Severe injuries, cancer, sepsis, AIDS or CHF are the most common causes of deaths in United States and Europe. Common feature of the above-mentioned diseases in their chronic state is a progressive loss of body mass resulting from muscle cachexia (1). In contrast to starvation, which mainly depletes fat stores from adipose tissue but not muscle proteins, both fat and muscle proteins are lost in cachexia (2). Additionally, during experimental cancer cachexia fat stores are mobilized prior to muscle protein degradation suggestive that adipose tissue spares muscle proteins (3). Several cachectic factors are used to experimentally evoke muscle cachexia in laboratory animals including administration of lipopolysaccharide (LPS), glucocorticoids, TNF-, IL-6 or cancer inoculations. Each approach is aimed to mimic certain type of muscle cachexia with its classic features such as anorexia, insulin resistance and oxidative stress (4, 5). When loss of skeletal muscles is grounded by chronic inflammatory disease or cancer the level of inflammatory cytokines is markedly elevated (6, 7). For long it has been known that TNF- is the most prominent among them (8). By some authors TNF- was reported to induce muscle protein loss (9-11), by others being insufficient to evoke it on its own (12, 13). In line with the last findings some cytokines (IFN-, IL-1ß, IL-6) facilitate (14, 15) whereas other (IL-15, leptin) inhibit TNF--induced muscle cachexia (16, 17). One has to imagine, that muscle cachexia to occur requires conditions that are in favor of atrophying fibers. Such situation is met if mononucleated satellite cells/myoblasts or myofibers perish extensively causing sarcopenia and/or muscle fiber protein synthesis is retarded and/or protein breakdown is accelerated. In general, collection or lack of particular cytokines pace the catabolic processes. Muscle cells undergo extrinsic apoptosis provoked by death receptor ligands as TNF- (18). The death receptor-induced, caspase-8-mediated apoptosis is linked through a truncated Bid with mitochondrial pathway where reactive oxygen species (ROS) are formed to amplify cell death machinery (19). Cellular prooxidant-antioxidant homeostasis is disturbed with enhanced susceptibility to oxidant-induced stress (20). Apoptosis in multinucleated muscle fibers differs from that of mononucleated myoblasts. In intact myofibers, myonuclei undergo typical caspase-3-mediated apoptosis with DNA fragmentation reducing the myonuclear domain size (finite ratio between myoplasmic volume and the number of myonuclei, MDS). It is believed that below certain value of MDS (several apoptotic myonuclei) atrophy of muscle fibers unavoidably has to occur (21). Calcium-dependent and caspase-independent cell death also affects muscle cells. The so called calpain/calpastatin proteolytic system disrupts myofibrillar proteins in myocytes and permits ubiquitination and subsequent proteasome degradation of disassembled proteins (1). Calpains (µ- and m-calpain) trigger muscle cell death without DNA fragmentation, that is overturned by antioxidants or calpain inhibitors (22, 23). Apoptotic nuclei have also been detected with terminal deoxyribonucleotidyl nick-end labeling (TUNEL) in atrophying muscles of dexamethasone-treated cachectic rats (20). Unlike slow oxidative (SO) type skeletal muscle (soleus muscle) the glycolytic type muscles (fast glycolytic, fast oxidative-glycolytic, FG and FOG, respectively) are prone to cachexia. Our recent study indicates that relative resistance of the SO to muscle cachexia (14) is established during metabolic differentiation of skeletal muscles (24). Apparently, adaptation to oxidative metabolism lowers vulnerability of SO muscles to oxidative stress and reduces the need for insulin and/or IGF-1. It has to be stressed that in reduced serum insulin/insulin-like growth factor-1 (IGF-1) levels, as reported in states of undernutrition, reduces the antiapoptotic actions of these cytokines on the intrinsic apoptotic pathway. Furthermore, despite the absolute deficiency of insulin (insulin-dependent diabetes mellitus, IDDM) tissue resistance to anabolic factors