Modulation of PGC-1α activity as a treatment for metabolic and muscle-related diseases

Physical inactivity is a predisposing factor for various disease states including obesity, cardiovascular disease, as well as for certain types of cancer. Regular endurance exercise mediates several beneficial effects such as increased energy expenditure and improved skeletal muscle function, and has been suggested as a therapeutic strategy for both metabolic and muscle‐related disorders. "Exercise mimetic" is a collective term for compounds that can pharmacologically activate pathways which are normally induced during skeletal muscle contraction, and that could be used in the treatment of metabolic or muscle related diseases. Two such experimental "exercise mimetics" are AICAR and resveratrol, which have both been extensively studied in the context of metabolic dysfunction and muscle wasting in rodent disease models. These compounds have been postulated to activate AMP‐activated protein kinase (AMPK) and sirtuin 1 (SIRT1), respectively, in skeletal muscle, and to increase the activation of the peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α). PGC‐1α can mediate several metabolic and functional adaptations in skeletal muscle in response to physical exercise and is therefore an interesting target for the development of new "exercise mimetic" drugs

Laser-Produced Plasmas for Particle Acceleration

This thesis describes experimental studies that aim to stabilise and optimise laser-based particle accelerators. The technique is called laser wakefield acceleration, where electric fields of the order of 102 GV/m accelerate electrons to high energies (⇠102 MeV) over mm-distances in laser-produced plasmas. Among the prerequisites for this acceleration technique to produce electron beams are laser intensities higher than 1018W/cm2 and sub-ps laser-pulse durations, both of which have seen rapid development since the invention of chirped pulse amplification. The laser is focused in a gas, which instantly ionises. In the created plasma, the propagating laser pulse creates a wave, which can accelerate injected electrons. Under the right experimental conditions, the injection mechanism is automatic, and is called self-injection. The conditions required for self-injection to occur are experimentally explored and presented in the thesis. In addition to the accelerated electrons, collimated beams of x-rays, called betatron radiation, are produced during the interaction. The thesis also discusses several ways to enhance important parameters, such as relative energy spread and divergence, of the resulting particle beams, which is important for future applications. By using smart target designs, it is possible to reduce both the spectral and spatial spread of laser wakefield accelerated electrons. In the experiment where density-downramp injection was implemented, relative energy spreads as low as 1% were achieved. During the experiment when the target consisted of a gas-filled capillary, the x-ray fluence was increased by a factor of ten when compared to betatron radiation generated in a supersonic gas jet. It is also shown in the thesis that the choice of gas is important, and increased stability is achieved if hydrogen is used as target gas instead of helium

KONTRAKTUALISM OCH KONSTRUKTIVISM Om ursprungspositionens funktion i John Rawls rättviseteori

John Rawls rättviseteori har tagit stor plats i den filosofiska argumentationen de senaste trettio åren. Den teori han presenterade i A Theory of Justice 1971, innebar ett brott mot den rådande moralfilosofiska diskussionen som var starkt utilitaristiskt präglad. Den allmänna uppfattningen var att utilitarismen helt enkelt måste vara den riktiga teorin, om man bara kunde komma ifrån de kontraintuitiva inslagen som utilitarismen hade och fortfarande har

Muscle PGC-1α is required for long-term systemic and local adaptations to a ketogenic diet in mice

Low-carbohydrate/high-fat (LCHF) diets are increasingly popular dietary interventions for body weight control and as treatment for different pathological conditions. However, the mechanisms of action are still poorly understood, in particular, in long-term administration. Besides liver, brain, and heart, skeletal muscle is one of the major organs involved in the regulation of physiological and pathophysiological ketosis. We assessed the role of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in skeletal muscle of male wild-type control and PGC-1α muscle-specific knockout mice upon 12 wk of LCHF diet feeding. Interestingly, LCHF diet administration increased oxygen consumption in a muscle PGC-1α-dependent manner, concomitant with a blunted transcriptional induction of genes involved in fatty acid oxidation and impairment in exercise performance. These data reveal a new role for muscle PGC-1α in regulating the physiological adaptation to long-term LCHF diet administration

Skeletal muscle PGC-1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice

Ketone bodies (KBs) are crucial energy substrates during states of low carbohydrate availability. However, an aberrant regulation of KB homeostasis can lead to complications such as diabetic ketoacidosis. Exercise and diabetes affect systemic KB homeostasis, but the regulation of KB metabolism is still enigmatic. In our study in mice with either knockout or overexpression of the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α in skeletal muscle, PGC-1α regulated ketolytic gene transcription in muscle. Furthermore, KB homeostasis of these mice was investigated during withholding of food, exercise, and ketogenic diet feeding, and after streptozotocin injection. In response to these ketogenic stimuli, modulation of PGC-1α levels in muscle affected systemic KB homeostasis. Moreover, the data demonstrate that skeletal muscle PGC-1α is necessary for the enhanced ketolytic capacity in response to exercise training and overexpression of PGC-1α in muscle enhances systemic ketolytic capacity and is sufficient to ameliorate diabetic hyperketonemia in mice. In cultured myotubes, the transcription factor estrogen-related receptor-α was a partner of PGC-1α in the regulation of ketolytic gene transcription. These results demonstrate a central role of skeletal muscle PGC-1α in the transcriptional regulation of systemic ketolytic capacity.-Svensson, K., Albert, V., Cardel, B., Salatino, S., Handschin, C. Skeletal muscle PGC-1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice

mTORC2 sustains thermogenesis via Akt-induced glucose uptake and glycolysis in brown adipose tissue

