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BACKGROUND: Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for anabolic reactions. We hypothesize that a similar metabolic remodelling occurs during skeletal muscle hypertrophy. METHODS: We used mass spectrometry in hypertrophying C2C12 myotubes in vitro and plantaris mouse muscle in vivo and assessed metabolomic changes and the incorporation of the [U-13C6]glucose tracer. We performed enzyme inhibition of the key serine synthesis pathway enzyme phosphoglycerate dehydrogenase (Phgdh) for further mechanistic analysis and conducted a systematic review to align any changes in metabolomics during muscle growth with published findings. Finally, the UK Biobank was used to link the findings to population level. RESULTS: The metabolomics analysis in myotubes revealed insulin-like growth factor-1 (IGF-1)-induced altered metabolite concentrations in anabolic pathways such as pentose phosphate (ribose-5-phosphate/ribulose-5-phosphate: +40%; P = 0.01) and serine synthesis pathway (serine: -36.8%; P = 0.009). Like the hypertrophy stimulation with IGF-1 in myotubes in vitro, the concentration of the dipeptide l-carnosine was decreased by 26.6% (P = 0.001) during skeletal muscle growth in vivo. However, phosphorylated sugar (glucose-6-phosphate, fructose-6-phosphate or glucose-1-phosphate) decreased by 32.2% (P = 0.004) in the overloaded muscle in vivo while increasing in the IGF-1-stimulated myotubes in vitro. The systematic review revealed that 10 metabolites linked to muscle hypertrophy were directly associated with glycolysis and its interconnected anabolic pathways. We demonstrated that labelled carbon from [U-13C6]glucose is increasingly incorporated by ~13% (P = 0.001) into the non-essential amino acids in hypertrophying myotubes, which is accompanied by an increased depletion of media serine (P = 0.006). The inhibition of Phgdh suppressed muscle protein synt

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.

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 Arbe

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.

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. To, 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

Human metabolism is highly variable. At one end of the spectrum, defects of enzymes, transporters, and metabolic regulation result in metabolic diseases such as diabetes mellitus or inborn errors of metabolism. At the other end of the spectrum, favorable genetics and years of training combine to result in physiologically extreme forms of metabolism in athletes. Here, we investigated how the highly glycolytic metabolism of sprinters, highly oxidative metabolism of endurance athletes, and highly anabolic metabolism of natural bodybuilders affect their serum metabolome at rest and after a bout of exercise to exhaustion. We used targeted mass spectrometry-based metabolomics to measure the serum concentrations of 151 metabolites and 43 metabolite ratios or sums in 15 competitive male athletes (6 endurance athletes, 5 sprinters, and 4 natural bodybuilders) and 4 untrained control subjects at fasted rest and 5 minutes after a maximum graded bicycle test to exhaustion. The analysis of all 194 metabolite concentrations, ratios and sums revealed that natural bodybuilders and endurance athletes had overall different metabolite profiles, whereas sprinters and untrained controls were more similar. Specifically, natural bodybuilders had 1.5 to 1.8-fold higher concentrations of specific phosphatidylcholines and lower levels of branched chain amino acids than all other subjects. Endurance athletes had 1.4-fold higher levels of a metabolite ratio showing the activity of carnitine-palmitoyl-transferase I and 1.4-fold lower levels of various alkyl-acyl-phosphatidylcholines. When we compared the effect of exercise between groups, endurance athletes showed 1.3-fold higher increases of hexose and of tetradecenoylcarnitine (C14:1). In summary, physiologically extreme metabolic capacities of endurance athletes and natural bodybuilders are associated with unique blood metabolite concentrations, ratios, and sums at rest and after exercise. Our results suggest that long-term specific training

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.

Background Advanced footwear technology improves average running economy compared with racing flats in sub-elite athletes. However, not all athletes benefit as performance changes vary from a 10% drawback to a 14% improvement. The main beneficiaries from such technologies, world-class athletes, have only been analyzed using race times. Objective The aim of this study was to measure running economy on a laboratory treadmill in advanced footwear technology compared to a traditional racing flat in world-class Kenyan (mean half-marathon time: 59:30 min:s) versus European amateur runners. Methods Seven world-class Kenyan and seven amateur European male runners completed a maximal oxygen uptake assessment and submaximal steady-state running economy trials in three different models of advanced footwear technology and a racing flat. To confirm our results and better understand the overall effect of new technology in running shoes, we conducted a systematic search and meta-analysis. Results Laboratory results revealed large variability in both world-class Kenyan road runners, which ranged from a 11.3% drawback to a 11.4% benefit, and amateur Europeans, which ranged from a 9.7% benefit to a 1.1% drawback in running economy of advanced footwear technology compared to a flat. The post-hoc meta-analysis revealed an overall significant medium benefit of advanced footwear technology on running economy compared with traditional flats. Conclusions Variability of advanced footwear technology performance appears in both world-class and amateur runners, suggesting further testing should examine such variability to ensure validity of results and explain the cause as a more personalized approach to shoe selection might be necessary for optimal benefit.

