Background: Physical activity (PA) can impact chronic pain positively but it can be affected by both facilitating and hindering, e.g. motivation and self-efficacy (S-E).  Aim: Through self-rated causal networks the study explored which factors adults with chronic pain rated as facilitating for PA, their PA level and which types of physical activities they engaged in. Relationships were investigated between S-E and PA and whether the causal networks differed between participants who met the recommendations for PA or not.   Method: A comparative, correlating and descriptive pilot-study with a cross-sectional design was used and conducted via online questionnaires using Perceived Causal Networks. Results: There were two common items, Conditions and Thoughts about pain, that significantly facilitated the engagement in both intended exercise and everyday exercise. As everyday exercise the respondents mostly engaged in walks, household- and gardening chores and stair climbing. For intended exercise they mostly did walks, home exercise and swimming/water gymnastics. The majority of respondents (52%) had a self-rated PA-level that corresponded to a “higher level”. No difference emerged when comparing facilitating factors between those who met the recommendations for PA and those who didn´t. There were moderate correlations between S-E and activity minutes (r=0.443, p=0.002) as well as S-E and intended exercise (r=0.418, p=0.003). There was no statistically significant correlation between S-E and everyday PA (r=0.257, p=0.078).  Conclusion: Although there was a correlation between S-E and activity minutes and physical exercise, further research is required on the subject in order to increase knowledge about facilitating factors for PA in people with chronic pain. / Bakgrund: Träning kan ha en positiv påverkan på långvarig smärta. Att utföra fysisk aktivitet (FA)påverkas av både underlättande och försvårande faktorer där bland annat motivation och tilltro till den egna förmågan avseende fysisk aktivitet kan ha en viktig roll. Syfte: Genom självskattade orsaksnätverk utforskade studien vilka faktorer vuxna personer medlångvarig smärta skattade som underlättande för att utöva FA, deras aktivitetsnivå samt vilkatyper av fysiska aktiviteter de ägnade sig åt. Eventuella samband mellan tilltro till den egnaförmågan att vara fysiskt aktiv och FA samt om orsaksnätverken skiljde sig åt beroende påom en uppfyllde respektive inte uppfyllde rekommendationerna för FA utforskades. Metod: En jämförande, korrelerande och deskriptiv pilotstudie med tvärsnittsdesign användes ochgenomfördes via strukturerade frågeformulär online med hjälp av Perceived CausalNetworks. Resultat: Enligt genomsnittsnätverket förekom två gemensamma faktorer, Förutsättningar och Tankeom träning, som var betydligt underlättade för såväl utförandet av planerad FA somvardagsmotion. Som Vardagsmotion ägnade sig deltagarna framför allt åt; promenader,hushålls- och trädgårdssysslor samt trappgång. Som Planerad FA utfördes främst;promenader, hemträning och simning/vattengymnastik. Majoriteten av respondenterna (52%)hade en självskattad fysisk aktivitetsnivå som motsvarade en “högre nivå”. Det framkomingen statistiskt säkerställd skillnad avseende skattningen av underlättande faktorer mellan desom uppnådde respektive inte uppnådde rekommendationerna för FA. Sambandet var måttligtstarkt mellan tilltro till den egna förmågan avseende fysisk aktivitet och aktivitetsminuter(r=0.443, p=0.002) och mellan tilltro till den egna förmågan avseende fysisk aktivitet ochfysisk träning (r=0.418, p=0.003). Mellan tilltro till den egna förmågan avseende fysiskaktivitet och vardagsmotion fanns inget statistiskt samband (r=0.257, p=0.078). Slutsats: Trots att det verkar finnas ett samband mellan tilltro till den egna förmågan avseende fysiskaktivitet och aktivitetsminuter respektive fysisk träning krävs vidare forskning kring ämnetför att öka kunskapen om vad som kan underlätta utförandet av FA hos personer medlångvarig smärta.

