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Time is considered a primary barrier to exercise adherence. Therefore, developing time-efficient resistance training (RT) strategies that optimize muscular adaptations is of primary interest to practitioners. A novel approach to the problem involves combining intensive stretch protocols with RT. Conceivably, integrating stretch into the inter-set period may provide an added stimulus for muscle growth without increasing session duration. Mechanistically, stretch can regulate anabolic signaling via both active and passive force sensors. Emerging evidence indicates that both lengthening contractions against a high load as well as passive stretch can acutely activate anabolic intracellular signaling pathways involved in muscle hypertrophy. Although longitudinal research investigating the effects of stretching between RT sets is limited, some evidence suggests it may in fact enhance hypertrophic adaptations. Accordingly, the purpose of this paper is threefold: (1) to review how the active force of a muscle contraction and the force of a passive stretched are sensed; (2) to present evidence for the effectiveness of RT with inter-set stretch for muscle hypertrophy (3) to provide practical recommendations for application of inter-set stretch in program design as well as directions for future research.

In skeletal muscle tissue, oxygen (O2) plays a pivotal role in both metabolism and the regulation of several intercellular pathways, which can modify proliferation, differentiation and survival of cells within the myogenic lineage. The concentration of oxygen in muscle tissue is reduced during embryogenesis and pathological conditions. Myogenic progenitor cells, namely satellite cells, are necessary for muscular regeneration in adults and are localized in a hypoxic microenvironment under the basal lamina, suggesting that the O2 level could affect their function. This review presents the effects of reduced oxygen levels (hypoxia) on satellite cell survival, myoblast regeneration and differentiation in vertebrates. Further investigations and understanding of the pathways involved in adult muscle regeneration during hypoxic conditions are maybe clinically relevant to seek for novel drug treatments for patients with severe muscle damage. We especially outlined the effect of hypoxia-inducible factor 1-alpha (HIF1A), the most studied transcriptional regulator of cellular and developmental response to hypoxia, whose investigation has recently been awarded with the Nobel price.

Hippo pathway downstream effectors Yap and Taz play key roles in cell proliferation and regeneration, regulating gene expression especially via Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analyzed Taz in vivo and ex vivo in comparison with Yap. Small interfering RNA knockdown or retroviral-mediated expression of wild-type human or constitutively active TAZ mutants in satellite cells showed that TAZ promoted proliferation, a function shared with YAP. However, at later stages of myogenesis, TAZ also enhanced myogenic differentiation of myoblasts, whereas YAP inhibits such differentiation. Functionally, while muscle growth was mildly affected in Taz (gene Wwtr1-/-) knockout (KO) mice, there were no overt effects on regeneration. Conversely, conditional KO of Yap in satellite cells of Pax7Cre-ERT2/+: Yapfl°x/fl°x: Rosa26Lacz mice produced a marked regeneration deficit. To identify potential mechanisms, microarray analysis showed many common TAZ/YAP target genes, but TAZ also regulates some genes independently of YAP, including myogenic genes such as Pax7, Myf5, and Myod1 (ArrayExpress-E-MTAB-5395). Proteomic analysis revealed many novel binding partners of TAZ/YAP in myogenic cells, but TAZ also interacts with proteins distinct from YAP that are often involved in myogenesis and aspects of cytoskeleton organization (ProteomeXchange-PXD005751). Neither TAZ nor YAP bind members of the Wnt destruction complex but both regulated expression of Wnt and Wnt-cross talking genes with known roles in myogenesis. Finally, TAZ operates through Tead4 to enhance myogenic differentiation. In summary, Taz and Yap have overlapping functions in promoting myoblast proliferation but Taz then switches to enhance myogenic differentiation.

Additional file 3: Table S7. Metabolites changed in relation to time point of sampling (with Fig. 4).

Additional file 1: Table S1. Carbohydrate Metabolites and TCA cycle intermediates. Table S2. Lipids and intermediates of lipid metabolism. Table S3. Amino Acids and Peptides. Table S4. Nucleotides. Table S5. Cofactors/Vitamins and Xenometabolites.

Additional file 2: Table S6. Descriptive summary of 57 experiments that reported metabolites concentration changes after a bout of exercise.

