessi DR, Hemmings BA, Hundal HS. Constitutive activation of protein kinase B alpha by membrane targeting promotes glucose and system A amino acid transport, protein synthesis, and inactivation of glycogen synthase kinase 3 in L6 muscle cells. Diabetes 47: 1006–1013, 1998.[Abstract]
43. Halseth AE, Bracy DP, Wasserman DH. Functional limitations to glucose uptake in muscles comprised of different fiber types. Am J Physiol Endocrinol Metab 280: E994–E999, 2001.[Abstract/Free Full Text]
44. He J, Kelley DE. Muscle glycogen content in type 2 diabetes mellitus. Am J Physiol Endocrinol Metab 287: E1002–E1007, 2004.[Abstract/Free Full Text]
45. Heckmann A, Waltzinger C, Jolicoeur P, Dreano M, Kosco-Vilbois MH, Sagot Y. IKK2 inhibitor alleviates kidney and wasting diseases in a murine model of human AIDS. Am J Pathol 164: 1253–1262, 2004.[Abstract/Free Full Text]
46. Heo JS, Han HJ. ATP stimulates mouse embryonic stem cell proliferation via protein kinase C, phosphatidylinositol 3-kinase/Akt, and mitogen-activated protein kinase signaling pathways. Stem Cells 24: 2637–2648, 2006.[Abstract/Free Full Text]
47. Hresko RC, Mueckler M. mTOR RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3–L1 adipocytes. J Biol Chem 280: 40406–40416, 2005.[Abstract/Free Full Text]
48. Hribal ML, Nakae J, Kitamura T, Shutter JR, Accili D. Regulation of insulin-like growth factor-dependent myoblast differentiation by Foxo forkhead transcription factors. J Cell Biol 162: 535–541, 2003.[Abstract/Free Full Text]
49. Huang C, Thirone AC, Huang X, Klip A. Differential contribution of insulin receptor substrates 1 versus 2 to insulin signaling and glucose uptake in l6 myotubes. J Biol Chem 280: 19426–19435, 2005.[Abstract/Free Full Text]
50. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4: 648–657, 2002.[CrossRef][Web of Science][Medline]
51. Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127: 125–137, 2006.[CrossRef][Web of Science][Medline]
52. Judge AR, Koncarevic A, Hunter RB, Liou HC, Jackman RW, Kandarian SC. Role for IB, but not c-Rel, in skeletal muscle atrophy. Am J Physiol Cell Physiol 292: C372–C382, 2007.[Abstract/Free Full Text]
53. Kimball SR, Jefferson LS. Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis. J Nutr 136: 227S–231S, 2006.[Abstract/Free Full Text]
54. Kramer HF, Witczak CA, Taylor EB, Fujii N, Hirshman MF, Goodyear LJ. AS160 regulates insulin- and contraction-stimulated glucose uptake in mouse skeletal muscle. J Biol Chem 281: 31478–31485, 2006.[Abstract/Free Full Text]
55. Lai KM, Gonzalez M, Poueymirou WT, Kline WO, Na E, Zlotchenko E, Stitt TN, Economides AN, Yancopoulos GD, Glass DJ. Conditional activation of akt in adult skeletal muscle induces rapid hypertrophy. Mol Cell Biol 24: 9295–9304, 2004.[Abstract/Free Full Text]
56. Lang CH, Fan J, Cooney R, Vary TC. IL-1 receptor antagonist attenuates sepsis-induced alterations in the IGF system and protein synthesis. Am J Physiol Endocrinol Metab 270: E430–E437, 1996.[Abstract/Free Full Text]
57. Lang CH, Frost RA. Differential effect of sepsis on ability of leucine and IGF-I to stimulate muscle translation initiation. Am J Physiol Endocrinol Metab 287: E721–E730, 2004.[Abstract/Free Full Text]
58. Lang CH, Frost RA. Endotoxin disrupts the leucine-signaling pathway involving phosphorylation of mTOR, 4E-BP1, and S6K1 in skeletal muscle. J Cell Physiol 203: 144–155, 2005.[CrossRef][Web of Science][Medline]
59. Lang CH, Frost RA. Sepsis-induced suppression of skeletal muscle translation initiation mediated by tumor necrosis factor alpha. Metabolism 56: 49–57, 2007.[CrossRef][Web of Science][Medline]
60. Lang CH, Frost RA, Svanberg E, Vary TC. IGF-I/IGFBP-3 ameliorates alterations in protein synthesis, eIF4E availability, and myostatin in alcohol-fed rats. Am J Physiol Endocrinol Metab 286: E916–E926, 2004.[Abstract/Free Full Text]
61. Lang CH, Hong-Brown L, Frost RA. Cytokine inhibition of JAK-STAT signaling: a new mechanism of growth hormone resistance. Pediatr Nephrol 20: 306–312, 2005.[CrossRef][Web of Science][Medline]
62. Lang CH, Huber D, Frost RA. Burn-induced increase in atrogin-1 and MuRF-1 in skeletal muscle is glucocorticoid independent but downregulated by IGF-I. Am J Physiol Regul Integr Comp Physiol 292: R328–R336, 2007.[Abstract/Free Full Text]
