an alle, die Interesse an Kraft und Muskelmasse haben

[kurt]

http://www.ncbi.nlm.nih.gov/entrez/q...422&query_hl=4

auf diesen übersichtsartikel hat mich "Bon" hingewiesen, wofür ich mich bedanke. man kann den gesamten text herunterladen.

gruß, kurt

[Dimitri]

http://www.ncbi.nlm.nih.gov/entrez/q...422&query_hl=4

auf diesen übersichtsartikel hat mich "Bon" hingewiesen, wofür ich mich bedanke. man kann den gesamten text herunterladen.

gruß, kurt

Da bist du glaub ich bevorzugt, ich kann nur den Abstract lesen, für den Artikel müsst ich einiges berappen

Aber du könntest ja eine kurze Zusammenfassung abgeben, dann wird auch mein Englisch nicht überstrapaziert

Passt heute 17 Uhr an der üblichen Kreuzung?

[kurt]

Da bist du glaub ich bevorzugt, ich kann nur den Abstract lesen, für den Artikel müsst ich einiges berappen

Aber du könntest ja eine kurze Zusammenfassung abgeben, dann wird auch mein Englisch nicht überstrapaziert

Passt heute 17 Uhr an der üblichen Kreuzung?

passt!
zum paper: du brauchst nur auf das icon unterhalb von "Annu Rev Physiol. 2004;66:799-828" zu klicken.

cu, kurt

[Dimitri]

passt!
zum paper: du brauchst nur auf das icon unterhalb von "Annu Rev Physiol. 2004;66:799-828" zu klicken.

cu, kurt

Weiß ich schon, aber bei mir kommt dannach nur nochmal der Abstract und zwei Links für Full Text oder PDF. Drückt man da allerdings drauf, dann steht bei mir, dass ich für den Artikel 20 Dollar hinlegen muss. Vielleicht hat bei dir ja die Klinik schon ein Abo bezogen und du kannst deshalb gratis die Artikel lesen.

Gruazi

[kurt]

Weiß ich schon, aber bei mir kommt dannach nur nochmal der Abstract und zwei Links für Full Text oder PDF. Drückt man da allerdings drauf, dann steht bei mir, dass ich für den Artikel 20 Dollar hinlegen muss. Vielleicht hat bei dir ja die Klinik schon ein Abo bezogen und du kannst deshalb gratis die Artikel lesen.

Gruazi

so wird es ein. dienstleistung der TILAK.
aber ich kopier die die publikation und bring sie dir heut mit.

cu, kurt

p.s.: 20 "bucks" is really heavy!
du könntest die arbeit auch über die uni-bibliothek beziehen.

[Widar]

Schade, aber 20 Dollar ist mir der Spaß nicht wert.

Trotzdem danke.

Vielleicht eine kleine Zusammenfassung? (Ich Bettler ).

Gruß
Sascha

[barbara]

Danke lieber Kurt. Gibt es aber auch eine Version auf Deutsch? Mein Englisch ist nicht so toll:-(

Liebe Grüsse
Barbara

[kurt]

Schade, aber 20 Dollar ist mir der Spaß nicht wert.

Trotzdem danke.

Vielleicht eine kleine Zusammenfassung? (Ich Bettler ).

Gruß
Sascha

die zusammenfassung steht im abstract. es sind noch einige fragen offen...
welche uni ist in deiner nähe? besorg dir das paper über die uni-bibliothek, das kostet dich fast nichts.

gruß, kurt

[kurt]

Danke lieber Kurt. Gibt es aber auch eine Version auf Deutsch? Mein Englisch ist nicht so toll:-(

Liebe Grüsse
Barbara

leider gibt es die nicht. wissenschaftliche studien werden auf englisch publiziert (zumindest die, die in "medline" gelistet sind)

lg, kurt

[moul]

Ich hab leider auch keinen freien Zugriff aus das Journal.
Vielleicht kannst du den Artikel ja einfach hier rein kopieren?

[kurt]

Ich hab leider auch keinen freien Zugriff aus das Journal.
Vielleicht kannst du den Artikel ja einfach hier rein kopieren?

ich versuch's mal.

gruß, kurt

[kurt]

der text hat 99680 zeichen, ein posting kann nur 10000 zeichen fassen - also muss ich es auf raten kopieren.

