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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.

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.

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

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.

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.

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.

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.

Resistance training promotes metabolic health and stimulates muscle hypertrophy, but the precise routes by which resistance exercise (RE) conveys these health benefits are largely unknown. Aim: To investigate how acute RE affects human skeletal muscle metabolism. Methods: We collected vastus lateralis biopsies from six healthy male untrained volunteers at rest, before the first of 13 RE training sessions, and 45 min after the first and last bouts of RE. Biopsies were analysed using untargeted mass spectrometry-based metabolomics. Results: We measured 617 metabolites covering a broad range of metabolic pathways. In the untrained state RE altered 33 metabolites, including increased 3-methylhistidine and N-lactoylvaline, suggesting increased protein breakdown, as well as metabolites linked to ATP (xanthosine) and NAD (N1-methyl-2-pyridone-5-carboxamide) metabolism; the bile acid chenodeoxycholate also increased in response to RE in muscle opposing previous findings in blood. Resistance training led to muscle hypertrophy, with slow type I and fast/intermediate type II muscle fibre diameter increasing by 10.7% and 10.4%, respectively. Comparison of post-exercise metabolite levels between trained and untrained state revealed alterations of 46 metabolites, including decreased N-acetylated ketogenic amino acids and increased beta-citrylglutamate which might support growth. Only five of the metabolites that changed after acute exercise in the untrained state were altered after chronic training, indicating that training induces multiple metabolic changes not directly related to the acute exercise response. Conclusion: The human skeletal muscle metabolome is sensitive towards acute RE in the trained and untrained states and reflects a broad range of adaptive processes in response to repeated stimulation.

Low- and moderate-intensity exercise is safe and feasible during childhood cancer treatment. The feasibility of a bout of high-intensity interval training (HIIT) in this population has not been analyzed to date. Pediatric cancer patients aged between 6 and 18 years were selected based on clinical conditions to perform ten sets of 15 s HIIT (>90% of estimated maximal heart rate (HRmax)) and 1 min active recovery on a bicycle ergometer within the first three chemotherapy courses. We assessed safety and feasibility criteria and the following parameters: perceived exertion rate, heart rate, and lactate and adrenaline concentrations. Out of 212 eligible patients, 11 patients aged 13.9 ± 3.6 years (n = 7 ♂) with lymphoma, leukemia, rhabdomyosarcoma, nephroblastoma, and synovial sarcoma completed the bout of HIIT without serious adverse events. During exercise, patients reached a BORG value maxima of 16 ± 1.2, and their heart rates rose from 78 ± 17 beats per minute (bpm) at rest to 178 ± 12 bpm after exercise (90 ± 6% estimated HRmax). The power-to-weight ratio was 2 ± 0.5 W/kg (watt per kilogram). Blood lactate concentrations increased from 1.09 ± 0.50 mmol/L (millimole per liter) at rest to 5.05 ± 1.88 mmol/L post-exercise. Our preliminary data suggest that HIIT is applicable only in a small number of childhood cancer patients. Individually adapted exercise protocols for patients with multiple impairments are needed.

Background: Face masks are an effective, non-pharmacological strategy to reduce the transmission of Severe Acute Respiratory Syndrome Coronavirus-2 and other pathogens. However, it is a challenge to keep masks sealed during exercise, as ventilation can increase from 5 to 10 L/min at rest to up to 200 L/min so that masks may be blown away from the face. To reduce leakage e.g. during exercise, a face mask was developed that is taped onto the face. The aim of this study was to investigate during a graded exercise test the effect of a taped filter mask on the perception of breathlessness, heart rate, blood lactate concentration, and oxygen saturation when compared to a surgical mask and no mask. Methods: Eight healthy trained participants (4 females), aged 24.5 ± 3.3 years performed graded exercise test until volitional exhaustion under three conditions: (1) No mask/control, (2) surgical mask or (3) taped filter mask. During these tests, we measured perception of breathlessness, heart rate, blood lactate concentration and peripheral oxygen saturation and analysed the resultant data with one or two-way repeated measures ANOVAs. We also used a questionnaire to evaluate mask comfort and analysed the data with paired t-tests. Results: When compared to wearing no mask, maximal workload was significantly reduced with a taped filter face mask by 12 ± 6% (p < 0.001) and with a surgical mask by 3 ± 6% (p > 0.05). Moreover, subjects perceive the sensation of "severe breathlessness" at a 12 ± 9% lower workload (p = 0.012) with a taped face mask, and 7 ± 13% lower workload with a surgical mask (p > 0.05) when compared to wearing no mask. Oxygen saturation at 65% of the maximal workload is 1.5% lower (p = 0.018) with a taped mask than no mask. Heart rate and blood lactate concentration are not significantly different in-between no mask, surgical mask and taped mask at any workload. When compared to wearing a surgical mask, wearing a taped filter face mask has a significantly better