63. Lang CH, Silvis C, Nystrom G, Frost RA. Regulation of myostatin by glucocorticoids after thermal injury. FASEB J 15: 1807–1809, 2001.[Free Full Text]
64. Latres E, Amini AR, Amini AA, Griffiths J, Martin FJ, Wei Y, Lin HC, Yancopoulos GD, Glass DJ. Insulin-like growth factor-1 (IGF-1) inversely regulates atrophy-induced genes via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. J Biol Chem 280: 2737–2744, 2005.[Abstract/Free Full Text]
65. Lee SJ, McPherron AC. Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci USA 98: 9306–9311, 2001.[Abstract/Free Full Text]
66. Lee WJ, Kim M, Park HS, Kim HS, Jeon MJ, Oh KS, Koh EH, Won JC, Kim MS, Oh GT, Yoon M, Lee KU, Park JY. AMPK activation increases fatty acid oxidation in skeletal muscle by activating PPARalpha and PGC-1. Biochem Biophys Res Commun 340: 291–295, 2006.[CrossRef][Web of Science][Medline]
67. Li X, Lu Y, Jin W, Liang K, Mills GB, Fan Z. Autophosphorylation of Akt at threonine 72 and serine 246. A potential mechanism of regulation of Akt kinase activity. J Biol Chem 281: 13837–13843, 2006.[Abstract/Free Full Text]
68. Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, Spiegelman BM. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418: 797–801, 2002.[CrossRef][Medline]
69. Luo J, Sobkiw CL, Hirshman MF, Logsdon MN, Li TQ, Goodyear LJ, Cantley LC. Loss of class IA PI3K signaling in muscle leads to impaired muscle growth, insulin response, and hyperlipidemia. Cell Metab 3: 355–366, 2006.[CrossRef][Web of Science][Medline]
70. Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K, Chandel NS, Thompson CB, Robey RB, Hay N. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell 16: 819–830, 2004.[CrossRef][Web of Science][Medline]
71. Masure S, Haefner B, Wesselink JJ, Hoefnagel E, Mortier E, Verhasselt P, Tuytelaars A, Gordon R, Richardson A. Molecular cloning, expression and characterization of the human serine/threonine kinase Akt-3. Eur J Biochem 265: 353–360, 1999.[Web of Science][Medline]
72. McFarlane C, Plummer E, Thomas M, Hennebry A, Ashby M, Ling N, Smith H, Sharma M, Kambadur R. Myostatin induces cachexia by activating the ubiquitin proteolytic system through an NF-kappaB-independent, FoxO1-dependent mechanism. J Cell Physiol 209: 501–514, 2006.[CrossRef][Web of Science][Medline]
73. Mills P, Lafreniere JF, Benabdallah BF, El Fahime EM, Tremblay JP. A new pro-migratory activity on human myogenic precursor cells for a synthetic peptide within the E domain of the mechano growth factor. Exp Cell Res, 2006.
74. Minnich DJ, Moldawer LL. Anti-cytokine and anti-inflammatory therapies for the treatment of severe sepsis: progress and pitfalls. Proc Nutr Soc 63: 437–441, 2004.[CrossRef][Web of Science][Medline]
75. Miura S, Kai Y, Ono M, Ezaki O. Overexpression of peroxisome proliferator-activated receptor gamma coactivator-1alpha down-regulates GLUT4 mRNA in skeletal muscles. J Biol Chem 278: 31385–31390, 2003.[Abstract/Free Full Text]
76. Miura S, Tomitsuka E, Kamei Y, Yamazaki T, Kai Y, Tamura M, Kita K, Nishino I, Ezaki O. Overexpression of peroxisome proliferator-activated receptor gamma co-activator-1alpha leads to muscle atrophy with depletion of ATP. Am J Pathol 169: 1129–1139, 2006.[Abstract/Free Full Text]
77. Mourkioti F, Kratsios P, Luedde T, Song YH, Delafontaine P, Adami R, Parente V, Bottinelli R, Pasparakis M, Rosenthal N. Targeted ablation of IKK2 improves skeletal muscle strength, maintains mass, and promotes regeneration. J Clin Invest 116: 2945–2954, 2006.[CrossRef][Web of Science][Medline]
78. Musaro A, McCullagh K, Paul A, Houghton L, Dobrowolny G, Molinaro M, Barton ER, Sweeney HL, Rosenthal N. Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet 27: 195–200, 2001.[CrossRef][Web of Science][Medline]
79. Musaro A, McCullagh KJ, Naya FJ, Olson EN, Rosenthal N. IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. Nature 400: 581–585, 1999.[CrossRef][Medline]
80. Pawlikowska P, Gajkowska B, Hocquette JF, Orzechowski A. Not only insulin stimulates mitochondriogenesis in muscle cells, but mitochondria are also essential for insulin-mediated myogenesis. Cell Prolif 39: 127–145, 2006.[CrossRef][Web of Science][Medline]