Background: Patients with critical illness can lose more than 15% of muscle mass in one week, and this can have long-term detrimental effects. However, there is currently no synthesis of the data of intensive care unit (ICU) muscle wasting studies, so the true mean rate of muscle loss across all studies is unknown. The aim of this project was therefore to systematically synthetise data on the rate of muscle loss and to identify the methods used to measure muscle size and to synthetise data on the prevalence of ICU-acquired weakness in critically ill patients. Methods: We conducted a systematic literature search of MEDLINE, PubMed, AMED, BNI, CINAHL, and EMCARE until January 2022 (International Prospective Register of Systematic Reviews [PROSPERO] registration: CRD420222989540. We included studies with at least 20 adult critically ill patients where the investigators measured a muscle mass-related variable at two time points during the ICU stay. We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and assessed the study quality using the Newcastle-Ottawa Scale. Results: Fifty-two studies that included 3251 patients fulfilled the selection criteria. These studies investigated the rate of muscle wasting in 1773 (55%) patients and assessed ICU-acquired muscle weakness in 1478 (45%) patients. The methods used to assess muscle mass were ultrasound in 85% (n = 28/33) of the studies and computed tomography in the rest 15% (n = 5/33). During the first week of critical illness, patients lost every day -1.75% (95% CI -2.05, -1.45) of their rectus femoris thickness or -2.10% (95% CI -3.17, -1.02) of rectus femoris cross-sectional area. The overall prevalence of ICU-acquired weakness was 48% (95% CI 39%, 56%). Conclusion: On average, critically ill patients lose nearly 2% of skeletal muscle per day during the first week of ICU admission.

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.

Exercise improves the insulin sensitivity of glucose uptake in skeletal muscle. Due to that, exercise has become a cornerstone treatment for type 2 diabetes mellitus (T2DM). The mechanisms by which exercise improves skeletal muscle insulin sensitivity are, however, incompletely understood. We conducted a systematic review to identify all genes whose gain or loss of function alters skeletal muscle glucose uptake. We subsequently cross-referenced these genes with recently generated data sets on exercise-induced gene expression and signaling. Our search revealed 176 muscle glucose-uptake genes, meaning that their genetic manipulation altered glucose uptake in skeletal muscle. Notably, exercise regulates the expression or phosphorylation of more than 50% of the glucose-uptake genes or their protein products. This included many genes that previously have not been associated with exercise-induced insulin sensitivity. Interestingly, endurance and resistance exercise triggered some common but mostly unique changes in expression and phosphorylation of glucose-uptake genes or their protein products. Collectively, our work provides a resource of potentially new molecular effectors that play a role in the incompletely understood regulation of muscle insulin sensitivity by exercise.

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.

Diese Dissertation zeigt die Entwicklung und Validierung tragbarer Systeme zur nicht-invasiven Ermittlung wichtiger Vitalparameter für Sport und Gesundheit, um Sportler vor gesundheitsschädlichen Situationen zu schützen. Die Körperkerntemperatur und der Wasserhaushalt spielen in warmen Bedingungen eine übergeordnete, hitzebestimmte und leistungsbestimmende Rolle. In der Arbeit werden Zusammenhänge zwischen invasiven und nicht-invasiven Messungen dieser Parameter untersucht, anschließend ein Prototyp aufgebaut und validiert. Zusätzlich werden Faktoren der Mensch-Maschine-Umwelt Interaktion betrachtet und Ansätze für die Anwendbarkeit von Wearables in Sport und Gesundheit geliefert., This dissertation shows the development and validation of wearable systems for non-invasive assessment of important vital parameters in sports and health care to protect the athlete from harmful events. Body core temperature and hydration are heat relevant and performance determinating parameters, which play a superior role in hot environements. This work analyzes relationships between invasive and non-invasive measurments of these variables. Based on the results a prototype was designed, build up and validated. Additionally, important factors of human-machine-environment-interaction are considered and provide attempts for applications of wearables in sports and health care.

In 1924, Otto Warburg asked “How does the metabolism of a growing tissue differ from that of a non-growing tissue?” Currently, we know that proliferating healthy and cancer cells reprogramme their metabolism. This typically includes increased glucose uptake, glycolytic flux and lactate synthesis. A key function of this reprogramming is to channel glycolytic intermediates and other metabolites into anabolic reactions such as nucleotide-RNA/DNA synthesis, amino acid-protein synthesis and the synthesis of, for example, acetyl and methyl groups for epigenetic modification. In this review, we discuss evidence that a hypertrophying muscle similarly takes up more glucose and reprogrammes its metabolism to channel energy metabolites into anabolic pathways. We specifically discuss the functions of the cancer-associated enzymes phosphoglycerate dehydrogenase and pyruvate kinase muscle 2 in skeletal muscle. In addition, we ask whether increased glucose uptake by a hypertrophying muscle explains why muscularity is often negatively associated with type 2 diabetes mellitus and obesity.