Exercise is recommended for the healthy population as it increases fitness and prevents diseases. Moreover, exercise is also applied as an adjunct therapy for patients with various chronic diseases including cancer. Childhood cancer is a rare, heterogeneous disease that differs from adult cancer. Improved therapeutic strategies have increased childhood cancer survival rates to above 80% in developed countries. Although this is higher than the average adult cancer survival rate of about 50%, therapy results often in substantial long-term side effects in childhood cancer survivors. Exercise in adult cancer patients has many beneficial effects and may slow down tumor progression and improve survival in some cancer types, suggesting that exercise may influence cancer cell behavior. In contrast to adults, there is not much data on general effects of exercise in children. Whilst it seems possible that exercise might delay cancer progression or improve survival in children as well, there is no reliable data yet to support this hypothesis. Depending on the type of cancer, animal studies of adult cancer types show that the exercise-induced increase of the catecholamines epinephrine and norepinephrine, have suppressive as well as promoting effects on cancer cells. The diverse effects of exercise in adult cancer patients require investigating whether these results can be achieved in children with cancer.

Endurance is not only a key factor in many sports but endurance-related variables are also associated with good health and low mortality. Twin and family studies suggest that several endurance-associated traits are ≈50% inherited. However, we still poorly understand what DNA sequence variants contribute to endurance heritability. To address this issue, we conducted a systematic review to identify genes whose experimental loss or gain-of-function increases endurance capacity in mice. We found 31 genes including two isoforms of Ppargc1a whose manipulation increases running or swimming endurance performance by up to 1800%. Genes whose gain-of-function increases endurance are Adcy5, Adcy8, Hk2, Il15, Mef2c, Nr4a3, Pck1 (Pepck), Ppard, Ppargc1a (both the a and b isoforms of the protein Pgc-1α), Ppargc1b, Ppp3ca (calcineurin), Scd1, Slc5a7, Tfe3, Tfeb, Trib3 & Trpv1. Genes whose loss-of-function increases endurance in mice are Actn3, Adrb2, Bdkrb2, Cd47, Crym, Hif1a, Myoz1, Pappa, Pknox1, Pten, Sirt4, Thbs1, Thra, and Tnfsf12. Of these genes, human DNA sequence variants of ACTN3, ADCY5, ADRB2, BDKRB2, HIF1A, PPARD, PPARGC1A, PPARGC1B, and PPP3CA are also associated with endurance capacity and/or VO2max trainability suggesting evolutionary conservation between mice and humans. Bioinformatical analyses show that there are numerous amino acid or copy number-changing DNA variants of endurance genes in humans, suggesting that genetic variation of endurance genes contributes to the variation of human endurance capacity, too. Moreover, several of these genes/proteins change their expression or phosphorylation in skeletal muscle or the heart after endurance exercise, suggesting a role in the adaptation to endurance exercise.

VGLL proteins are transcriptional co-factors that bind TEAD family transcription factors to regulate events ranging from wing development in fly, to muscle fibre composition and immune function in mice. Here, we characterise Vgll3 in skeletal muscle. We found that mouse Vgll3 was expressed at low levels in healthy muscle but that its levels increased during hypertrophy or regeneration; in humans, VGLL3 was highly expressed in tissues from patients with various muscle diseases, such as in dystrophic muscle and alveolar rhabdomyosarcoma. Interaction proteomics revealed that VGLL3 bound TEAD1, TEAD3 and TEAD4 in myoblasts and/or myotubes. However, there was no interaction with proteins from major regulatory systems such as the Hippo kinase cascade, unlike what is found for the TEAD co-factors YAP (encoded by YAP1) and TAZ (encoded by WWTR1). Vgll3 overexpression reduced the activity of the Hippo negative-feedback loop, affecting expression of muscle-regulating genes including Myf5, Pitx2 and Pitx3, and genes encoding certain Wnts and IGFBPs. VGLL3 mainly repressed gene expression, regulating similar genes to those regulated by YAP and TAZ. siRNA-mediated Vgll3 knockdown suppressed myoblast proliferation, whereas Vgll3 overexpression strongly promoted myogenic differentiation. However, skeletal muscle was overtly normal in Vgll3-null mice, presumably due to feedback signalling and/or redundancy. This work identifies VGLL3 as a transcriptional co-factor operating with the Hippo signal transduction network to control myogenesis., Summary: VGLL3 interacts with TEAD transcription factors to direct expression of crucial muscle regulatory genes and contribute to the control of skeletal myogenesis.