The Hippo signal transduction network regulates transcription through Yap/Taz-Tead1-4 in many tissues including skeletal muscle. Whilst transgenic mice have been generated for many Hippo genes, the resultant skeletal muscle phenotypes were not always characterized. Here, we aimed to phenotype the hindlimb muscles of Hippo gene-mutated Lats1−/−, Mst2−/−, Vgll3−/−, and Vgll4+/− mice. This analysis revealed that Lats1−/− mice have 11% more slow type I fibers than age and sex-matched wild-type controls. Moreover, the mRNA expression of slow Myh7 increased by 50%, and the concentration of type I myosin heavy chain is 80% higher in Lats1−/− mice than in age and sex-matched wild-type controls. Second, to find out whether exercise-related stimuli affect Lats1, we stimulated C2C12 myotubes with the hypertrophy agent clenbuterol or the energy stress agent AICAR. We found that both stimulated Lats1 expression by 1.2 and 1.3 fold respectively. Third, we re-analyzed published datasets and found that Lats1 mRNA in muscle is 63% higher in muscular dystrophy, increases by 17–77% after cardiotoxin-induced muscle injury, by 41–71% in muscles during overload-induced hypertrophy, and by 19–21% after endurance exercise when compared to respective controls. To conclude, Lats1 contributes to the regulation of muscle fiber type proportions, and its expression is regulated by physiological and pathological situations in skeletal muscle.

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.

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.

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 trainin

Vitamin B12 deficiency has been shown to affect bone mass in rodents and negatively impact bone formation in humans. In this study using mouse models, we define the effect of B12 supplementation in the wild-type mother and B12 deficiency in a mouse genetic model (Gif−/− mice) during gestation on bone and muscle architecture and mechanical properties in the offspring. Analysis of bones from 4-wk-old offspring of the wild-type mother following vehicle or B12 supplementation during gestation (from embryonic day 0.5 to 20.5) showed an increase in bone mass caused by an isolated increase in bone formation in the B12-supplemented group compared with vehicle controls. Analysis of the effect of B12 deficiency in the mother in a mouse genetic model (Gif−/− mice) on the long bone architecture of the offspring showed a compromised cortical and trabecular bone mass, which was completely prevented by a single injection of B12 in the B12-deficient Gif−/− mothers. Biomechanical analysis of long bones of the offspring born from B12-supplemented wild-type mothers showed an increase in bone strength, and conversely, offspring born from B12-deficient Gif−/− mothers revealed a compromised bone strength, which could be rescued by a single injection of B12 in the B12-deficient Gif−/− mother. Muscle structure and function analysis however revealed no significant effect on muscle mass, structure, and grip strength of B12 deficiency or supplementation in Gif−/− mice compared with littermate controls. Together, these results demonstrate the beneficial effect of maternally derived B12 in the regulation of bone structure and function in the offspring.

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.

The secondary prevention of cardiac disease is an imperative of the medical and exercise science community. Regular exercise is a cornerstone of secondary prevention and long-term cardiac rehabilitation. Current methods of exercise prescription have been inadequately examined. This randomized controlled trial compares traditional calisthenics-based cardiac maintenance to individualized endurance-resistance exercise in 70 patients with heart disease and low exercise capacity on exercise performance, risk status, quality of life and leisure time physical activity levels., Die sekundäre Prävention von Herzerkrankungen ist ein Imperativ in der Medizin und Sportwissenschaft. Regelmäßiger Bewegung spielt einer Hauptrolle der Sekundärprävention und Kardiologische Rehabilitation. Aktuelle Methoden zum Sport sind nicht ausreichend untersucht worden. Diese randomisierte kontrollierte Studie vergleicht traditionelle Gymnastik-basierte kardiale Rehabilitation (Herzsportgruppe) zu individualisierten Ausdauer-Kraftsport bei 70 Patienten mit Herzerkrankungen und geringe Belastbarkeit auf Leistungsfähigkeit, Risikostatus, Lebensqualität und körperliche Aktivität.