81. Peng XD, Xu PZ, Chen ML, Hahn-Windgassen A, Skeen J, Jacobs J, Sundararajan D, Chen WS, Crawford SE, Coleman KG, Hay N. Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. Genes Dev 17: 1352–1365, 2003.[Abstract/Free Full Text]
82. Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol 98: 1154–1162, 2005.[Abstract/Free Full Text]
83. Peyrollier K, Hajduch E, Blair AS, Hyde R, Hundal HS. L-leucine availability regulates phosphatidylinositol 3-kinase, p70 S6 kinase and glycogen synthase kinase-3 activity in L6 muscle cells: evidence for the involvement of the mammalian target of rapamycin (mTOR) pathway in the L-leucine-induced up-regulation of system A amino acid transport. Biochem J 350: 361–368, 2000.[CrossRef][Web of Science][Medline]
84. Planavila A, Sanchez RM, Merlos M, Laguna JC, Vazquez-Carrera M. Atorvastatin prevents peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) downregulation in lipopolysaccharide-stimulated H9c2 cells. Biochim Biophys Acta 1736: 120–127, 2005.[Medline]
85. Rathmell JC, Elstrom RL, Cinalli RM, Thompson CB. Activated Akt promotes increased resting T cell size, CD28-independent T cell growth, and development of autoimmunity and lymphoma. Eur J Immunol 33: 2223–2232, 2003.[CrossRef][Web of Science][Medline]
86. Rennie MJ, Wackerhage H, Spangenburg EE, Booth FW. Control of the size of the human muscle mass. Annu Rev Physiol 66: 799–828, 2004.[CrossRef][Web of Science][Medline]
87. Rommel C, Bodine SC, Clarke BA, Rossman R, Nunez L, Stitt TN, Yancopoulos GD, Glass DJ. Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat Cell Biol 3: 1009–1013, 2001.[CrossRef][Web of Science][Medline]
88. Ruggero D, Montanaro L, Ma L, Xu W, Londei P, Cordon-Cardo C, Pandolfi PP. The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 10: 484–486, 2004.[CrossRef][Web of Science][Medline]
89. Sajan MP, Standaert ML, Miura A, Kahn CR, Farese RV. Tissue-specific differences in activation of atypical protein kinase C and protein kinase B in muscle, liver, and adipocytes of insulin receptor substrate-1 knockout mice. Mol Endocrinol 18: 2513–2521, 2004.[Abstract/Free Full Text]
90. Sakamoto K, Hirshman MF, Aschenbach WG, Goodyear LJ. Contraction regulation of Akt in rat skeletal muscle. J Biol Chem 277: 11910–11917, 2002.[Abstract/Free Full Text]
91. Sandri M, Lin J, Handschin C, Yang W, Arany ZP, Lecker SH, Goldberg AL, Spiegelman BM. PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci USA 103: 16260–16265, 2006.[Abstract/Free Full Text]
92. Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117: 399–412, 2004.[CrossRef][Web of Science][Medline]
93. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307: 1098–1101, 2005.[Abstract/Free Full Text]
94. Schieke SM, Phillips D, McCoy JP Jr, Aponte AM, Shen RF, Balaban RS, Finkel T. The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem 281: 27643–27652, 2006.[Abstract/Free Full Text]
95. Song YH, Li Y, Du J, Mitch WE, Rosenthal N, Delafontaine P. Muscle-specific expression of IGF-1 blocks angiotensin II-induced skeletal muscle wasting. J Clin Invest 115: 451–458, 2005.[CrossRef][Web of Science][Medline]
96. Southgate RJ, Bruce CR, Carey AL, Steinberg GR, Walder K, Monks R, Watt MJ, Hawley JA, Birnbaum MJ, Febbraio MA. PGC-1alpha gene expression is down-regulated by Akt- mediated phosphorylation and nuclear exclusion of FoxO1 in insulin-stimulated skeletal muscle. FASEB J 19: 2072–2074, 2005.[Abstract/Free Full Text]
97. Stewart CE, Newcomb PV, Holly JM. Multifaceted roles of TNF-alpha in myoblast destruction: a multitude of signal transduction pathways. J Cell Physiol 198: 237–247, 2004.[CrossRef][Web of Science][Medline]
98. Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell 14: 395–403, 2004.[CrossRef][Web of Science][Medline]
99. Sugita H, Kaneki M, Sugita M, Yasukawa T, Yasuhara S, Martyn JA. Burn injury impairs insulin-stimulated Akt/PKB activation in skeletal muscle. Am J Physiol Endocrinol Metab 288: E585–E591, 2005.[Abstract/Free Full Text]
100. Sumitani S, Goya K, Testa JR, Kouhara H, Kasayama S. Akt1 and Akt2 differently regulate muscle creatine kinase and myogenin gene transcription in insulin-induced differentiation of C2C12 myoblasts. Endocrinology 143: 820–828, 2002.[Abstract/Free Full Text]
