<p>Insulin as well as glucagon are important hormones in maintaining glucose homeostasis and regulating the metabolism in the body. Insulin receptors (IR) are transmembrane receptors that promote a signal transduction when activated by insulin. This can for example cause an increased influx of glucose into the cell performed by so called glucose transporters (GLUTs). These membrane proteins facilitate the transport of glucose from the blood into the cells, so the cell always has a constant supply of energy. Peroxisome proliferator-activated receptors (PPAR) are nuclear fatty acid receptors. They are activated by lipids and regulate fatty acid transcription. PPARδ/β is located in skeletal muscle and can promote fatty acid catabolism as well as cause a switch in fuel preference from glucose to fatty acids. It has been suggested that ligands for PPARδ could act as insulin sensitizers. The PPARγ coactivator-1α can increase mitochondrial content in skeletal muscle if over expressed. The same is true for endurance exercise.</p><p>Hormones released from adipose tissue can cause hyperphagia<strong> </strong>and obesity if over- or under expressed. They can also work in the opposite way by decreasing appetite with weight loss as an effect. Impaired signalling or dysfunctional receptor can cause insulin resistance, obesity and diabetes. Lipolysis occurs in adipose tissues and is conducted by three enzymes, namely adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL). There are some factors that can increase lipolysis such as caffeine, a low glycemic index, high protein intake and training.</p><p>The enzyme PEPCK is involved in the gluconeogensis in the liver and kidney cortex, and also in the glyceroneogenesis in the liver, as well as in brown and white adipose tissue. When overexpressed in skeletal muscle the enzyme increases the muscle activity. The overexpression of the enzyme did promote the β-oxidation as energy source for the muscles during exercise, instead of muscle glycogen as fuel.</p><p>The processes of protein synthesis and breakdown are together called protein turnover. Muscle grows when synthesis is greater than breakdown, and withers if breakdown exceeds the level of synthesis. Acute effects of training is catabolic, but long time exercise causes however an increased protein synthesis. Leucine, an essential amino acid, has an important role in the initiation phase of translation. Glutamine is probably important in the regulation of muscle protein synthesis and breakdown. Together with glutamate, aspartate and asparagine, these are responsible for the amino acid metabolism that occurs in the muscles. Protein synthesis reaches its maximum in the recovery phase after intense training.</p>

Insulin as well as glucagon are important hormones in maintaining glucose homeostasis and regulating the metabolism in the body. Insulin receptors (IR) are transmembrane receptors that promote a signal transduction when activated by insulin. This can for example cause an increased influx of glucose into the cell performed by so called glucose transporters (GLUTs). These membrane proteins facilitate the transport of glucose from the blood into the cells, so the cell always has a constant supply of energy. Peroxisome proliferator-activated receptors (PPAR) are nuclear fatty acid receptors. They are activated by lipids and regulate fatty acid transcription. PPARδ/β is located in skeletal muscle and can promote fatty acid catabolism as well as cause a switch in fuel preference from glucose to fatty acids. It has been suggested that ligands for PPARδ could act as insulin sensitizers. The PPARγ coactivator-1α can increase mitochondrial content in skeletal muscle if over expressed. The same is true for endurance exercise. Hormones released from adipose tissue can cause hyperphagia and obesity if over- or under expressed. They can also work in the opposite way by decreasing appetite with weight loss as an effect. Impaired signalling or dysfunctional receptor can cause insulin resistance, obesity and diabetes. Lipolysis occurs in adipose tissues and is conducted by three enzymes, namely adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL). There are some factors that can increase lipolysis such as caffeine, a low glycemic index, high protein intake and training. The enzyme PEPCK is involved in the gluconeogensis in the liver and kidney cortex, and also in the glyceroneogenesis in the liver, as well as in brown and white adipose tissue. When overexpressed in skeletal muscle the enzyme increases the muscle activity. The overexpression of the enzyme did promote the β-oxidation as energy source for the muscles during exercise, instead of muscle glycogen as fuel. The processes of protein synthesis and breakdown are together called protein turnover. Muscle grows when synthesis is greater than breakdown, and withers if breakdown exceeds the level of synthesis. Acute effects of training is catabolic, but long time exercise causes however an increased protein synthesis. Leucine, an essential amino acid, has an important role in the initiation phase of translation. Glutamine is probably important in the regulation of muscle protein synthesis and breakdown. Together with glutamate, aspartate and asparagine, these are responsible for the amino acid metabolism that occurs in the muscles. Protein synthesis reaches its maximum in the recovery phase after intense training.