Full Text
Annual Review of Physiology
Vol. 66: 799-828 (Volume publication date March 2004)
(doi:10.1146/annurev.physiol.66.052102.134444)

First posted online on September 22, 2003

Control of the Size of the Human Muscle Mass
Michael J. Rennie,1,4 *Henning Wackerhage,1 *Espen E. Spangenburg,3 and *Frank W. Booth2*

1Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee, DD1 4HN, Scotland, United Kingdom; email: michael.rennie@nottingham.ac.uk; h.wackerhage@dundee.ac.uk

2Department of Biomedical Sciences, Medical Pharmacology and Physiology, and Dalton Cardiovascular Center, University of Missouri-Columbia, Columbia, Missouri 65211; email: boothf@missouri.edu

current addresses: 3Exercise Biology Program, University of California, Davis, California 95616; email: spangenburge@missouri.edu (current: eespangenburg@ucdavis.edu),

4University of Nottingham, Graduate Entry Medical School, City Hospital, Derby, DE22 3NE, United Kingdom

ABSTRACT

This review is divided into two parts, the first dealing with the cell and molecular biology of muscle in terms of growth and wasting and the second being an account of current knowledge of physiological mechanisms involved in the alteration of size of the human muscle mass. Wherever possible, attempts have been made to interrelate the information in each part and to provide the most likely explanation for phenomena that are currently only partially understood. The review should be of interest to cell and molecular biologists who know little of human muscle physiology and to physicians, physiotherapists, and kinesiologists who may be familiar with the gross behavior of human muscle but wish to understand more about the underlying mechanisms of change.

INTRODUCTION

Great strides have been made recently in understanding the regulation of the size of the muscle mass in humans. Dual X-ray absorptiometry (DEXA) (1, 2) and magnetic resonance imaging (MRI) (35), together with advances in immunohistochemical muscle fiber typing (6), have allowed the size of the human muscle mass and its components to be defined with previously unparalleled precision and sensitivity. We are now able to follow accurately small, relatively slow changes in muscle size during the extended timescales of sarcopenia (7, 8) and hypertrophy (9). The application of stable isotope tracer technology to the study of amino acids has markedly increased our knowledge of their transport and intermediary metabolism and protein turnover in skeletal muscle (1013), and positron emission spectroscopy (PET) promises to provide additional information (14). In parallel, ever more signal transduction pathways involved in the regulation of muscle growth are being elucidated, and powerful microarray methods enable identification of genes whose transcription is altered during muscle growth (15). The explosion of knowledge of the molecular cell biology of skeletal muscle (16, 17) has provided us with concepts, techniques, and reagents with which to probe the mechanisms underlying the observed changes in muscle mass in response to altered nutrition and physical activity.1

Hitherto, research on the human muscle mass and muscle growth signaling has usually been conducted by separate groups of researchers with limited mutual communication. The aim of this article is to review both areas and to show connections between them. We first discuss recent findings on muscle growth mechanisms; we then relate these findings to muscle growth in humans.


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[kurt]

MUSCLE GROWTH MECHANISMS - SIGNAL TRANSDUCTION AND REGULATION OF PROTEIN TURNOVER

The specific aim of the first section is to review (a) the signal transduction pathways that sense the muscle's environment and respond to various factors within it, inputting upstream signals to the muscle growth regulation system; (b) the transcriptional regulation of myostatin and IGF-1/MGF expression in response to growth-inducing stimuli; and (c) the specific regulation of muscle growth via regulation of mRNA translation and satellite cell proliferation in response to myostatin, IGF-1/MGF, and other factors. Most of the research has been carried out in nonhuman species, but the results are likely to be relevant to the observations made in human muscle.