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Introduktion Försvarsmakten (FM) genomför en revidering av hur fysisk träning (FT) ska bedrivas inom myndigheten. I revideringen är FM avsikt att de civilanställda arbetstagarna (CVAT) ska få som krav att bedriva FT i samma omfattning som den militära. Dock är kunskapsläget över vad som motiverar, respektive inte motiverar, den civila personalen till FT relativt outforskat.  Syfte Studiens syfte har varit att undersöka hur anställdas upplevelse av fysisk träning påverkar motivationen till att bedriva fysisk träning under arbetstid.  Metod Studien genomfördes som en kvalitativ intervjustudie baserad på semistrukturerad intervjumetod. Fem individer intervjuades och data från intervjuerna analyserades genom kvalitativ innehållsanalys med abduktiv ansats. Resultat Från analysen framkom ett antal motivationsfaktorer och barriärer kopplat till att bedriva FT på arbetstid. De mest framträdande motivationsfaktorerna var att FT skulle vara rolig och att FTskulle förbättra individens hälsa. Vidare framkom att krav som inte är kopplade till en för individen tydlig målbild inte bidrar till en ökad motivation till FT. De största barriärerna till att utöva FT var tidsbrist och att FT inte värderades lika högt som andra arbetsuppgifter. Diskussion/slutsats FM:s vilja att implementera FT på arbetstid som ett krav för CVAT kommer troligen inte leda till att fler inom FM genomför FT. För att på längre sikt motivera CVAT till FT så behöver FMförstår de underliggande motiven till varför en individ bedriver FT. Det finns troligtvis inte en generell formel för att motivera individer till att bedriva FT. Därför bör de riktlinjer FM eller andra organisationer tar fram vara tillräckligt flexibla i sin utformning för att de ska kunna anpassas till individens rådande motivationsbehov och följas upp kontinuerligt.Inom FM förefaller det finnas en kultur där arbetsuppgiften FT inte likställs med övriga arbetsuppgifter vilket leder till att det är det första som prioriteras bort. FM bör utreda omkulturen existerar i hela myndigheten och i så fall arbeta fram en strategi för att motverka den. / Introduction The Swedish Armed Forces (SAF) is carrying out a revision of how physical training (PT) is to be conducted within the organization. In this revision, the SAF intends to impose requirements on civilian employees (CE) to engage in PT to the same extent as military personnel. However, the knowledge regarding what motivates or demotivates civilian personnel to participate in PT is relatively unexplored. Aim The aim of the study was to examine how employees' experience of PT affects their motivation to engage in PT during working hours. Method The study was conducted as a qualitative interview study based on a semi-structured interview method. Five individuals were interviewed, and the data from the interviews was analysed using qualitative content analysis with an abductive approach. Results The analysis revealed several motivational factors and barriers related to engaging in PT during working hours. The most prominent motivational factors were that PT should be enjoyable and contribute to improving individuals' health. Furthermore, results show that requirements that are not connected to a clear goal for the individual do not contribute to increased motivation for PT. The main barriers to engage in PT were lack of time and PT not being valued as highly as other work tasks. Discussion/Conclusion The SAF intention to implement mandatory PT during working hours for CE is unlikely to result in more individuals within the SAF engaging in PT. In order to motivate CE in the long term, the SAF needs to understand the underlying motives for why individuals participate in PT. There is likely no universal formula for motivating individuals to engage in PT, and the guidelines developed by the SAF, or other organizations should be sufficiently flexible in their design to adapt to individuals' current needs and be continuously reviewed.Within the SAF, there seems to be a culture where the task of PT is not considered equal to other work tasks and is often prioritized last. The SAF should investigate whether this culture exists throughout the organization and, if so, develop a strategy to counteract it.