may considerably contribute to the lack of signals which stimulate survival of muscle cells and myocytes. The advantage of death over life stimuli activates intrinsic proteolytic systems. Overall, it is indicative that elimination of mononucleated muscle cells through caspase- or calpain-dependent mechanism impairs myogenesis at the level of muscle fiber set up (growth and differentiation), while in the atrophying fibers these systems directly reduce muscle mass (1). Lysosomal proteases play minor role in muscle cachexia, although they are prominent mediators of proteolysis stimulated by amino acid starvation of myofibers (25). In any case, cytokines are of special merit, since they modulate muscle cell viability, growth, differentiation and finally death. Inflammatory cytokines widely known as cachectic factors are produced by host immune cells in response to the inflammation or tumor, or by tumor cells themselves. However, either factor can also be released from macrophages infiltrating exercised skeletal muscle (26). Additionally, TNF-, IL-1ß, and IL-6 were shown to be produced and secreted by muscle fibers (27-29). In addition, rise in the level of insulin-like growth factor 1B (mechano growth factor - MGF) was observed after exercise (30). The latter cytokine is also of myogenic origin and promotes myogenesis. Cytokines might induce the effects in antagonistic or agonistic manner. Noticeable synergism between TNF- and IFN- in full degradation of mature muscle was observed (13, 14, 31). It suggests that in order to induce muscle cachexia, TNF- has to act in concert with other inflammatory cytokines. Consistent with this thinking, IL-1ß or IL-6 also promoted TNF--mediated muscle cachexia (14, 31). Anyway, the molecular mechanisms of synergistic effect of TNF- with other cytokines have neither been identified nor outlined. One has to bear in mind that cytokines affect rather differently undifferentiated muscle cells, myotubes and muscle fibers. Distinction has to be made with respect to metabolic muscle fiber type, as well. Overall, this review delineates possible signal transduction pathways involved in cytokine actions on the growing and mature skeletal muscles. The evidence is provided from in vitro and in vivo studies carried out with the aim to validate most attractive hypotheses.


TNF- RECEPTORS AND TNF- SIGNALING IN SKELETAL MUSCLE
TNF- acts on target cells through the cognate membrane receptors TNF-R1 (p55TNFR) and TNF-R2 (p75TNFR). Both receptor types are expressed in muscle fibers but their respective roles have to be distinguished. TNF-R1 represents typical surface receptor with cytoplasmic death domain (DD), forms functional homotrimers upon ligand binding which are able to recruit cytoplasmic proteins with DD. Distinctive feature of TNF-R1-mediated signaling is the sequential formation of signalosomes (32). Initially, to activate NF-B with subsequent induction of survival genes the complex I assembles (TRADD/FADD/RIP/TRAF2) with TNF-R1 trimer. Next, complex I dissociates from TNF-R1 and complex II is formed (TRADD/FADD/FLICE). FADD protein is released from complex I and interacts with TRADD. Subsequently, procaspase-8 is recruited to FADD through their respective death effector domains (DED) (33). Both TRADD and FADD play the role of adaptor proteins. If TRADD associates to FADD it signals extrinsic apoptosis through FLICE (procaspase-8) autocatalytic activation, whereas TRAF-2 initiates the sequence of pro-survival events contingent on activation of NF-B (34, 35). However, death signalosome (TNF-/TNF-R1/TRADD/FADD/FLICE) could be abrogated by FLIP protein which competitively blocks FLICE assembly to FADD (36). TNF-R2 receptor is also membrane anchored but its cytoplasmic tail lacks ability to attract signaling complexes. Its role is elusive, although it is well documented that the activation of TNF-R2 results in remarkable augmentation of TNF-R1-mediated cell death. The explanation is that TNF-R2 stimulates substantial depletion of TRAF-2 complexes which are critical to TNF-R1-mediated NF-B activation. By this route, the anti-apoptotic response of NF-B