Activation of non-shivering thermogenesis (NST) in brown adipose tissue (BAT) has been proposed as an anti-obesity treatment. Moreover, cold-induced glucose uptake could normalize blood glucose levels in insulin-resistant patients. It is therefore important to identify novel regulators of NST and cold-induced glucose uptake. Mammalian target of rapamycin complex 2 (mTORC2) mediates insulin-stimulated glucose uptake in metabolic tissues, but its role in NST is unknown. We show that mTORC2 is activated in brown adipocytes upon β-adrenergic stimulation. Furthermore, mice lacking mTORC2 specifically in adipose tissue (AdRiKO mice) are hypothermic, display increased sensitivity to cold, and show impaired cold-induced glucose uptake and glycolysis. Restoration of glucose uptake in BAT by overexpression of hexokinase II or activated Akt2 was sufficient to increase body temperature and improve cold tolerance in AdRiKO mice. Thus, mTORC2 in BAT mediates temperature homeostasis via regulation of cold-induced glucose uptake. Our findings demonstrate the importance of glucose metabolism in temperature regulation

Revealing the Compact Structure of Lactic Acid Bacterial Heteroexopolysaccharides by SAXS and DLS

Molecular structures of exopolysaccharides are required to understand their functions and the relationships between the structure and physical and rheological properties. Small-angle X-ray scattering and dynamic light scattering were used in conjunction with molecular modeling to characterize solution structures of three lactic acid bacterial heteroexopolysaccharides (HePS-1, HePS-2, and HePS-3). Values of radius of gyration <i>R</i>_G, cross-sectional radius of gyration <i>R</i>_XS, approximate length <i>L</i>, and hydrodynamic diameter were not directly proportional to the molar mass and indicated the HePSs adopted a compact coil-like rather than an extended conformation. Constrained molecular modeling of 15000 randomized HePS-1 conformers resulted in five best-fit structures with <i>R</i> factor of 3.9−4.6% revealing random coil-like structure. Φ and Ψ angle analysis of glycosidic linkages in HePS-1 structures suggests Gal<i>f</i> residues significantly influence the conformation. Ab initio scattering modeling of HePS-2 and HePS-3 gave excellent curve fittings with χ² of 0.43 and 0.34 for best-fit models, respectively, compatible with coil-like conformation. The findings disclose solution behavior of HePS relevant for their interactions with biomacromolecules, for example, milk proteins

The coactivator PGC-1α regulates skeletal muscle oxidative metabolism independently of the nuclear receptor PPARβ/δ in sedentary mice fed a regular chow diet

Aims/hypothesis: Physical activity improves oxidative capacity and exerts therapeutic beneficial effects, particularly in the context of metabolic diseases. The peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α (PGC-1α) and the nuclear receptor PPARβ/δ have both been independently discovered to play a pivotal role in the regulation of oxidative metabolism in skeletal muscle, though their interdependence remains unclear. Hence, our aim was to determine the functional interaction between these two factors in mouse skeletal muscle in vivo. Methods: Adult male control mice, PGC-1α muscle-specific transgenic (mTg) mice, PPARβ/δ muscle-specific knockout (mKO) mice and the combination PPARβ/δ mKO + PGC-1α mTg mice were studied under basal conditions and following PPARβ/δ agonist administration and acute exercise. Whole-body metabolism was assessed by indirect calorimetry and blood analysis, while magnetic resonance was used to measure body composition. Quantitative PCR and western blot were used to determine gene expression and intracellular signalling. The proportion of oxidative muscle fibre was determined by NADH staining. Results: Agonist-induced PPARβ/δ activation was only disrupted by PPARβ/δ knockout. We also found that the disruption of the PGC-1α-PPARβ/δ axis did not affect whole-body metabolism under basal conditions. As expected, PGC-1α mTg mice exhibited higher exercise performance, peak oxygen consumption and lower blood lactate levels following exercise, though PPARβ/δ mKO + PGC-1α mTg mice showed a similar phenotype. Similarly, we found that PPARβ/δ was dispensable for PGC-1α-mediated enhancement of an oxidative phenotype in skeletal muscle. Conclusions/interpretation: Collectively, these results indicate that PPARβ/δ is not an essential partner of PGC-1α in the control of skeletal muscle energy metabolism