La stéatose hépatique et la détérioration du profil lipidique plasmatique sont des pathologies métaboliques favorisées par la carence œstrogénique post-ménopausique. Cependant les mécanismes à la base de ces pathologies n’ont été que très peu étudiés. Le but de cette thèse a été d’investiguer les mécanismes moléculaires possibles à l’origine de l’hypercholestérolémie et de l’accumulation des lipides (triglycérides : TG et cholestérol) dans le foie en utilisant un modèle animal de la ménopause, la rate Sprague Dawley ovariectomisée (Ovx). Nous avons également examiné si le changement des habitudes de vie comme la pratique de l’exercice physique pouvait prévenir ou corriger les modifications induites par l’Ovx. Enfin, rosuvastatine (statine) a été utilisée comme thérapie pharmacologique de l’hypercholestérolémie dans le but de comprendre son effet au niveau moléculaire chez la rate Ovx. L’objectif de la première étude était de déterminer comment l’Ovx peut affecter les niveaux de TG et de cholestérol dans le foie des rates nourries avec une diète riche en lipides (HF : 42% gras). Les rates ont été soumises à la diète HF ou normale pendant 6 semaines avant d’être Ovx ou Sham (ovariectomie simulée), puis maintenues aux mêmes conditions diététiques pour 6 autres semaines. L’Ovx a provoqué une accumulation de TG dans le foie, mais pas la diète HF seule. Cependant, lorsque l’Ovx était combinée à la diète HF, l’accumulation des TG était beaucoup plus importante comparé à ce qui était observé chez les rates Ovx soumises à la diète normale. L’expression génique (ARNm) de CPT1 (Carnitine palmitoyltransferase 1), PGC1α (Peroxisome proliferator-activated receptor gamma, coactivator 1) et PPARα (Peroxysome proliferetor activated receptor alpha) intervenant dans l’oxydation des acides gras dans le foie était augmentée par la diète HF (p ˂ 0.001; p ˂ 0.01; p ˂ 0.05 respectivement) ; mais atténuée (p ˂ 0.05; p ˂ 0.05; p ˂ 0.07 respectivement) lorsque les rates ont été Ovx, favorisant ainsi l’accumulation des TG dans le foie. La combinaison de la diète HF à l’Ovx a également provoqué une hypercholestérolémie et une accumulation de cholestérol dans le foie malgré la diminution de l’expression de la HMGCoA-r (3-hydroxy-3-methylglutaryl-CoA reductase), enzyme clé de la synthèse du cholestérol. Ceci était associé à l’inhibition de l’expression génique de CYP7a1 (Cytochrome P450, family 7, subfamily a, polypeptide 1), suggérant une diminution de la synthèse des acides biliaires. Ayant constaté dans la première étude que l’Ovx élevait les niveaux de cholestérol hépatique et plasmatique, nous nous sommes fixés comme objectif dans la deuxième étude d’évaluer les effets de l’Ovx sur l’expression génique des transporteurs et enzymes responsables du métabolisme du cholestérol et des acides biliaires dans le foie et l’intestin, et de vérifier si l’exercice sur tapis roulant pouvait prévenir ou corriger les changements causés par l’Ovx. L’hypercholestérolémie constatée chez les rates Ovx comparativement aux Sham était accompagnée de la diminution de l’expression génique des récepteurs des LDL (R-LDL), des résidus de lipoprotéines (LRP1), de SREBP-2 (Sterol regulatory element binding protein 2) et de PCSK9 (Proprotein convertase subtilisin/kexin type 9) dans le foie, suggérant une défaillance dans la clairance des lipoprotéines plasmatiques. L’Ovx a aussi inhibé l’expression génique de la MTP (Microsomal triglyceride transfer protein) et stimulé celle de SR-B1 (Scavenger receptor class B, member 1); mais aucun changement n’a été observé avec CYP7a1. Ces changements moléculaires pourraient par conséquent favoriser l’accumulation de cholestérol dans le foie. L’exercice physique n’a pas corrigé les modifications causées par l’Ovx sur l’expression génique de ces molécules au niveau hépatique à l’exception de SREBP-2. Par contre, au niveau intestinal (iléum), l’exercice sur tapis roulant a inhibé l’expression génique des marqueurs moléculaires intervenant dans l’absorption des acides biliaires (OSTα/β, FXR, RXRα, Fgf15) et du cholestérol (LXRα, NCP1L1) au niveau de l’iléum chez les rates Sham entraînées. Ces adaptations pourraient prévenir le