Sensing of Growth Stimuli and Transcriptional Regulation

Strenuous, growth-inducing muscle activity is associated with changes in one or more of variables such as passive- and contraction-induced strain, sarcoplasmic calcium concentration, energy demand, intramuscular oxygen concentration, availability of hormones, growth factors and cytokines, temperature, and cellular damage (see Figure 1). A sufficient change in any of these variables will result in the altered activity of signal transduction pathways that regulate the transcription of genes differentially expressed during muscle growth. Signal transduction pathways shown to be activated in response to various forms of muscle contraction include those involving AMPK (18), calcineurin (19), ERK1/2 and p38 (20), JNK (20, 21) NF-B (22), PI3K-PKB/AKT-mTOR (23), and PKC (24). In addition to these pathways, many of the transcription factors involved in myogenesis (25, 26) continue to be active in adaptive and regenerative processes in adult muscle. Thus, strenuous, growth-inducing muscle activity and other growth stimuli are likely to activate a signal transduction network rather than just one or two signal transduction pathways. Skeletal muscle hypertrophy signaling appears to mirror, to some extent, that observed during cardiac hypertrophy (27, 28). Here, we focus on the calcineurin and mechanical-chemical transduction pathways because these two signaling systems have been shown to be involved in muscle growth signaling.


View larger version (33K)

Figure 1
Overview of the main events during signal transduction and gene regulation leading to muscle hypertrophy. (1) Via receptor binding and cellular signals, cytokines and other growth factors are sensed and activate a network of signal transduction pathways that result (2) in the nuclear translocation or activation of transcription factors. Active, nuclear transcription factors (together with androgens and glucocorticoids via their soluble receptors) change the expression of the major muscle growth regulators IGF-1/MGF and myostatin or other muscle genes including ribosomal RNA (rRNA). Pathways that regulate translation or satellite cell function may also be activated by mechanisms other than IGF-1/MGF or myostatin (not shown). (3) IGF-1/MGF and insulin activate the PI3K-PKB/AKT-mTOR pathway, which enhances protein synthesis via increased translational initiation and the synthesis of ribosomal proteins for ribosome biogenesis. Availability of essential amino acids will activate mTOR signaling, whereas an increased energy demand sensed by AMPK will inhibit mTOR. (4) IGF-1/MGF, myostatin, and various other factors regulate an increased proliferation and differentiation of satellite cells.

CALCINEURIN-SIGNALING Ca2+ acts as a regulatory signal during skeletal muscle hypertrophy (29) and is of particular interest because during contraction there is a large transient change in cytosolic Ca2+. Calcineurin is a Ca2+-calmodulin-activated protein phosphatase that dephosphorylates the transcription factor NFAT, enabling its nuclear translocation and DNA binding. The calcineurin pathway has been linked not only to the regulation of skeletal muscle bulk growth but also to that of fast-to-slow phenotype conversion (30) and IGF-1 and Ca2+-induced skeletal muscle hypertrophy, at least in cultured skeletal muscle (31).

However, regulation of nuclear Ca2+ concentrations may occur independently of transient changes in cytoplasmic Ca2+ calcium concentrations (32). In heart, Ca2+-mediated cardiac muscle hypertrophy is induced partly through capacitative Ca2+ entry from the extracellular space by the way of transient receptor potential (Trp) proteins (33). It is not yet clear to what extent such a situation could occur in skeletal muscle, in which a much smaller proportion of Ca2+ flux arises via the sarcoplasmic reticulum. However, it seems likely that Ca2+ may be differentially routed toward nuclear Ca2+-induced gene transcription, inducing activation of the Ca2+-sensitive transcription factor (NFAT).

Activation of NFAT transcriptional signaling is mediated by Ca2+-induced increases in the phosphatase activity of calcineurin, which induces translocation of cytoplasmic NFAT to the nucleus (34). Overexpression of NFAT in transgenic mice results in cardiac hypertrophy and its knockout prevents it (35, 36). NFAT overexpression also results in inactivation of glycogen synthase kinase-3, which mediates the nuclear location of NFAT (37) and possibly induces skeletal myotube hypertrophy (38).

With regard to skeletal muscle hypertrophy in animal models, the role of calcineurin remains controversial owing to the use of cyclosporin A, a nonspecific inhibitor of calcineurin. Inhibition of the calcineurin pathway in vivo with cyclosporin A prevents overload hypertrophy (39). Interestingly, overexpression of calcineurin in transgenic mice does not induce skeletal muscle hypertrophy (40, 41), which may indicate that skeletal muscle already contains sufficient calcineurin activity for muscle growth, and thus the addition of a constitutively active calcineurin is redundant (39). This contention is supported by the finding that cyclosporin blocked the growth of plantaris muscle after induced atrophy, which is noteworthy because the study clearly demonstrated that inhibition of calcineurin with cyclosporine is dependent upon the appropriate concentration of cyclosporine, the muscle, and selection of appropriate time points. Current thought suggests that the hyperactivation of calcineurin alone is not sufficient to induce skeletal muscle hypertrophy but that activation of various upstream or downstream regulators in conjunction with calcineurin activation may play a significant role in muscle hypertrophy (40).