transcription factor is down-regulated and apoptotic cell death mediated through caspase-8 is gained (34). NF-B family of proteins is involved in the regulation of a variety of cellular responses essential to sustain homeostasis (cell proliferation, differentiation, viability). They hold REL homology domain to dimerize, DNA binding and the nuclear localization signal (NLS) to translocate into nucleus. In the inactive form NF-B proteins (RelA/p65, c-Rel, RelB, p50 - p105 precursor, and p52 - p100 precursor) reside in the cytoplasm arrested by IB inhibitory proteins (IB, IBß, IB, Bcl-3, p100 and p105) which by ankyrin repeats bind to REL domain of NF-B. Consequently, the NLS site is camouflaged to unable nuclear translocation of NF-B (37). The activation of NF-B come first, prior to death signal transmission indicative that signals from TNF-R1 advances sequentially (38). Pro-survival signalosome (TNF-/TNF-R1/TRADD/RIP/TRAF-2/c-IAP/CIKS/IKK) stimulates IB kinase complex (IKK) that targets two serine residues of IB inhibitory protein. Phosphorylated IB is ubiquitinated and degraded by 26S proteasome complex so it can’t inhibit NF-B anymore (39). Now the active NF-B homo- or heterodimer (mostly p55/p65 heterodimer) is able to translocate to nucleus where it binds to its cognate DNA sequence (GGGGATTCCC). The NF-B binding sites allow this transcription factor to interact with transcription machinery and transcriptional co-activators to stimulate gene expression (40). Because NF-B activates IB gene, the IB inhibitory protein is resynthesized, shortly after (1 hour) reaches nucleus where it binds to NF-B and reverses genomic reaction. Nuclear export signal (NES) of IB allows the return and cytoplasmic sequestration of NF-B.

Among a wide variety of stimuli, TNF- is one of the most potent activators of NF-B in cell types expressing TNF- surface receptors. The position of TNF- within the number of inflammatory cytokines is also unique, since this cytokine functions as initial mediator of inflammation by recruiting immune cells to release chemokines and other inflammatory cytokines. It is obvious, that in the in vivo conditions TNF- does not seem to act separately. Even though, study performed with TNF- alone on C2C12 muscle cells revealed distinct cellular responses depending on the stage of muscle development. Serum restriction routinely used to stimulate differentiation in confluent myoblast cultures enhanced the expression of TNF- which by autocrine fashion accelerated myogenesis (27). This reaction was transient and peaked at 10 hours from the onset of myogenesis with marked raise in the level of fast type myosin heavy chain protein (MyHC) - a differentiation marker. Most importantly, by the use of anti-TNF- antibody which reversed the effect of TNF-, the authors demonstrated that NF-B mediates TNF--induced MyHC expression. They hypothesized that myogenic stimuli up-regulate TNF- expression that in turn induces NF-B and serum response factor (SRF) activities, which up-regulate the expression of muscle genes. Three days later (72 hours after the onset of myogenesis) the same cells (multinucleated C2C12 myotubes) and rat myocytes kept in primary culture responded in opposite way to exogenous TNF- (11). TNF- treatment of C2C12 myotubes stimulated time- and concentration-dependent reductions in total protein content and loss of fast type MyHC content. Again binding of NF-B to its targeted DNA sequence was observed. Exogenous hydrogen peroxide (200 mM) activated, whereas catalase (1000 U/mL) inhibited NF-B activation. They acted in accordance with our observations from studies carried out on murine C2C12 and rat L6 myogenic cells (41). Expression of fast type MyHC is critical since this is a distinctive marker of both muscle growth and muscle cachexia. It means, that rise in the expression of MyHC signs formation of myofibrills (myogenicity), while fall indicates muscle fiber decay (muscle cachexia) (14). Continuation of the study of C2C12 myotubes upon treatment with TNF- revealed another type of cellular response. Seven days after the onset of myogenesis by serum restriction muscle fibers