VGLL proteins are transcriptional co-factors that bind TEAD family transcription factors to regulate events ranging from wing development in fly, to muscle fibre composition and immune function in mice. Here, we characterise Vgll3 in skeletal muscle. We found that mouse Vgll3 was expressed at low levels in healthy muscle but that its levels increased during hypertrophy or regeneration; in humans, VGLL3 was highly expressed in tissues from patients with various muscle diseases, such as in dystrophic muscle and alveolar rhabdomyosarcoma. Interaction proteomics revealed that VGLL3 bound TEAD1, TEAD3 and TEAD4 in myoblasts and/or myotubes. However, there was no interaction with proteins from major regulatory systems such as the Hippo kinase cascade, unlike what is found for the TEAD co-factors YAP (encoded by YAP1) and TAZ (encoded by WWTR1). Vgll3 overexpression reduced the activity of the Hippo negative-feedback loop, affecting expression of muscle-regulating genes including Myf5, Pitx2 and Pitx3, and genes encoding certain Wnts and IGFBPs. VGLL3 mainly repressed gene expression, regulating similar genes to those regulated by YAP and TAZ. siRNA-mediated Vgll3 knockdown suppressed myoblast proliferation, whereas Vgll3 overexpression strongly promoted myogenic differentiation. However, skeletal muscle was overtly normal in Vgll3-null mice, presumably due to feedback signalling and/or redundancy. This work identifies VGLL3 as a transcriptional co-factor operating with the Hippo signal transduction network to control myogenesis.

The ubiquitous transcriptional co-activators Yap (gene symbol Yap1) and Taz (gene symbol Wwtr1) regulate gene expression mainly by co-activating the Tead transcription factors. Yap and Taz lie at the centre of the Hippo signalling network and are not only regulated by the Hippo kinase cassette itself but also by a plethora of exercise-associated signals and signalling modules. These include mechanotransduction, the AKT-mTORC1 network, SMAD transcription factors, hypoxia, glucose, AMPK, adrenaline/epinephrine and angiotensin II through G protein-coupled receptors, and interleukin 6 (Il-6). Consequently exercise should alter Hippo signalling in several organs to mediate at least some aspects of organ-specific adaptations to exercise. Consistent with this idea Tead1 over expression in muscle fibres has been shown to promote a fast-to-slow fibre type switch whereas Yap in muscle fibres and cardiomyocytes promotes skeletal muscle and cardiac hypertrophy, respectively. Finally TEAD1, YAP1, VGLL2, VGLL3 and VGLL4 have all been linked in genome wide-association studies to body height, a key factor in sports.

Introduction The control of differentiation of mesenchymal stromal/stem cells (MSCs) is crucial for tissue engineering strategies employing MSCs. The purpose of this study was to investigate whether the transcriptional co-factor Yes-associated protein (YAP) regulates chondrogenic differentiation of MSCs. Methods Expression of total YAP, its paralogue transcriptional co-activator with PDZ-binding motif (TAZ), and individual YAP transcript variants during in vitro chondrogenesis of human MSCs was determined by quantitative reverse transcription polymerase chain reaction (RT-PCR). YAP expression was confirmed by western blotting. To determine the effect of high YAP activity on chondrogenesis, C3H10T1/2 MSC-like cells were transduced with human (h)YAP and treated in micromass with bone morphogenetic protein-2 (BMP-2). Chondrogenic differentiation was assessed by alcian blue staining and expression of chondrocyte-lineage genes. BMP signalling was determined by detection of pSmad1,5,8 by western blotting and expression of BMP target genes by quantitative RT-PCR. Finally, YAP and pYAP were detected in mouse embryo hindlimbs by immunohistochemistry. Results YAP, but not TAZ, was downregulated during in vitro chondrogenesis of human MSCs. One of the YAP transcript variants, however, was upregulated in high-density micromass culture. Overexpression of hYAP in murine C3H10T1/2 MSCs inhibited chondrogenic differentiation. High YAP activity in these cells decreased Smad1,5,8 phosphorylation and expression of the BMP target genes Inhibitor of DNA binding/differentiation (Id)1, Id2 and Id3 in response to BMP-2. In developing mouse limbs, Yap was nuclear in the perichondrium while mostly phosphorylated and cytosolic in cells of the cartilage anlage, suggesting downregulation of Yap co-transcriptional activity during physiological chondrogenesis in vivo. Conclusions Our findings indicate that YAP is a negative regulator of chondrogenic differentiation of MSCs. Downregulation of YAP is required for chondrogenesis through derepression of chondrogenic signalling. Therapeutic targeting of YAP to promote cartilage repair and prevent secondary osteoarthritis is an exciting prospect in rheumatology. Electronic supplementary material The online version of this article (doi:10.1186/s13075-015-0639-9) contains supplementary material, which is available to authorized users.