Diss. (sammanfattning) Umeå : Sveriges lantbruksuniv., 2007. / Härtill 3 uppsatser.

Diss. (sammanfattning). Uppsala : Sveriges lantbruksuniv., 2003. / Härtill 6 uppsatser.

The development of lean body mass (LBM) is closely linked to protein feeding. Along with resistance exercise protein feeding, or amino acid provision, stimulate muscle protein synthesis (MPS). Repeated stimulation of MPS above protein breakdown results in lean mass accretion. Many athletes aim to build or maintain LBM. The aim of this thesis was to better understand the relationship between LBM and protein feeding in trained individuals. This aim was studied in the applied setting and at whole body, muscle and molecular level. Chapter 2 revealed differences in total body mass and LBM between young rugby union players competing at different playing standards. Protein consumption was higher in players that played at a higher standard. The protein consumption of players at both playing standards was higher than current protein recommendations for athletes. The Under 20 (U20) rugby union players in Chapter 3 also consumed more protein than current recommendations state. Their dietary habits changed depending on their environment and they consumed more protein while in Six Nations (6N) camp compared with out of camp. Also, there were changes in dietary habits for individuals, however, those changes did not occur at the group level. Using the camp as an education tool for good nutrition habits could be advantageous. As a group, rugby union players’ body composition did not change from pre to post a 6N tournament. However, there was individual variation, which could be meaningful for the individual players. We provide evidence suggesting that in elite sport, athletes should be considered as individuals as well as part of a group if appropriate. The protein ribosomal protein S6 kinase 1 (p70S6K1) is part of the mammalian target of rapamycin complex 1 (mTORC1) pathway, which regulates MPS. The response of p70S6K1 activity was 62% greater following resistance exercise coupled with protein feeding compared with protein feeding alone in Chapter 3. P70S6K1 activity explained a small amount of the variation in previously published MPS data. The activity of the signalling protein p70S6K1 was unchanged in response to different doses of whey protein in Chapter 4 and 5. These data suggest that resistance exercise is a larger stimulus of p70S6K1 activity and when manipulating aspects of protein feeding p70S6K1 activation may be a limited measure. Consumption of 40 g of whey protein stimulated myofibrillar MPS to a greater extent than 20 g after a bout of whole body resistance exercise. The amount of LBM that the trained individual possessed did not influence this observed response. These data suggest that the amount of muscle mass exercised may influence the amount of protein required to increase MPS stimulation. For those engaging in whole body resistance exercise 20 g of protein is not sufficient to maximally stimulate MPS. The athletes in Chapters 2 and 3 of this thesis consumed more protein than current recommendations that do not take into account whole body exercise. Current post-exercise protein recommendations may no longer be optimal given this new information. Future work should directly investigate the MPS response to protein ingestion following resistance exercise engaging different amounts of muscle mass in well trained and elite populations. Identifying the protein dose required for maximal stimulation of MPS following whole body exercise would be an informative area of future research.