développement de l’hypercholestérolémie protégeant en partie contre la survenue de l’athérosclérose. Au vue des effets délétères (hypercholestérolémie et diminution de l’expression du R-LDL, PCSK9, LRP1, SREBP-2 et HMGCOA-r dans le foie) causés par l’Ovx sur le métabolisme du cholestérol constatés dans l’étude 2, la 3ième étude a été conçue pour évaluer l’efficacité de rosuvastatine (Ros) sur l’expression génique de ces marqueurs moléculaires chez les rates Ovx sédentaires ou soumises à l’entraînement volontaire. Ros a été administrée aux rates Ovx pendant 21 jours par voie sous-cutanée à la dose de 5mg/kg/j à partir de la 9ième semaine après l’Ovx. Ros n’a pas diminué la concentration plasmatique de LDL-C et de TC chez les rates Ovx. Par contre, Ros a stimulé (P ˂ 0.05) l’expression génique de PCSK9, SREBP-2, LRP1, HMGCoA-r et ACAT2 (Acyl-CoA cholesterol acyltransferase) mais pas significativement (P = 0.3) celle du R-LDL dans le foie des rates Ovx sédentaires et entraînées. Ros n’a pas réduit la concentration plasmatique de LDL-C probablement à cause de l’induction plus importante de PCSK9 par rapport au R-LDL. Cependant, la stimulation de LRP1 par Ros protège partiellement contre la survenue des maladies cardiovasculaires. En conclusion, les études de cette thèse indiquent que la baisse du niveau des œstrogènes entraîne des changements radicaux du métabolisme hépatique des TG et du cholestérol provoqués par des altérations de l’expression des gènes clés des voies métaboliques associées. / Hepatic steatosis and plasma lipid profile deterioration are metabolic diseases favored by post-menopausal estrogen deficiency. However, mechanisms underlying these diseases have not been systematically adressed. The aim of this thesis was to investigate molecular mechanisms causing hypercholesterolemia and lipids (triglycerides: TG and cholesterol) accumulation in the liver using animal model of menopause, the ovariectomized (Ovx) Sprague Dawley rat. We also examined whether lifestyle modifications such as physical activity can prevent or correct changes induced by Ovx. Finally, rosuvastatin (statine) was used as a pharmacological therapy of hypercholesterolemia in order to understand its effect at the molecular level in Ovx rats. The first study was designed to determine how the Ovx may affect levels of TG and cholesterol in the liver of rats fed a high-fat diet (HF: 42% fat). Rats were submitted to a HF or a normal diet for 6 weeks prior to Ovx or being sham operated, and then kept on the same diets for another 6 weeks. The Ovx increased liver TG content, but not the HF diet alone. However, the combination of Ovx and HF diet resulted in a greater liver TG accumulation than that observed in Ovx submitted to normal diet. The mRNA levels of CPT-1, PGC1 and PPARα involved in liver lipid oxidation significantly increased in rats fed the HF diet (p ˂ 0.001; p ˂ 0.01; p ˂ 0.05 respectively); but this increase was substantially less if HF fed rats were Ovx (p ˂ 0.05; p ˂ 0.05; p ˂ 0.07 respectively), thus favouring TG accumulation in the liver. The combination of HF diet and Ovx also induced hypercholesterolemia and an increase in liver total cholesterol content, in spite of the reduction of liver HMGCoA-r gene expression, the key enzyme for cholesterol synthesis. This was also associated with a decrease of liver CYP7a1 gene expression, suggesting a reduction in bile acids synthesis. Having found in the first study that the Ovx increases liver and plasma cholesterol levels, we aimed in the second study at determining the effects of Ovx on gene expression of hepatic and intestinal transporters and enzymes involved in cholesterol and bile acids metabolism; and to verify whether treadmill exercise could prevent or correct changes induced by Ovx. The Ovx resulted in hypercholesterolemia associated with a reduction in gene expression of hepatic low-density lipoprotein receptor (LDL-R), lipoprotein remnants receptor (LRP1), SREBP-2 and PCSK9, suggesting a failure in the clearance of plasma lipoproteins particles. The Ovx also inhibited the expression of MTP and stimulated that of SR-B1 in the liver, but no change was observed with