The aim of this study was to investigate the function of the Hippo pathway member Yes-associated protein (Yap, gene name Yap1) in skeletal muscle fibres in vivo. Specifically we bred an inducible, skeletal muscle fibre-specific knock-in mouse model (MCK-tTA-hYAP1 S127A) to test whether the over expression of constitutively active Yap (hYAP1 S127A) is sufficient to drive muscle hypertrophy or stimulate changes in fibre type composition. Unexpectedly, after 5–7 weeks of constitutive hYAP1 S127A over expression, mice suddenly and rapidly lost 20–25% body weight and suffered from gait impairments and kyphosis. Skeletal muscles atrophied by 34–40% and the muscle fibre cross sectional area decreased by ≈40% when compared to control mice. Histological analysis revealed evidence of skeletal muscle degeneration and regeneration, necrotic fibres and a NADH-TR staining resembling centronuclear myopathy. In agreement with the histology, mRNA expression of markers of regenerative myogenesis (embryonic myosin heavy chain, Myf5, myogenin, Pax7) and muscle protein degradation (atrogin-1, MuRF1) were significantly elevated in muscles from transgenic mice versus control. No significant changes in fibre type composition were detected using ATPase staining. The phenotype was largely reversible, as a cessation of hYAP1 S127A expression rescued body and muscle weight, restored muscle morphology and prevented further pathological progression. To conclude, high Yap activity in muscle fibres does not induce fibre hypertrophy nor fibre type changes but instead results in a reversible atrophy and deterioration.

The British Association of Sport and Exercise Sciences (BASES) Molecular Exercise Physiology Interest Group has produced a position stand to advise on ethical and other issues associated with genetic research in sport and exercise science. This article is an updated summary of the position stand. The heritability of sport and exercise-related traits such as maximal oxygen uptake, muscle fibre composition and trainability is often approximately 50%. Little is known about the variations in DNA responsible and a major aim of current research is to identify the variations in DNA (or genetic loci) that determine heritable traits. Identifying the genetic loci will also inform us about the mechanisms that regulate a trait and could be used to develop applications such as genetic performance tests or genetic screens for individuals at high risk of sudden death during sport, for example, due to a gene mutation related to cardiac function. Another application could be to use genetic tests to prescribe personalised training or exercise therapy programmes for athletes or patients, respectively. Serious ethical concerns are associated with genetic testing especially when such testing is performed on embryos or minors, requested by others such as parents, coaches or physicians and when it is used to discriminate against athletes, for example by selecting squad athletes on the basis of genetic performance tests. Recommendations from the position stand include: (i) Scientists should be aware of the ethical implications of their work and engage knowledgably in public debates; (ii) genetic testing in the sport and exercise context (with the possible exception of preparticipation risk screening) should be confined to mature individuals who fully understand the relevant issues and a system of counselling should be introduced; (iii) pre-participation genetic risk screening should not be obligatory and the confidentiality of such testing should be ensured.

Physical exercise contributes to a healthy lifestyle and decreases the risk of developing several diseases, including cancer. Exercise might also be beneficial to cancer treatment and its side effects. The work of this dissertation emphasizes the need for specific research in pediatric exercise oncology and shows that the expression of adrenergic receptor isoforms could be an essential mediator of the effect of exercise on cancer. Sport und Bewegung sind wesentliche Bestandteile eines gesunden Lebensstils. Wer sich regelmäßig bewegt, beugt damit Krankheiten vor; unter anderem auch Krebs. Sport schützt nicht nur vor der Entstehung einer Reihe von Krebsarten sondern kann auch die Therapie begünstigen und Nebenwirkungen verringern. Die Ergebnisse dieser Dissertation legen nahe, dass Kinder in der Sportonkologie stärker in den Fokus rücken sollten und adrenerge Rezeptoren eine Schlüsselrolle bei der Wirkung von Sport auf Krebs haben könnten.