originated from C2C12 muscle cells were chased with TNF- with resultant symptoms of apoptosis (18). The NF-B activity in response to TNF- alone was elevated but tremendous potentiation occurred upon concomitant application of IFN- (18). The symptoms of apoptosis such as poly-ADP-ribose polymerase (PARP) fragmentation and caspase-3 activity were detected after TNF-, but they disappeared when additionally IFN- was present. The authors suggest that IFN- reverses TNF--induced apoptosis through unknown regulatory mechanism, although they observed lower immunoreactivity of TNF-R2 (apoptotic) whereas higher for anti-apoptotic cellular inhibitor of apoptosis (cIAP). In contrast to general trust, where IFN- seem to promote muscle cachexia (42) one should be cautious about the possible consequences of IFN applications. Additionally, there is evidence that chronic treatment of three-day old C2C12 myofibers with TNF- causes NF-B activation in a biphasic manner (31). Initial stimulation was transient and persisted 1 hour with subsequent IkBa proteasomal degradation and resynthesis, whereas second phase of activation occurred for an additional 24-36 hours with elimination of both IB and IBß proteins. The first phase was typical canonical pathway of NF-B with transcriptionally-mediated expression of A20 protein, which negatively affects TNF- signaling. On the other hand, the long lasting second phase was required for TNF--induced loss of skeletal muscle gene products MyoD and fast type MyHC. Biological significance of the TNF--mediated biphasic activation of NF-B is not clear, although it might explain distinct character of muscle response to chronic exposure to cytokines. Prominently, IFN- presence was indispensable for TNF--dependent repression of myogenesis in three-day old C2C12 myofibers. If we wish to know more about side-effects of cytokine therapy, the setting of IFNs in TNF--mediated muscle cachexia needs further examination particularly in light of the role of IFNs in autoimmunity (43). It will widen our scope about anti-cancer therapy with the use of IFNs.


INTERFERONS AFFECT TNF- SIGNALING IN SKELETAL MUSCLE
IFNs are multifunctional cytokines which block viral infections, but they also affect cell proliferation and differentiation (44). Two classes of interferons (class I and class II) were described (38). An assortment of class I interferons exists (IFN-, IFN-ß, IFN-, IFN- and IFN-) and only one interferon represents class II (IFN-). IFNs act on their cognate surface receptors that form functional heterodimers (IFNAR1 and IFNAR2 for class I, as well as IFNGR1 and IFNGR2 for class II, respectively). Ligand binding to extracellular receptor sites activates Janus kinases which act redundantly: TYK2 for IFNAR1, JAK1 for IFNAR2, or JAK1 for IFNGR1 and JAK2 for IFNGR2. The JAK/TYK kinases by phosphorylating tyrosine residues at the cytoplasmic tail of the IFN receptors recruit signal transducer and activator of transcription (STAT) proteins and activate them to form homo- or heterodimers through subsequent tyrosine phosphorylation (Fig. 1). The dimerization is necessary to exert transcriptional activity by STATs. Now they may interact with IFN-regulatory factors (IRFs) in complexes which recognize DNA binding sites called interferon-stimulated response elements (ISRE). Interestingly, both classes of IFNs might induce identical configuration of STAT dimers (STAT-1-STAT-1) which translocate to the nucleus to bind to DNA strand at interferon gamma activated sites (GAS) present in the promoter regions of interferon-stimulated genes to be transcribed. The position of STAT-1 at the cytoplasmic site of cytokine receptors is unique in efforts to explain horizontal interactions between cytokine-mediated signals. The STAT-1 role remains vague, nonetheless this protein was reported to modulate TNF--mediated anti-apoptotic signal from TNF-R1 receptor (45). The examination of HeLa cells revealed that phosphorylated form of STAT-1 is assembled to TRADD protein, which in turn is recruited to DD domain after ligand binding to TNF-R1. Furthermore, similar location of STAT-1 was reported to take place