101. Suryawan A, Escobar J, Frank JW, Nguyen HV, Davis TA. Developmental regulation of the activation of signaling components leading to translation initiation in skeletal muscle of neonatal pigs. Am J Physiol Endocrinol Metab 291: E849–E859, 2006.[Abstract/Free Full Text]
102. Svanberg E, Frost RA, Lang CH, Isgaard J, Jefferson LS, Kimball SR, Vary TC. IGF-I/IGFBP-3 binary complex modulates sepsis-induced inhibition of protein synthesis in skeletal muscle. Am J Physiol Endocrinol Metab 279: E1145–E1158, 2000.[Abstract/Free Full Text]
103. Takahashi A, Kureishi Y, Yang J, Luo Z, Guo K, Mukhopadhyay D, Ivashchenko Y, Branellec D, Walsh K. Myogenic Akt signaling regulates blood vessel recruitment during myofiber growth. Mol Cell Biol 22: 4803–4814, 2002.[Abstract/Free Full Text]
104. Trotman LC, Alimonti A, Scaglioni PP, Koutcher JA, Cordon-Cardo C, Pandolfi PP. Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441: 523–527, 2006.[CrossRef][Medline]
105. Turner JD, Rotwein P, Novakofski J, Bechtel PJ. Induction of mRNA for IGF-I and -II during growth hormone-stimulated muscle hypertrophy. Am J Physiol Endocrinol Metab 255: E513–E517, 1988.[Abstract/Free Full Text]
106. Urbich C, Knau A, Fichtlscherer S, Walter DH, Bruhl T, Potente M, Hofmann WK, de Vos S, Zeiher AM, Dimmeler S. FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells. FASEB J 19: 974–976, 2005.[Abstract/Free Full Text]
107. Van den Heuvel AP, de Vries-Smits AM, van Weeren PC, Dijkers PF, de Bruyn KM, Riedl JA, Burgering BM. Binding of protein kinase B to the plakin family member periplakin. J Cell Sci 115: 3957–3966, 2002.[Abstract/Free Full Text]
108. Vary TC, Lynch CJ. Meal feeding enhances formation of eIF4F in skeletal muscle: role of increased eIF4E availability and eIF4G phosphorylation. Am J Physiol Endocrinol Metab 290: E631–E642, 2006.[Abstract/Free Full Text]
109. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2: 489–501, 2002.[CrossRef][Web of Science][Medline]
110. Wackerhage H, Rennie MJ. How nutrition and exercise maintain the human musculoskeletal mass. J Anat 208: 451–458, 2006.[CrossRef][Web of Science][Medline]
111. Wan M, Wu X, Guan KL, Han M, Zhuang Y, Xu T. Muscle atrophy in transgenic mice expressing a human TSC1 transgene. FEBS Lett 580: 5621–5627, 2006.[CrossRef][Web of Science][Medline]
112. Wijesekara N, Konrad D, Eweida M, Jefferies C, Liadis N, Giacca A, Crackower M, Suzuki A, Mak TW, Kahn CR, Klip A, Woo M. Muscle-specific Pten deletion protects against insulin resistance and diabetes. Mol Cell Biol 25: 1135–1145, 2005.[Abstract/Free Full Text]
113. Williamson DL, Bolster DR, Kimball SR, Jefferson LS. Time course changes in signaling pathways and protein synthesis in C2C12 myotubes following AMPK activation by AICAR. Am J Physiol Endocrinol Metab 291: E80–E89, 2006.[Abstract/Free Full Text]
114. Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, LeRoith D. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci USA 96: 7324–7329, 1999.[Abstract/Free Full Text]
115. Yamauchi T, Tobe K, Tamemoto H, Ueki K, Kaburagi Y, Yamamoto-Honda R, Takahashi Y, Yoshizawa F, Aizawa S, Akanuma Y, Sonenberg N, Yazaki Y, Kadowaki T. Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice. Mol Cell Biol 16: 3074–3084, 1996.[Abstract]
115. Yang SY, Goldspink G. Different roles of the IGF-I Ec peptide (MGF) and mature IGF-I in myoblast proliferation and differentiation. FEBS Lett 522: 156–160, 2002.[CrossRef][Web of Science][Medline]
116. Yang Q, Inoki K, Ikenoue T, Guan KL. Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev 20: 2820–2832, 2006.[Abstract/Free Full Text]
117. Yasukawa T, Tokunaga E, Ota H, Sugita H, Martyn JA, Kaneki M. S-nitrosylation-dependent inactivation of Akt/protein kinase B in insulin resistance. J Biol Chem 280: 7511–7518, 2005.[Abstract/Free Full Text]
118. Yu XX, Barger JL, Boyer BB, Brand MD, Pan G, Adams SH. Impact of endotoxin on UCP homolog mRNA abundance, thermoregulation, and mitochondrial proton leak kinetics. Am J Physiol Endocrinol Metab 279: E433–E446, 2000.[Abstract/Free Full Text]