CYP7a1. These molecular changes might, therefore, favor cholesterol accumulation in the liver. Exercise training did not correct the deleterious effects caused by Ovx on gene expression of these molecular markers in the liver with the exception of SREBP-2. However, in the intestine (ileum) treadmill exercise reduced gene expression of molecular markers involved in the absorption of bile acids (OSTα/β, FXR, RXRα, Fgf15) and cholesterol (LXRα, NCP1L1) in Sham trained rats compared to sedentary rats. This could prevent the development of cholestasis and hypercholesterolemia protecting partially against the onset of atherosclerosis. In view of the deleterious effects (hypercholesterolemia and decreased in gene expression of LDL-R, PCSK9, LRP1, SREBP-2 and HMGCoA-r in the liver) caused by Ovx on cholesterol metabolism observed in the second study, the 3rd study was designed to test the effect of rosuvastatin (Ros) on gene expression of these molecular markers in Ovx sedentary rats or in Ovx rats submitted to voluntary training. Ros was injected to Ovx rats subcutaneously at dose of 5mg/kg/day during 21 days from the ninth week after ovariectomy. Ros failed to decrease plasma LDL-C and TC in Ovx rats. In contrast, Ros increased (P ˂ 0.05) PCSK9, SREBP-2, LRP1, HMGCoA-r and ACAT2 but not significantly (P ˂ 0.3) LDL-R mRNA in the Ovx sedentary and trained rat liver. Ros failed to decrease plasma LDL-C in Ovx rats probably because of a stronger induction of PCSK9 than LDL-R gene expression. However by increasing LRP1 expression, Ros could decrease circulating lipoprotein remnants and, therefore, protects partially against the onset of cardiovascular diseases. In conclusion, the studies of this thesis indicate that the decrease of ovarian estrogen levels causes radical changes in hepatic TG and cholesterol metabolism caused by alterations in the expression of key genes associated with metabolic pathways.

Suite à l’exposition à des facteurs de risque incluant la malnutrition, la dyslipidémie, la sédentarité et les désordres métaboliques, les maladies cardiovasculaires (MCV) sont caractérisées par un état pro-oxydant et pro-inflammatoire, et une dérégulation de l’expression de divers facteurs responsables de l’homéostasie de l’environnement rédox et inflammatoire. L’implication d’enzymes antioxydantes telles que les superoxyde dismutases (SOD) et les glutathion peroxydases (Gpx), ainsi que la contribution de médiateurs pro-inflammatoires tels que l’angiopoietin-like 2 (Angptl2) ont été rapportées dans le cadre des MCV. Toutefois, les mécanismes moléculaires sensibles aux facteurs de risque et menant au développement des MCV sont peu connus. L’épigénétique est un mécanisme de régulation de l’expression génique sensible aux stimuli extracellulaires et pourrait donc contribuer au développement des MCV. La méthylation de l’ADN est un des mécanismes épigénétiques pouvant varier tant de manière gène-spécifique qu’à l’échelle génomique, et la conséquence de tels changements sur l’expression des gènes ciblés dépend du site de méthylation. Puisqu’il a été démontré que des variations au niveau de la méthylation de l’ADN peuvent être associées à divers contextes pathologiques incluant les MCV, le but de nos travaux était d’étudier le lien entre la méthylation de gènes antioxydants et pro-inflammatoires avec leurs répercussions fonctionnelles biologiques en présence de facteurs de risques associés aux MCV, tels que le vieillissement, la dyslipidémie et la sédentarité. Dans la première étude, nous avons observé que dans l’artère fémorale de souris vieillissantes, la méthylation au niveau du promoteur du gène Sod2, codant pour l’enzyme antioxydante superoxyde dismutase de type 2 (SOD2 ou MnSOD), diminue avec l’âge. Ceci serait associé à l’induction de l’expression de MnSOD, renforçant ainsi la défense antioxydante endogène. Le vieillissement étant associé à une accumulation de la production de radicaux libres, nous avons étudié la vasodilatation dépendante de l’endothélium qui est sensible au stress oxydant. Nous avons observé que la capacité vasodilatatrice globale a été maintenue chez les souris âgées, aux dépens d’une diminution des