Through incorporation of the existent literature and two experimental studies, this cumulative thesis aims to answer the first set of questions that arise during an individualization in exercise science by using omics techniques. Metabolites and proteins were quantified in healthy human subjects in response to short- and long-term exercise. This thesis showed that exercise related phenotypes are reflected in the blood metabolome and that proteins can be used to predict trainability of endurance. Diese Thesis vereint die bestehende Literatur mit zwei experimentellen Studien und beantwortet Fragen, die bei einer verstärkten Individualisierung des sportlichen Trainings auftreten. Dafür wurden Metaboliten und Proteine beim gesunden Menschen nach kurzer und langer sportlicher Belastung mit sogenannten Omics Methoden gemessen. Die Thesis zeigte, dass der sportliche Phänotyp auch im Blutmetabolom abgebildet wird und dass man mit Proteinen die Trainierbarkeit der Ausdauer vorhersagen kann.

We use our ≈650 skeletal muscles to move, stand, speak, generate force, heat, store glucose as glycogen, and amino acids as protein. Many of these functions vary greatly in the human population and twin and family studies suggest that much of this variability can be explained by genetics. Whilst transgenic mouse studies and human genome-wide association studies (GWAS) have identified some causal genes and DNA variants, much still needs to be discovered. The aim of this thesis was therefore to identify genes and DNA variants that are associated with sports and exercise-related skeletal muscle phenotypes such as muscle hypertrophy, endurance, and fiber type distribution. A special focus is on genes that are part of the so-called Hippo signal transduction network, a regulatory system involved in proliferation, stem cell function, regeneration, growth, organ size, and other phenotypes. In the first study systematic review, I conducted a systematic review of genes whose gain or loss-of-function increases endurance capacity in mice. We found 31 genes whose manipulation increases running or swimming endurance performance by up to 1800%. Several of endurance capacity regulating genes are also associated with endurance capacity and/or VO2max trainability indicating evolutionary conservation between humans and mice. The second study is an experimental study in which I phenotyped and compared the muscles of hind limbs of mice where Hippo genes were mutated (Lats1-/-, Mst2-/-, Vgll3-/-, and Vgll4+/- mutated mice) with those of wild-type control mice. I found that Lats1-/- mice had 11% more slow type I fibers and 11% fewer type IIa fibers, suggesting a slow-twitch phenotype. Taken together, the results of this thesis give a deeper insight into the genetics of endurance performance and identify Lats1 as a gene that contributes to determining whether a muscle is slow versus a fast-twitch muscle. Wir benutzen unsere 650 Skelettmuskeln, um uns zu bewegen, zu stehen, zu sprechen, Kraft und Wärme zu erzeugen, und um Glukose als Glykogen und Aminosäuren als Protein zu speichern. Viele dieser Funktionen variieren stark in der menschlichen Bevölkerung und Zwillings- und Familienstudien legen nahe, dass ein Großteil dieser Variabilität durch genetische Variabilität erklärt werden kann. Während transgene Mausstudien und humane genomweite Assoziationsstudien (GWAS) einige kausale Gene und DNA-Varianten identifiziert haben, muss noch viel entdeckt werden. Das Ziel dieser Arbeit war es daher, Gene und DNA-Varianten zu identifizieren, die mit sport- und trainingsbezogenen Skelettmuskelphänotypen wie Muskelhypertrophie, Ausdauer und Fasertypverteilung assoziiert sind. Ein besonderer Fokus liegt dabei auf Genen, die Teil des sogenannten Hippo-Signaltransduktionsnetzwerks sind, einem regulatorischen System, das an der Regulation von Proliferation, Stammzellfunktion, Regeneration, Wachstum, Organgröße und anderen Phänotypen beteiligt ist. In der ersten systematischen Übersichtsarbeit haben wir nach Genen gesuch, deren Funktionsgewinn oder -verlust die Ausdauerleistung bei Mäusen erhöht. Wir fanden 31 Gene, deren Manipulation die Ausdauerleistung beim Laufen oder Schwimmen um bis zu 1800% erhöht. Mehrere der die Ausdauerleistung regulierenden Gene sind auch mit der Ausdauerleistung und/oder der VO2max-Trainierbarkeit assoziiert, was auf eine evolutionäre Konservierung zwischen Mäusen und Menschen hindeutet. Die zweite Studie war eine experimentelle Studie, in der ich die Muskeln der Hintergliedmaßen von Mäusen, in denen Hippo-Gene mutiert waren (Lats1-/-, Mst2-/-, Vgll3-/- und Vgll4+/- mutierte Mäuse), phänotypisiert und mit denen von Wildtyp-Kontrollmäusen verglichen habe. Ich fand heraus, dass Lats1-/- Mäuse 11 % mehr langsame Typ-I-Fasern und 11 % weniger Typ-IIa-Fasern hatten, was auf einen Slow-Twitch-Phänotyp hindeutet. Zusammengenommen geben die Ergebnisse dieser Arbeit einen tieferen Einblick in die Genetik die Ausdauerleistung und identifizieren Lats1 als ein Gen, das dazu beiträgt zu bestimmen, ob ein Muskel ein langsam- oder schnell zuckender Muskel ist.