This article has been cited by other articles:

				V. Varma, A. Yao-Borengasser, N. Rasouli, G. T. Nolen, B. Phanavanh, T. Starks, C. Gurley, P. Simpson, R. E. McGehee Jr., P. A. Kern, et al. Muscle inflammatory response and insulin resistance: synergistic interaction between macrophages and fatty acids leads to impaired insulin action Am J Physiol Endocrinol Metab, June 1, 2009; 296(6): E1300 - E1310. [Abstract] [Full Text] [PDF]

				D. R. Blair, K. Funai, G. G. Schweitzer, and G. D. Cartee A myosin II ATPase inhibitor reduces force production, glucose transport, and phosphorylation of AMPK and TBC1D1 in electrically stimulated rat skeletal muscle Am J Physiol Endocrinol Metab, May 1, 2009; 296(5): E993 - E1002. [Abstract] [Full Text] [PDF]

				P. A. Singleton, S. Chatchavalvanich, P. Fu, J. Xing, A. A. Birukova, J. A. Fortune, A. M. Klibanov, J. G. N. Garcia, and K. G. Birukov Akt-Mediated Transactivation of the S1P1 Receptor in Caveolin-Enriched Microdomains Regulates Endothelial Barrier Enhancement by Oxidized Phospholipids Circ. Res., April 24, 2009; 104(8): 978 - 986. [Abstract] [Full Text] [PDF]