Although the long-term therapeutic benefits of exercise are indisputable, contractile activity may induce divergent adaptations in insulin-resistant vs. insulin-sensitive skeletal muscle. The purpose of this study was to elucidate if the anabolic response following resistance exercise (RE) is altered in myocellular sub-fractions in the face of insulin resistance. Lean (Fa/?) and obese (fa/fa) Zucker rats were assigned to sedentary and RE groups and engaged in either cage rest or four lower-body RE sessions over an 8-d period. Despite obese Zucker rats having significantly smaller hindlimb muscles when compared to age-matched lean rats, basal 24-h fractional synthesis rates (FSR) of mixed protein pools were near normal in distally located muscle groups (gastrocnemius, plantaris, and soleus) and even augmented in those located more proximally (P<0.05; quadriceps). Although 2 x 2 ANOVA indicated a significant main effect of phenotype on mixed FSR in gastrocnemius and soleus (P < 0.05), phenotypic differences were partially accounted for by an exercise effect in the lean phenotype. Interestingly, obese rats exhibited a significant suppression of myofibrillar FSR compared to their lean counterparts (P<0.05; gastrocnemius), while synthesis rates of mitochondrial and cytosolic proteins were normal (gastrocnemius and quadriceps), suggesting a mechanism whereby translation of specific mRNA pools encoding for metabolic enzymes may be favored over other transcripts (e.g., contractile proteins) to cope with nutrient excess in the insulin-resistant state. Immunoblotting of the cytosolic fraction in gastrocnemius muscle indicated an augmented phosporylation of eIF4EBP1 (+ 9%) and p70s6k (+85%) in obese vs. lean rats, but a more potent baseline inhibition of polypeptide-chain elongation as evidenced by an increased phospho/total ratio of eEF2 (+78%) in the obese phenotype. Resistance exercise did not improve synthesis rates of myofibrillar, cytosolic, or mitochondrial proteins to the same extent in obese vs. lean rats, suggesting a desensitization to contractile-induced anabolic stimuli in the insulin-resistant state. We conclude that insulin resistance has diverse effects on protein metabolism, which may vary between muscle groups depending on fiber type distribution, location along the proximodistal body axis, and myocellular sub-fraction, and may blunt the anabolic response to voluntary resistance exercise.

La méthylation de l’uridine sur son carbone 5 est apparue au cours de l’évolution sous plusieurs formes. Tout d’abord, les thymidylate synthases permettent la synthèse de novo du dTMP, un précurseur essentiel de l’ADN des trois règnes du vivant. Deux familles de thymidylate synthases sont connues à ce jour : ThyA et la flavo-enzyme ThyX, codées par des gènes hétérologues et ayant des structures et mécanismes réactionnels radicalement différents. En outre, cette méthylation de l’uridine est apparue (probablement plus tard) sous forme de modifications post-transcriptionnelles des ARNt et ARNr. Cette thèse vise à questionner les contraintes évolutives ayant menés indépendament à ces quatres types de méthylation de l’uridine.Une première partie décrit l’identification d’une voie métabolique permetant la complémentation du phénotype d’auxotrophie pour la thymidine par des analogues nucléotidiques chez Escherichia coli. Une approche de biologie synthétique en vue d’établir une voie alternative de biosynthèse du thymidylate a aussi été mise en œuvre. Une technique de sélection de gènes de complémentation du phénotype d’auxotrophie pour la thymidine, issus de mutagénèse aléatoire, a pu être développée. Dans une seconde partie, des études biochimiques et sppectroscopiques ont été réalisées sur la méthyle-transférase flavine-dépendante TrmFO, responsable de la méthylation post-transciptionnelle de l’uridine 54 des ARNt de certains microorganismes.L’implication de certains résidus dans la fixation du substrat a pu être déterminée d’une part, et certains intermédiaires réactionnels potentiels ont été caractérisés spectralement d’autre part. Ces dernières observations s’appuient, en