91 Skirennläufer (9-14a) wurden prospektiv beobachtet, um die Inzidenz von Verletzungen und Erkrankungen zu registrieren. Die traumatischen Verletzungen zeigten eine Inzidenz von 1,1/1000 Trainingsstunden, die Überlastungsverletzungen 0,3/1000 Trainingsstunden. Trainingsvolumen und Intensität stellten keinen signifikanten Risikofaktor für Verletzungen dar. Die Trainingsintensität stellte einen Risikofaktor für gehäufte Erkrankungen in der gleichen Woche dar, das Trainingsvolumen zeigte sich als Risikofaktor für Erkrankungen in der Folgewoche. 91 elite youth ski racers (9-14a) were prospectively recorded to monitor injuries and illnesses. Injuries represented an incidence of 1.1/1000 hours of training, overuse injuries 0.3/1000 hours of training. Weekly training volume and training intensity did not represent a significant risk factor for traumatic and overuse injuries. Training intensity was a significant risk factor for illnesses in the same week, whereas training volume represents a risk factor for illnesses in the following week.

Maintaining or increasing skeletal muscle mass is important to prevent age-associated decline in daily functioning. Resistance exercise increases skeletal muscle mass and offers a tool to a prevent muscle loss. Furthermore, resistance exercise increases glucose uptake in skeletal muscle, which is beneficial for glycaemic control. On the other hand, recently it has been proposed that glucose can be used as a building block for anabolic processes, at least in non- muscle cells. We do not know whether glucose metabolism contributes to muscle growth. Therefore, the aim of this thesis is to identify genes and study mechanisms through which skeletal muscle can use glucose for growth processes. In study I, II and III we searched the scientific literature to identify genes whose gain- or loss-of-function increases skeletal muscle mass in mice, or alter skeletal muscle glucose uptake or increases endurance capacity. We found 47 genes that cause muscle hypertrophy after gene manipulation. Several of these genes are connected to signalling pathways that are able to induce hypertrophy, including 1) IGF1-AKT-MTOR pathway, 2) myostatin-Smad signalling, and 3) the angiotensin-bradykinin signalling pathway. Whether these hypertrophy genes also regulate glucose uptake remains to be determined. We found 176 glucose uptake genes that alter glucose uptake in skeletal muscle after gene manipulation. 12 of these genes also control muscle mass. 46 of the glucose uptake genes respond to acute resistance exercise, which warrant further investigation to determine their role in muscle size regulation. In study IV, we investigated the contribution of Warburg effect-associated enzyme PKM2 to muscle growth. Resistance exercise in humans for 6 weeks increases PKM2 abundance which is associated with increased muscle fiber size. In vitro, we determined that PKM2 is essential for IGF1 mediated myotube growth. Whether glucose incorporation in myotube is controlled by PKM2 remains to be determined. Together, the work in this thesis shows that candidates involved in glucose metabolism are important for muscle growth. In addition, we found genes previously unrecognised to play a dual role in both glucose metabolism and muscle hypertrophy. Thus, the studies in this thesis suggest that the interplay between skeletal muscle metabolism and hypertrophy warrant further investigation. Der Erhalt oder die Zunahme der Skelettmuskelmasse ist wichtig, um altersbedingte Beeinträchtigungen der täglichen Funktionen zu verhindern. Krafttraining erhöht die Skelettmuskelmasse und bietet ein Weg um Muskelverlust zu verhindern. Außerdem erhöht Krafttraining die Glukoseaufnahme in der