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[kurt]

MECHANICAL-CHEMICAL TRANSDUCTION Nearly 30 years ago, Goldberg et al. summarized their work demonstrating that muscular activity appears to the fundamental determinant of muscle mass (42). This concept has been extended and reinforced by more recent workers: Various sensors of mechanical strain seem to possess the ability to translate strain into chemical signals that induce the activation of the skeletal muscle -actin promoter (43). The existence of a mechano-transduction mechanism in skeletal muscle is reinforced by the tensegrity hypothesis (44), which suggests that a protein framework within the cell maintains its overall cellular architecture; in response to mechanical forces, cell structural networks interact with gene and protein signaling networks to allow cytoskeletal proteins to reposition and renew themselves, permitting the cell to resist deformation from the applied forces. A possible candidate sensor of the increase in mechanical strain is focal adhesion kinase (FAK), a protein localized to the sacrolemma (45, 46); FAK autokinase activity increases during high mechanical loading. In addition, during mechanical loading of muscles, there are significant increases in both the total amount of FAK and its tyrosine phosphorylation status (47). The transcription factor, serum response factor (SRF), is a substrate of FAK, thereby providing a transcriptional link between membrane, the genome, and subsequent expression of muscle protein (43). Furthermore, binding of SRF to the serum response element (SRE1) within the chicken skeletal -actin promoter is both necessary and sufficient for increased transcriptional activity of the skeletal -actin promoter (46). The putative link between FAK and SRF has been strengthened by results indicating that SRF-mediated, skeletal -actin promoter activity is dependent upon activation of 1D-integrin-RhoA signaling and that this activity can be completely abolished by cotransfection of a dominant-negative FAK, termed FRNK (48).

Different modes of exercise affect extracellular signal-regulated kinase (ERK1/2) and the 38-kDa stress-activated protein kinase (p38) in an almost universal way (20, 49) that seems to be intensity dependent. However, only those stimuli likely to result in hypertrophy, such as high-frequency electrical stimulation, increased p70S6 kinase and protein kinase B phosphorylation (49). In a study designed to untangle the effects of concentric and eccentric contractions on the phosphorylation of ERK1/2 and p38, Wretman and coworkers applied a panoply of stimuli to isolated rat extensor digitorum longus muscle in vitro: These included electrically stimulated concentric (shortening) or eccentric (lengthening) contractions or severe passive stretch, and application of antioxidants likely to counteract reactive oxygen species and induce intracellular acidosis (50). They concluded that mechanical activity, whether through contraction or stretch, increased the activity of both ERK1/2 and p38, whereas the ionic changes and increase in reactive oxygen species and acidosis exhibited after concentric contraction increased phosphorylation only of ERK1/2. This suggested that high mechanical stress was required for activation of p38. Because stretch per se does not appear to increase MPS in human muscle (see below), and because changes in ERK1/2 are common to types of exercise that differ markedly in their sequelae (hypertrophy or mitochondrial biogenesis), the likelihood of these signaling molecules being involved in hypertrophy is lessened.


TRANSCRIPTIONAL REGULATION Most of the cellular signaling pathways discussed above control the location and activity of transcription factors that, in turn, regulate gene transcription. However, for many years the processes of protein turnover in skeletal muscle were thought to be modulated without requiring extensive gene expression, which, when it did occur, was considered a relatively sluggish process with a long latency, possibly up to days. These concepts are wrong: In addition to any translational regulation, metabolic alterations, such as an increase in the availability of insulin and glucose (51), or environmental stimuli such as exercise (52), can result in increases in gene transcription (not restricted to the so-called early response genes) within 1.53 h, even in adult human skeletal muscle. Thus the difference in the timescale between the adaptivity of transcription and the processes of protein turnover may be much less than previously thought. Skeletal muscle growth regulators such as IGF-1 and other regulatory factors, for instance cytokines, early genes, signal transduction proteins, and myogenic regulatory factors, are transcriptionally regulated in response to contractile overload induced by synergist ablation in rat. More microarray studies are needed to elucidate the behavior of genes during muscle growth in animals and humans. For more detailed reviews concerning the role of gene transcription in muscle hypertrophy, see Carson (53) and Baar et al. (54).