outre, sur des études en cours de spectroscopie résolue en temps et des simulations de dynamique moléculaire afin de mieux comprendre les flavoprotéines en général et les méthyle transférases flavine-dépendantes en particulier. / Enzymes catalyzing the methylation of uridine at its carbon 5 position have appeared independently in different forms across evolution. Thymidylate synthases ThyA and the flavoprotein ThyX catalyze the de novo synthesis of dTMP, an essential DNA precursor in the three domains of life. They are encoded by heterologous genes and have drastically different structures and reaction mechanisms. On the other hand, this uridine methylation is also performed by tRNA and rRNA post-transcriptional modification enzymes.This thesis assesses the question of the evolutionary constraints that have led independently to four kinds of uridine methylation. The first part describes the identification of a metabolic pathway allowing the complementation of thymidine auxotrophy by non-natural nucleotide analogs in Escherichia coli. A synthetic biology approach, aiming to establish an alternative pathway for thymidylate biosynthesis, was also implemented and a selection strategy for thymidine auxotrophy-complementing genes, could be developed.In a second part, biochemical and spectral studies where realised on the flavin-dependent methyltransferase TrmFO, responsible for the post-transcriptional methylation of uridine at the invariant position 54 of tRNA in several microorganisms. The involvement of specific amino acid residues in substrate fixation and in stabilization of potential reaction intermediates was demonstrated. Their spectral characterization supports previously proposed reaction schemes for flavin-dependent thymidylate forming enzymes. These observations are currently being pursued by parallel approaches combining time-resolved spectroscopy and molecular dynamics simulations, aiming to further our understanding of how flavin mediates the transfer of carbon molecules from folate to uracil rings.

本論文是以有生命的開放系統的觀點來描述與解釋組織內的資訊、知識、及智慧財產的整體作為一個知識體的存在與演化方式，以有別於目前許多學者以智慧資本偏向靜態觀點對於組織的知識的存在方式的描述。以系統科學與生理學及非線性的觀點來看待組織之內的知識價值累積過程，以有別於 Nonaka與 Takeuchi等以偏向機械論的觀點來看待組織內的知識形成過程。 本論文提出一個組織的知識系統理論，描述每一個存活著的經濟「組織」都有一個它賴以維生的「知識系統」，稱為「組織知識系統」。組織在處理資訊的同時，組織身實體部份發生的改變，其實是它的知識系統的知識價值新陳代謝發生在先所造成。理論的發展從Galarbith(1971)的組織處理資訊的方程式出發，以量子物理學家Schrödinger（1944）提出生物以負熵維生的理論及Wiener（1948）提出資訊是負熵的理論為依據，將Prigogine的耗散結構方程式轉換，得到「組織知識系統」是知識價值的「蓄積結構」的方程式。透過生理系統與知識系統的類比說明組織知識系統的知識價值的改變是其內部的同化作用與異化作用的總合。經由非線性模擬方程式的設計與模擬參數的組合選擇，模擬知識系統的知識價值在不同生命週期的變化，來說明知識系統的存在與演化方式。本論文研究的貢獻包括： 一、 在理論發展上，成功的將Galarbith的組織處理資訊的理論、Prigogine的耗散結構理論、Schrödinger的生物以負熵為食的理論及Wiener資訊等於負熵的理論，此四個理論整合為本論文的知識系統理論。 二、 在認識論的層次上，以活的開放系統的觀點描述組織裡的整個知識體的存在與演化方式。本體論的層次上，透過系統模擬及生理系統類比使知識系統的本體存在方式在認識論給出之後能被確立本體的存在。在方法論的層次上，由知識價值蓄積結構方程與非線性方程式的建立與聯結，使知識系統的知識價值在生命週期之中的變化的描述可被數量化。 三、 以知識系統內的新陳代謝類比清楚的說明整個知識系統的知識價值蓄積在不同生命週期階段的改變，是同化作用與異化作用的共同結果。 四、 知識系統的新陳代謝現象可由一個簡潔的非線性疊代方程式清楚說明，使以模擬來驗證直覺成為可能。 關鍵字：知識系統、耗散結構、蓄積結構、新陳代謝、同化作用、異化作用。 / This dissertation applies and extends a living open system view of organization in description and interpretation of being and becoming of knowledge body of organization，which is a metaphysical part of organization and constituted by information、knowledge and intellectual properties as elements of a living open system。This study provides a dynamic view of existence of knowledge in organization which is to critic and differentiate with contemplated intellectual capital theory with tendency toward a static aspect。System science approach、physiological analogy and non-linear model were applied in this study for describing the process of preservation of knowledge value in organization which is different with previous studies of Nonaka and Takeuchi with tendency toward the mechanic aspect of knowledge formation process in organization。 A theory of knowledge system of organization was developed which claimed every living economic organization who want to survive must rely on its knowledge system survive first。 Organization processes information，its physical part also is changing at the same time which is driving by knowledge value metabolism happened first in its knowledge system。