facteurs hyperpolarisants dérivés de l’endothélium (EDHF) et d’une contribution accentuée de la voie du monoxyde d’azote (NO). Nous avons ensuite utilisé deux approches visant à réduire les niveaux de stress oxydant in vivo, soit la supplémentation avec un antioxydant, la catéchine, et l’exposition chronique à de l’exercice physique volontaire. Ces interventions ont permis de prévenir à la fois les changements au niveau de la fonction endothéliale et de l’hypométhylation de Sod2. Cette première étude démontre donc la sensibilité de la méthylation de l’ADN à l’environnement rédox. Dans la deuxième étude, nous avons démontré une régulation de l’expression de l’enzyme antioxydante glutathion peroxydase 1 (Gpx1) en lien avec la méthylation de son gène codant, Gpx1, dans un contexte de dyslipidémie sévère. Nos résultats démontrent que dans le muscle squelettique de souris transgéniques sévèrement dyslipidémiques (LDLr-/-; hApoB+/+), Gpx1 est hyperméthylé, ce qui diminue l’expression de Gpx1 et affaiblit la défense antioxydante endogène. Chez ces souris, l’exercice physique chronique a permis d’augmenter l’expression de Gpx1 en lien avec une hypométhylation transitoire de son gène. Cette étude démontre que le stress oxydant associé à la dyslipidémie sévère altère les mécanismes de défense antioxydante, en partie via un mécanisme épigénétique. De plus, on observe également que l’exercice physique permet de renverser ces effets et peut induire des changements épigénétiques, mais de manière transitoire. La troisième étude avait pour but d’étudier la régulation de l’Angptl2, une protéine circulante pro-inflammatoire, dans le contexte des MCV. Nous avons observé que chez des patients coronariens, la concentration circulante d’Angptl2 est significativement plus élevée que chez des sujets sains et ce, en lien avec une hypométhylation de son gène, ANGPTL2, mesurée dans les leucocytes circulants. Nous sommes les premiers à démontrer qu’en réponse à l’environnement pro-inflammatoire associé à une MCV, l’expression de l’Angptl2 est stimulée par un mécanisme épigénétique. Nos études ont permis d’identifier des nouvelles régions régulatrices différentiellement méthylées situées dans les gènes impliqués dans la défense antioxydante, soit Sod2 en lien avec le vieillissement et Gpx1 en lien avec la dyslipidémie et l’exercice. Nous avons également démontré un mécanisme de régulation de l’Angptl2 dépendant de la méthylation d’ANGPTL2 et ce, pour la première fois dans un contexte de MCV. Ces observations illustrent la nature dynamique de la régulation épigénétique par la méthylation de l’ADN en réponse aux stimuli environnementaux. Nos études contribuent ainsi à la compréhension et l’identification de mécanismes moléculaires impliqués dans le développement du phénotype pathologique suite à l’exposition aux facteurs de risque, ce qui ouvre la voie à de nouvelles approches thérapeutiques. / Following exposure to risk factors including malnutrition, dyslipidemia, physical inactivity and metabolic disorders, cardiovascular diseases (CVD) are characterized by a pro-oxidative and pro-inflammatory state, and a dysregulation in the expression of various factors responsible for the redox and inflammatory environment homeostasis. The implication of antioxidant enzymes, such as superoxide dismutases (SOD) and glutathione peroxidases (Gpx), as well as the contribution of pro-inflammatory mediators such as angiopoietin-like 2 (Angptl2) are well characterized in the context of CVD. However, little is known about the molecular mechanisms sensitive to environmental cues leading to the development of CVD. Epigenetics are mechanisms regulating gene expression that are sensitive to extracellular stimuli and could therefore contribute to the pathogenesis of CVD. DNA methylation is an epigenetic mechanism that can vary both at gene and genomic levels; the consequence of these epigenetic changes on the expression of targeted genes is dependent on the methylation site. Since it has been reported that DNA methylation variations can be associated with diverse pathological conditions including CVD, the goal of our work was to study the link between the