in COLO 205 cells (46, 47), even though STAT-1 was not phosphorylated and ligand was absent. TRADD protein was also reported to tie up STAT-1 to IFNGRs (48). The precise role of interaction between STAT-1 and TRADD remains obscure, however, STAT-1 apparently inhibited NF-B response to TNF- (45-47). IFNs were previously reported to affect cell response to TNF- (45, 48-50). Furthermore, this effect was repeated in muscle cells (14, 18). IFNs act on their cognate surface receptors which activate JAK/STAT cascade. At this point it is important to stress the role of STATs. These tyrosine kinases after recruitment by JAKs to phosphotyrosine residues of IFN receptors (IFNAR and IFNGR) also undergo tyrosine phosphorylation by JAKs to form homo- or heterodimers with transcriptional activity. As above-mentioned, there is testimony that STAT-1 may also bind to TNF-R1 adaptor proteins (TRADD) where it inhibits activation of NF-B (45, 47, 48). This observation appears crucial in search for explanation how some reactions to TNF- and IFNs occurred in muscle cells. First, IFN- was reported to potentiate TNF--mediated repression of MyoD and MyHC in 3 day-old C2C12 myotubes (14), whereas it hampered apoptosis of 7-day old C2C12 muscle fibers (18). In both cases, the cellular homeostasis was affected by NF-B activity but the ability of IFN- to synergize with TNF- to induce muscle loss does not seem to be associated with an enhanced NF-B activity (verified with EMSA and EMSA supershift). This is in contrast to the reports pointing to STAT-1a as a constitutive inhibitor of TNF--dependent NF-B activation (45-48). When IFN- binds to its surface receptor, STAT-1 is recruited, phosphorylated at tyrosine residues by JAKs, forms dimers which translocate to the nucleus. Consequently, STAT-1 is unable to interact with TNF-R1 complexes allowing for stronger TNF--mediated NF-B activation (47). If this is not the case, some observations would imply that synergistic action of IFN- and TNF- could result from independent activation of their respective downstream effectors (NF-B for TNF-, and STATs/IRFs for IFN-) such as that described in T-cells (51). In addition, it was reported that STAT-1a functionally and physically interacts with GATA-4 transcription factor to synergistically activate its target genes and promoters in C2C12 muscle cells (52).

Fig. 1. Vertical and horizontal interactions in signal transduction of cytokines. Positive and negative influences with respect to muscle cachexia are shown.

INFLAMMATORY CYTOKINES AFFECT LEPTIN/INSULIN/IGF-1 SIGNALING IN SKELETAL MUSCLE
Well-known opposite effects exerted by the inflammatory cytokines (TNF-, IL-1ß, IL-6) and growth factors (leptin/insulin/IGF-1) are suggestive to promote muscle cachexia. First, the increased concentrations of TNF- and IL-6 were frequently observed in ageing, obesity and type 2 diabetes (53, 54) and are supposed to interfere with insulin action by suppressing insulin signal transduction (55-57). Chronic lack or lower levels of anabolic factors lead to negative balance in muscle protein turnover. In regard to insulin, TNF- causes an inhibition of auto-phosphorylation of tyrosine residues of the insulin receptor (IR). Additionally, it induces serine phosphorylation of insulin receptor substrate-1 (IRS-1), which in turn causes serine phosphorylation of the IR in adipocytes and inhibits tyrosine phosphorylation (58). On the other hand, IL-6 has been shown to inhibit insulin signal transduction through suppressor of cytokine signalling-3 protein (SOCS-3), a member of intracellular negative feedback regulators of JAK/STAT signal pathway (55). Similarly, SOCS-1 was demonstrated to inhibit IGF-1-mediated myogenesis from C2C12 muscle cells through concomitant reduction in Akt phosphorylation and augmented MEK phosphorylation (59). Thus, SOCS-1 protein represses myogenicity opposing the action of mitofusin-2 protein, mitochondrial GTPase that was shown to inhibit Ras/Raf/MEK cascade and to facilitate myogenesis through phosphatidylinositol-3 kinase (PI3-K)-dependent Akt activation (60). The contribution of mitochondria is indicative that