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[kurt]

Regulation of the Expression of the Specific Muscle Growth Factors IGF-1/MGF and Myostatin

Changing the availability of the muscle growth factors IGF-1/MGF and myostatin appears to be a central regulatory process in adaptive muscle growth. Obviously, IGF-1/MGF and myostatin are not directly regulated by stretch, overload, or muscle contraction but by the signal transduction pathways that sense these stimuli and consequently regulate the availability of these muscle growth factors for receptor binding. The protein availability depends on transcriptional regulation, translational regulation, splicing, localization, concentration of binding proteins, and proteolysis. The major regulatory step controlling the availability of IGF-1/MGF and myostatin in response growth-inducing stimuli appears to be transcriptional regulation. The transcriptional regulation of these factors involves some of the muscular signal transduction pathways mentioned above, as well as some developmental pathways and anabolic and catabolic steroid hormones.


REGULATION OF MYOSTATIN EXPRESSION Myostatin [growth/differentiation factor-8 (GDF-8)] is a member of the transforming growth factor- (TGF-) family (55). Depending upon the site of deletion in the myostatin gene, mice expressing the modified gene in muscle may exhibit either myofiber hyperplasia or hypertrophy (see 56 for references). Myostatin-null mice were, paradoxically, shown to be more susceptible than wild-type mice to hindlimb suspension-induced muscle atrophy (57). Myostatin expression is environmentally modifiable, i.e., it can be decreased during reloading but, oddly, it is unchanged during suspension-induced muscle atrophy hindlimb suspension (58). The regulation of myostatin expression appears to depend on major growth pathways. Binding sites for glucocorticoids, androgens, thyroid hormone receptors, myogenic differentiation factor 1, MEF2, PPAR, and NF-B, with appropriate positive and negative effects, have all been predicted for the myostatin promoter region and for glucocorticoids experimentally confirmed in human muscle (59, 60).


REGULATION OF IGF-1/MGF EXPRESSION In hypertrophying rodent muscle, IGF-1 mRNA rises nearly threefold within two days of functional overload and remains elevated thereafter (61), a phenomenon also observed in human skeletal muscle after a single resistance training bout (62). The increase in IGF-1 immunoreactivity was localized mostly within the fibers of rat anterior tibialis muscle four days after an eccentric-resistance training program that led eventually to hypertrophy (63), suggesting that pretranscriptional regulation is probably involved somehow in the exercise-induced increase. IGF-1 superfusion onto muscle in free-moving rats produces hypertrophy (64), and a similar maneuver rescues immobilized muscle from aging-associated sarcopenia (65), as does IGF-1 overexpression (66). The increase in IGF-1 and its splice variant MGF (IGF-1Eb) (see below) in skeletal muscle in response to mechanical loading may be regulated transcriptionally in rat muscle. However, the mechanisms that regulate MGF expression in response to an increase in muscle tension are currently unknown. Skeletal muscle IGF-1 expression increases in response to growth hormone and testosterone and decreases in response to glucocorticoid hormones, TNF, and interleukin-1 (67).


Specific Muscle Growth Regulation

Muscle growth stimuli lead to the activation of a signal transduction network and to a changed availability of the major muscle growth factors IGF-1/MGF and myostatin. The activated signal transduction pathways and changed growth factor availability will then regulate the activity of "muscle growth executors," which are the translational or protein synthesis machinery and satellite cells.


TRANSLATIONAL REGULATION The cellular and molecular mechanisms regulating the translation of mRNA in muscle have been elucidated to a much higher degree (68) than those regulating protein breakdown, partly because the protein/synthetic machinery forms a cohesive metabolic unit centered around the ribosome and the endoplasmic reticulum. There are a number of systems for achieving proteolysis, such as the ATP and ubiquitin-dependent proteasome (69), the lysosome, at least two cytoplasmic systems activated by various concentrations of Ca2+ (70), and even extracellular, lymphocyte-based systems, which act on muscle (71). There is good evidence that the myofibrillar apparatus is degraded by the proteasome; however, abundant amounts of proteasome mRNA or proteasome do not automatically produce an increase in proteolysis. For example, there are cases of paradoxical changes of proteasome activity in muscle in response to starvation and refeeding (72).