				M. Miyazaki and K. A. Esser Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals J Appl Physiol, April 1, 2009; 106(4): 1367 - 1373. [Abstract] [Full Text] [PDF]

				V. C. Foletta, M. J. Prior, N. Stupka, K. Carey, D. H. Segal, S. Jones, C. Swinton, S. Martin, D. Cameron-Smith, and K. R. Walder NDRG2, a novel regulator of myoblast proliferation, is regulated by anabolic and catabolic factors J. Physiol., April 1, 2009; 587(7): 1619 - 1634. [Abstract] [Full Text] [PDF]

				R. Nakai, T. Azuma, M. Sudo, S.-i. Urayama, O. Takizawa, and S. Tsutsumi MRI analysis of structural changes in skeletal muscles and surrounding tissues following long-term walking exercise with training equipment J Appl Physiol, September 1, 2008; 105(3): 958 - 963. [Abstract] [Full Text] [PDF]

				J. M. Peterson, R. W. Bryner, and S. E. Alway Satellite cell proliferation is reduced in muscles of obese Zucker rats but restored with loading Am J Physiol Cell Physiol, August 1, 2008; 295(2): C521 - C528. [Abstract] [Full Text] [PDF]

				P. Negredo, J.-L. L. Rivero, B. Gonzalez, A. Ramon-Cueto, and R. Manso Slow- and fast-twitch rat hind limb skeletal muscle phenotypes 8 months after spinal cord transection and olfactory ensheathing glia transplantation J. Physiol., May 15, 2008; 586(10): 2593 - 2610. [Abstract] [Full Text] [PDF]

				E. E. Spangenburg, D. Le Roith, C. W. Ward, and S. C. Bodine A functional insulin-like growth factor receptor is not necessary for load-induced skeletal muscle hypertrophy J. Physiol., January 1, 2008; 586(1): 283 - 291. [Abstract] [Full Text] [PDF]

				A. M. W. Petersen, F. Magkos, P. Atherton, A. Selby, K. Smith, M. J. Rennie, B. K. Pedersen, and B. Mittendorfer Smoking impairs muscle protein synthesis and increases the expression of myostatin and MAFbx in muscle Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E843 - E848. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Free All Versions of this Article: 103/1/378    most recent 00089.2007v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (17) Citing Articles via Google Scholar Google Scholar Articles by Frost, R. A. Articles by Lang, C. H. Search for Related Content PubMed PubMed Citation Articles by Frost, R. A. Articles by Lang, C. H.