ROS (regardless of origin) modulate muscle growth and differentiation. Nowadays, it is widely accepted that leptin/insulin/IGF-1 resistance develops in response to oxidative stress. Furthermore, skeletal muscle sensitivity to leptin/insulin/IGF-1 establishes prooxidant-antioxidant balance (61). Conversely, TNF- was frequently reported to induce oxidative stress of mitochondrial origin through caspase-8-dependent link (truncated Bid). In some studies the addition of TNF- to differentiating myoblasts completely inhibited myogenic differentiation (62). Previously, we reported in this article, that the loss of skeletal muscle might result from inability of myoblasts to differentiate into functional myofibers. Moreover, inflammatory cytokines, such as TNF- and IFN-, but also insulin all induce SOCS proteins (55, 63). Inflammatory cytokines revealed another mode of action in the regulation of muscle differentiation: SOCS that associates itself with the IR, inhibits its autophosphorylation, the tyrosine phosphorylation of IRS-1, the association of the p85 subunit of PI3-K to IRS-1 and the subsequent activation of Akt. These effects were demonstrated for IL-6 in vitro, and in mice, in vivo (64). The same protein (SOCS-1, SOCS-2 or SOCS-3) as a mediator of negative feedback to stop IGF-1 action might also mediate leptin resistance in skeletal muscle. One has to keep in mind, that leptin is a potent regulator of immune responses although its precise role in skeletal muscle immunity remains obscure. Leptin which is released from adipocytes (similarly to TNF-) stimulates IL-6 release from leukocytes (65) but whether this IL-6 stimulates and/or represses myogenesis is a matter of debate. Leptin uses JAK/STAT signal so theoretically it might similarly to IFNs compete for STAT with TRADD to affect the TNF--mediated NF-B activation. Taken together, and bearing in mind the reports showing considerable role of JAK/STAT/SOCS in growth regulation (66-68) it is highly probable that SOCS accelerate the loss of skeletal muscle proteins through the suppression of muscle-cell differentiation and cell growth. It provides new insight into the specific role of JAK/STAT/SOCS signaling in both prevention and augmented muscle decay. Besides, qualitative differences between the outcomes of reactions induced by the same cytokines (TNF-) at different stage of myogenesis suggest that considerable modifications had to occur at the level of nucleosomes during in vitro muscle differentiation. This issue is hardly scrutinized and needs vigorous scientific research. Attractive hypothesis could be formulated that the average product of cytokine activities in skeletal muscle resulted in the balance between positive (stimulated myogenesis) and negative (muscle loss) influences. Detailed knowledge of their respective effects and molecular regulations forwards a significant step to stop muscle cachexia.


CONCLUSION AND PERSPECTIVES
Although much is known about the role of cytokines in muscle cachexia (69) the details of molecular regulation of myogenesis are still difficult to understand. Additionally, recent studies on leptin and its effects on puberty and growth are suggestive for its marked influence on muscle development (70). The cytokine signaling pathways from TNF-, IFNs and leptin have a lot in common in terms of proteins (JAK/STAT/SOCS) involved in signal transduction and genomic and non-genomic regulation of cell function (Fig. 1). How do these proteins affect PI3-K pathway, well known to transmit anabolic stimuli to muscle cells is of great interest. Given that opposite effects between inflammatory cytokines and insulin/IGF-I were observed at the molecular level (71) further studies are needed to locate the role of JAK/STAT/SOCS in myogenesis. It could elucidate the impact of immune system in the molecular mechanisms of muscle cachexia.

Acknowledgements: Support for this work was provided by grants N401 033 32/0759 and 117/E-385/SPB/COST/P-06/DWM from the Ministry of Science and Higher Education in Poland.

Conflict of interest statement: None declared.


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