Skelettmuskulatur, was für die Blutzuckerkontrolle von Vorteil ist. Andererseits wurde vorgeschlagen, dass Glukose als Baustein für anabole Prozesse verwendet werden kann, zumindest in Nicht-Muskelzellen. Wir wissen nicht, ob der Glukosestoffwechsel zum Muskelwachstum beiträgt. Daher ist es das Ziel dieser Arbeit, Gene zu identifizieren und Mechanismen zu untersuchen, durch die der Skelettmuskel Glukose für Wachstumsprozesse nutzen kann. In den Studien I, II und III untersuchten wir die wissenschaftliche Literatur, um Gene zu identifizieren, deren gain- oder loss-of-function die Skelettmuskelmasse bei Mäusen erhöht, die Glukoseaufnahme der Skelettmuskulatur verändert oder die Ausdauerleistung erhöht. Wir fanden 47 Gene, die nach Genmanipulation eine Muskelhypertrophie verursachen. Mehrere dieser Gene sind mit Signalwegen verbunden, die in der Lage sind, Hypertrophie zu induzieren, darunter 1) IGF1-AKT-MTOR-Signalweg, 2) Myostatin-Smad- Signalweg und 3) der Angiotensin-Bradykinin-Signalweg. Ob diese Hypertrophie-Gene auch die Glukoseaufnahme regulieren, muss noch untersucht werden. Wir fanden 176 Gene für die Glukoseaufnahme, die die Glukoseaufnahme im Skelettmuskel nach Genmanipulation verändern. 12 dieser Gene steuern auch die Muskelmasse. 46 der Gene für die Glukoseaufnahme reagieren auf akutes Krafttraining, was weitere Untersuchungen rechtfertigt, um ihre Rolle bei der Regulation der Muskelgröße zu bestimmen. In Studie IV untersuchten wir den Beitrag des mit dem Warburg-Effekt assoziierten Enzyms PKM2 zum Muskelwachstum. Krafttraining beim Menschen über 6 Wochen erhöht die PKM2-Häufigkeit, was mit einer erhöhten Muskelfasergröße verbunden ist. In vitro haben wir festgestellt, dass PKM2 essentiell für IGF1-vermitteltes Myotubewachstum ist. Ob der Glukoseeinbau in die Myotube durch PKM2 kontrolliert wird, muss noch untersucht werden. Zusammengenommen zeigt die Arbeit in dieser Dissertation, dass Kandidaten, die am Glukosestoffwechsel beteiligt sind, wichtig für das Muskelwachstum sind. Darüber hinaus fanden wir Gene, von denen bisher nicht bekannt war, dass sie eine Doppelrolle sowohl im Glukosestoffwechsel als auch in der Muskelhypertrophie spielen. Somit legen die Studien in dieser Arbeit nahe, dass das Zusammenspiel von Skelettmuskelstoffwechsel und Hypertrophie weiter untersucht werden sollte.

Das Ziel dieser Studie war es, die Auswirkungen eines Ultramarathons auf die mediale Meniskusextrusion (MME) in gesunden Athleten zu untersuchen. Generell wird eine MME von mehr als 3 mm als pathologisch angesehen und ist ein indirektes Zeichen für einen Funktionsverlust des Meniskus. Untersucht wurde die MME mittels Ultraschall im Stehen und Liegen während eines siebentägigen Etappenlaufes in den Alpen. Dabei zeigte sich eine reversible MME von mehr als 3 mm in gesunden, symptomfreien Knien. Dies zeigt, dass der Meniskus eine enorme elastische Kapazität hat und sich kurzfristig an höhere Belastungen anpassen kann. Daher sollte der aktuelle Begriff der Meniskusextrusion nicht ausschließlich als Zeichen einer Pathologie im MRT bewertet werden. The aim oft the present study was to evaluate the influence of mountain ultramarathon running on the medial meniscus extrusion (MME) in healthy athletes. MME of more than 3 mm is seen as pathological and as an indirect sign for loss of function oft the meniscus. MME was determined in supine and standing position via ultrasound imaging during a seven day stage run in the alps. The meniscus showed a reversible MME of more than 3 mm in healthy knees. This suggests that the meniscus has viscoelastic capacities showing shortterm adaptions to high loads. Therefore the term of MME should not only be considered as a pathological sign in MRI imaging.