Polyglutamine expansions in the huntingtin gene cause Huntington's disease (HD). Huntingtin is ubiquitously expressed, leading to pathological alterations also in peripheral organs. Variations in the length of the polyglutamine tract explain up to 70% of the age-at-onset variance, with the rest of the variance attributed to genetic and environmental modifiers. To identify novel disease modifiers, we performed an unbiased mutagenesis screen on an HD mouse model, identifying a mutation in the skeletal muscle voltage-gated sodium channel (Scn4a, termed 'draggen' mutation) as a novel disease enhancer. Double mutant mice (HD;Scn4aDgn/+) had decreased survival, weight loss and muscle atrophy. Expression patterns show that the main tissue affected is skeletal muscle. Intriguingly, muscles from HD;Scn4aDgn/+ mice showed adaptive changes similar to those found in endurance exercise, including AMPK activation, fibre type switching and upregulation of mitochondrial biogenesis. Therefore, we evaluated the effects of endurance training on HD mice. Crucially, this training regime also led to detrimental effects on HD mice. Overall, these results reveal a novel role for skeletal muscle in modulating systemic HD pathogenesis, suggesting that some forms of physical exercise could be deleterious in neurodegeneration.

Endurance training induces a partial fast‐to‐slow muscle phenotype transformation and mitochondrial biogenesis but no growth. In contrast, resistance training mainly stimulates muscle protein synthesis resulting in hypertrophy. The aim of this study was to identify signaling events that may mediate the specific adaptations to these types of exercise. Isolated rat muscles were electrically stimulated with either high frequency (HFS; 6×10 repetitions of 3 s‐bursts at 100 Hz to mimic resistance training) or low frequency (LFS; 3 h at 10 Hz to mimic endurance training). HFS significantly increased myofibrillar and sarcoplasmic protein synthesis 3 h after stimulation 5.3‐ and 2.7‐fold, respectively. LFS had no significant effect on protein synthesis 3 h after stimulation but increased UCP3 mRNA 11.7‐fold, whereas HFS had no significant effect on UCP3 mRNA. Only LFS increased AMPK phosphorylation significantly at Thr172 by ∼2‐fold and increased PGC‐1α protein to 1.3 times of control. LFS had no effect on PKB phosphorylation but reduced TSC2 phosphorylation at Thr1462 and deactivated translational regulators. In contrast, HFS acutely increased phosphorylation of PKB at Ser473 5.3‐fold and the phosphorylation of TSC2, mTOR, GSK‐3β at PKB‐sensitive sites. HFS also caused a prolonged activation of the translational regulators p70 S6k, 4E‐BP1, eIF‐2B, and eEF2. These data suggest that a specific signaling response to LFS is a specific activation of the AMPK‐PGC‐1α signaling pathway which may explain some endurance training adaptations. HFS selectively activates the PKB‐TSC2‐mTOR cascade causing a prolonged activation of translational regulators, which is consistent with increased protein synthesis and muscle growth. We term this behavior the “AMPK‐PKB switch.” We hypothesize that the AMPK‐PKB switch is a mechanism that partially mediates specific adaptations to endurance and resistance training, respectively.

Endurance training induces a partial fast‐to‐slow muscle phenotype transformation and mitochondrial biogenesis but no growth. In contrast, resistance training mainly stimulates muscle protein synthesis resulting in hypertrophy. The aim of this study was to identify signaling events that may mediate the specific adaptations to these types of exercise. Isolated rat muscles were electrically stimulated with either high frequency (HFS; 6×10 repetitions of 3 s‐bursts at 100 Hz to mimic resistance training) or low frequency (LFS; 3 h at 10 Hz to mimic endurance training). HFS significantly increased myofibrillar and sarcoplasmic protein synthesis 3 h after stimulation 5.3‐ and 2.7‐fold, respectively. LFS had no significant effect on protein synthesis 3 h after stimulation but increased UCP3 mRNA 11.7‐fold, whereas HFS had no significant effect on UCP3 mRNA. Only LFS increased AMPK phosphorylation significantly at Thr172 by ∼2‐fold and increased PGC‐1α protein to 1.3 times of control. LFS had no effect on PKB phosphorylation but reduced TSC2 phosphorylation at Thr1462 and deactivated translational regulators. In contrast, HFS acutely increased phosphorylation of PKB at Ser473 5.3‐fold and the phosphorylation of TSC2, mTOR, GSK‐3β at PKB‐sensitive sites. HFS also caused a prolonged activation of the translational regulators p70 S6k, 4E‐BP1, eIF‐2B, and eEF2. These data suggest that a specific signaling response to LFS is a specific activation of the AMPK‐PGC‐1α signaling pathway which may explain some endurance training adaptations. HFS selectively activates the PKB‐TSC2‐mTOR cascade causing a prolonged activation of translational regulators, which is consistent with increased protein synthesis and muscle growth. We term this behavior the “AMPK‐PKB switch.” We hypothesize that the AMPK‐PKB switch is a mechanism that partially mediates specific adaptations to endurance and resistance training, respectively.