It is relatively easy to demonstrate regulatory changes in the machinery of protein synthesis, which are consonant with an increase in the synthesis of protein, e.g., ribosome, aggregation (73), whereas in the case of protein breakdown, changes in apparent activity of key components of the system may exist with no, or apparently opposite, changes in the extent of net protein balance. This has made it difficult to make much progress in understanding the physiological modulation of muscle protein breakdown, although some knowledge of the involvement of elements of signaling pathways also involved in regulation of protein breakdown is now being accumulated (70).

The mechanisms regulating translational regulation during muscle growth are becoming increasingly clear (see 7476 for more details). IGF-1 is capable of promoting muscle growth by activating regulators of translational initiation or efficiency via the PI3K-PKB/AKT-mTOR pathway (76, 77). IGF-1 treatment leads to an increased phosphorylation of PKB/AKT, mTOR, GSK3, and the translational regulators 4E-BP1 and p70S6k. When phosphorylated, 4E-BP1 detaches from eIF4E (78) (a translational initiation factor that mediates mRNA binding to the ribosome) and this initiates translation. Phosphorylated p70S6k promotes the increased translation of those mRNAs with a 5'-tract of pyrimidine (TOP), i.e., a series of cytosine or thymine repeats at the 5' gene terminus (79). All known ribosomal proteins have a TOP sequence, suggesting that mTOR regulates both ribosomal biogenesis and translation via p70S6k and 4E-BP1, respectively.

The main response of mTOR-dependent signaling occurs with a latency of only a few hours after growth-stimulating exercise. Hernandez et al. reported increases in PI3K and the translational regulator p70S6k occurring after 6 to 24 h and protein synthesis itself rising 12 to 24 h after resistance exercise in rat muscle (80). Similar results are available for human muscle (81). Rat muscles stimulated at high-frequency show p70S6k phosphorylation peaking at 3 to 6 h after stimulation, with some increased phosphorylation still apparent 36 h later in hypertrophying muscles (54). The delay in the activation of translational pathways and protein synthesis might be explained by the time necessary for strain-sensing and signaling, possibly via IGF-1 or MGF synthesis and secretion.

However, a recent paper shows that translational pathways and regulators are also transiently activated within 510 min after resistance exercise in rats (81a). This finding is interesting because a changed IGF-1 or MGF availability is unlikely to occur minutes after the stimulus and thus suggests other connections between the signal transduction pathways that sense resistance exercise signals and the translational regulators.

Essential amino acids stimulate protein synthesis via a nutrient-sensitive complex of two proteins, Raptor and mTOR, which, in humans, are expressed more in skeletal muscle than in other tissues (82, 83). It is likely that the Raptor-mTOR complex is destabilized and mTOR and the downstream translational regulators are activated when essential amino acid availability increases. An additional positive regulator, GL, appears to be involved (83). The binding of GL to mTOR strongly stimulates the kinase activity of mTOR toward S6K1 and 4E-BP1, an effect reversed by the stable interaction of Raptor with mTOR. The availability of essential amino acids sensed by this protein complex activates mTOR, as well as of the translational regulators eIF2, 4E-BP1, and p70S6k (84), which explains the observed stimulatory effect on protein synthesis.

In contrast, an increased energy demand (reflected by lowered ATP/ADP ratio, higher AMP, and lower creatine phosphate concentrations) leads to a depression of protein synthesis (85). A recently discovered interaction between AMPK and PKB-mTOR signaling in muscle has provided a possible mechanism for this effect: AMPK is activated by AMP and inhibited by ATP and creatine phosphate and is involved in the regulation of numerous cellular functions such as mitochondrial biogenesis and fuel metabolism (18, 86). Treatment of rats with the AMPK-activator, AICAR, resulted in a reduction in skeletal muscle protein synthesis. This was accompanied by a decreased activation of PKB-mTOR and its downstream targets p70S6k and 4E-BP1 (87).

(fortsetzung folgt)