To build the theory，a information processing theory (Galarbith, 1971)、a theoretical view of organism rely on feeding on negative entropy to survive (Schrödinger, 1944) and a theory of information is equal to negative entropy (Wiener, 1948) were integrated for converting the equation of dissipative structure theory of Prigogine to a equation of preservative structure theory of knowledge value of organization。On the analogy of knowledge system as a physiological system to interpret knowledge value change of knowledge system is the net of its system internal new knowledge value formation (termed anabolism) and existing knowledge value decay (termed catabolism)。Then this study uses non-linear equations to build mathematical models and selects different sets of simulation parameters to simulate knowledge value change in different life cycle stages of knowledge system to demonstrate being and becoming of knowledge system。The contributions of this study are： 1.On theory building，theories of Galarbith, Schrödinger, Wiener and Prigogine were successfully integrated into a theory of knowledge system of organization。 2. On the epistemological level，a living open system view was adopted to clearly describe the being and becoming of knowledge system of organization。On the ontological level，the physiological system analogy and non-linear system simulation make it is able to ensure the existence of knowledge system of organization。On the methodology level，the equation of preservation of knowledge value of knowledge system of organization was constructed and extended to linkage with non linear equations, make it feasible to qualitatively describe the knowledge value change in the whole life cycle of knowledge system of organization。 3. With an analogy of metabolism of physiological system and knowledge system of organization，it can be clearly explained that the knowledge value change of knowledge system is its sum of the system internal effect of anabolism and catabolism。 4. Metabolism of knowledge system can be clearly described via a concise non-linear equation，which makes it feasible to prove intuition by mathematical simulation。 Key Words：Knowledge System、Dissipative Structure、Preservative Structure、Metabolism、Anabolism、Catabolism。

Les muscles permettent de générer force et mouvements et ont des fonctions métaboliques importantes. Mon travail a consisté à caractériser le rôle et les mécanismes d’actions des androgènes dans le muscle strié. Nous avons montré que l’ablation du récepteur des androgènes dans les myofibres n’affecte pas la masse musculaire car à la fois les voies anaboliques (IGF1) et cataboliques (myostatine) sont dérégulées. Cependant, l’absence du récepteur dans les myofibres diminue l’hypertrophie musculaire induite par une surcharge mécanique et limite l’atrophie induite par les glucocorticoïdes. Son ablation augmente également l’autophagie, entrainant une déstructuration des sarcomères, conduisant à une diminution de la force musculaire. De plus, sa délétion diminue la vitesse d’absorption du glucose lors d’une surcharge glucidique. Le récepteur des androgènes dans les myofibres régule donc la masse et la force musculaire, ainsi que l’import du glucose. / Muscles generate strength and movement, and have important metabolic functions. The aim of my work was to characterize the role and mechanisms of action of androgen receptor in skeletal muscle. We show that ablation of the androgen receptor in skeletal muscle myofibers does not affect muscle mass as both anabolic (IGF1) and catabolic pathways (myostatin) are deregulated. However, the absence of this receptor in myofibers decreases muscle hypertrophy induced by mechanical overload and limits glucocorticoids-induced muscle atrophy. Its ablation also increases autophagy, leading to sacromeres destructuration, resulting in decreased muscle strength. Moreover, its deletion reduced the rate of glucose absorption during a glucidic overload. Thus, myofibres androgen receptor regulates muscle mass and strength, as well as glucose import.