Udgivelsesdato: 2002-Dec, Activation of either the calcineurin or the extracellular signal-regulated kinase (ERK1/2) pathway increases the percentage of slow fibres in vivo suggesting that both pathways can regulate fibre phenotypes in skeletal muscle. We investigated the effect of calcineurin blockade with cyclosporin A and mitogen-activated protein kinase kinase (MEK1/2) blockade with U0126 upon myosin heavy chain (MHC) isoform mRNA levels and activities of metabolic enzymes after 1 day, 3 days and 7 days of treatment in primary cultures of spontaneously twitching rat skeletal muscle. U0126 treatment significantly decreased MHC Ibeta mRNA levels and significantly increased MHC IIX, MHC IIB, embryonal MHC and perinatal MHC mRNA levels when compared to control. In addition, U0126 treatment significantly increased lactate dehydrogenase, creatine kinase, hexokinase, malate dehydrogenase and beta-hydroxyacyl-CoA dehydrogenase activities above control values while a significant reduction in the percentage of pyruvate dehydrogenase in the active form was also observed. Calcineurin blockade significantly decreased both MHC Ibeta and embryonal mRNA levels below control and significantly increased MHC IIX mRNA levels. Significant increases in the activities of both lactate dehydrogenase and creatine kinase above control values were also seen following cyclosporin A treatment. In conclusion, the results suggest that calcineurin upregulates slow-fibre genes and suppresses fast-fibre genes. Similarly, the ERK1/2 pathway upregulates slow-fibre MHC and suppresses fast-fibre MHC isoforms. However, the effect on enzyme activities is not fibre-type specific. The effect of U0126 on the percentage of pyruvate dehydrogenase in the active form suggests that the ERK1/2 pathway may also be involved in regulation of the phosphorylation state of this enzyme.

Udgivelsesdato: 2002-Dec, Activation of either the calcineurin or the extracellular signal-regulated kinase (ERK1/2) pathway increases the percentage of slow fibres in vivo suggesting that both pathways can regulate fibre phenotypes in skeletal muscle. We investigated the effect of calcineurin blockade with cyclosporin A and mitogen-activated protein kinase kinase (MEK1/2) blockade with U0126 upon myosin heavy chain (MHC) isoform mRNA levels and activities of metabolic enzymes after 1 day, 3 days and 7 days of treatment in primary cultures of spontaneously twitching rat skeletal muscle. U0126 treatment significantly decreased MHC Ibeta mRNA levels and significantly increased MHC IIX, MHC IIB, embryonal MHC and perinatal MHC mRNA levels when compared to control. In addition, U0126 treatment significantly increased lactate dehydrogenase, creatine kinase, hexokinase, malate dehydrogenase and beta-hydroxyacyl-CoA dehydrogenase activities above control values while a significant reduction in the percentage of pyruvate dehydrogenase in the active form was also observed. Calcineurin blockade significantly decreased both MHC Ibeta and embryonal mRNA levels below control and significantly increased MHC IIX mRNA levels. Significant increases in the activities of both lactate dehydrogenase and creatine kinase above control values were also seen following cyclosporin A treatment. In conclusion, the results suggest that calcineurin upregulates slow-fibre genes and suppresses fast-fibre genes. Similarly, the ERK1/2 pathway upregulates slow-fibre MHC and suppresses fast-fibre MHC isoforms. However, the effect on enzyme activities is not fibre-type specific. The effect of U0126 on the percentage of pyruvate dehydrogenase in the active form suggests that the ERK1/2 pathway may also be involved in regulation of the phosphorylation state of this enzyme.

Objective. To analyse the heterogeneity at the single-cell level of human mesenchymal progenitor cells from SM. Methods. Cell populations were enzymatically released from the knee joint synovium of adult human individuals. Single cell-derived clonal populations were obtained by limiting dilution and serially passaged to determine growth rates. Phenotypic analysis was carried out by flow cytometry. Replicative senescence was assessed by the senescence-associated β-galactosidase staining. Telomere lengths were determined semiquantitatively by Southern blotting. Telomerase activity was measured using a real-time quantitative telomerase repeat amplification procedure. Culture-expanded clonal populations were subjected to in vitro differentiation assays to investigate their mesenchymal multipotency. Results. The 50 clones analysed displayed wide variations in the proliferation rates, even within the same donor sample. The time taken to reach 20 population doublings ranged from 44 to 130 days. The phenotype of the clones tested was compatible with that of mesenchymal stem cells. Mean telomere lengths ranged from 5.2 to 10.9 kb with positive linear trend with telomerase activity, but no correlation with proliferative rates or cell senescence. All clones tested were capable of chondrogenic and osteogenic differentiation, though with large variability in potency. In contrast, only 30% of the clones were adipogenic. Conclusions. We report for the first time the co-existence, within the synovium, of progenitor cell subsets with distinct mesenchymal differentiation potency. Our findings further emphasize the need for strategies to purify cell populations with the clinically desired tissue formation potentials