methylation of antioxidant and pro-inflammatory genes, and their consequences on biological functions in the context of risk factors associated with CVD, such as aging, dyslipidemia and physical inactivity. In the first study, we observed that in the femoral artery of aging mice, the methylation at the promoter of the Sod2 gene, which codes for the antioxidant enzyme superoxide dismutase, type 2 (SOD2 or MnSOD), decreases with age. This suggests an induction of MnSOD expression and thus a strengthening of the endogenous antioxidant defense. Since aging is associated with an accumulation of free radicals, we studied the endothelium-dependant vasodilation, known to be sensitive to oxidative stress. We observed that, overall, vasodilatory capacity was preserved in aging mice, due to a concomitant decrease in endothelium-derived hyperpolarizing factors (EDHF) and an increased contribution of the nitric oxide (NO) pathway. We then used two in vivo oxidative stress-reducing approaches, namely the supplementation with the antioxidant catechin and chronic exposure to voluntary physical exercise. These interventions prevented the changes in endothelial function and the Sod2 hypomethylation-dependent induction of MnSOD expression. Hence, this first study demonstrates the sensitivity of DNA methylation to the redox environment. In the second study, we demonstrated that the antioxidant enzyme glutathione peroxidase 1 (Gpx1) expression was regulated through the methylation of its coding gene, Gpx1, in the context of severe dyslipidemia. Our results show that in the skeletal muscle of severely dyslipidemic transgenic mice (LDLr-/-; hApoB+/+), Gpx1 is hypermethylated, which in turn decreased Gpx1 expression and weakened the endogenous antioxidant defense. In these mice, chronic physical exercise managed to increase Gpx1 expression, an effect linked with a transient gene hypomethylation. This study demonstrates that oxidative stress associated with severe dyslipidemia alters antioxidant defense mechanisms, partially through an epigenetic mechanism. Moreover, we also observed that physical exercise can revert these changes and can induce epigenetic changes, at least transiently. The goal of the third project was to study Angptl2 regulation, a circulating pro-inflammatory protein, in the context of CVD. We observed that, in coronary patients, circulating Angptl2 concentration is significantly increased in conjunction with hypomethylation of its gene, ANGPTL2, measured in circulating leukocytes. We are the first to show that in response to the pro-inflammatory environment associated with a CVD, Angptl2 expression is stimulated by an epigenetic mechanism. In conclusion, our studies allowed the identification of novel regulatory differentially methylated regions located in genes involved in antioxidant defense, namely Sod2, in the context of aging, and Gpx1 in the context of dyslipidemia and exercise. We also revealed, for the first time, an Angptl2 regulating mechanism dependent on ANGPTL2 methylation in a context of CVD. These observations illustrate the dynamic nature of epigenetic regulation through DNA methylation in response to environmental cues. Our studies therefore contribute to the understanding and identification of molecular mechanisms involved in the development of pathological phenotypes following exposure to risk factors, which opens the way to novel therapeutic strategies.

O presente trabalho teve como objetivo verificar se a ingestão de dieta deficiente em magnésio altera o metabolismo oxidativo de ratos submetidos à atividade física moderada. Ratos Wistar machos (peso inicial 280g) foram divididos em controle (SED, n=9), controle exercitado (EX, n=9), marginalmente deficiente em Mg sedentário (MARG, n=9) e deficiente em Mg exercitado (EXMARG, n=9). A dieta controle apresentava 500 mg Mg/kg de ração e a dieta deficiente em Mg tinha 200 mg Mg/kg de ração. Os animais foram submetidos a 6 semanas de natação, 1 hora/dia, 5 vezes/semana. No soro foi determinada a atividade de creatina quinase (CK) e lactato desidrogenase (LDH). Foi determinada a atividade de superóxido dismutase (SOD), catalase (CAT) e glutationa peroxidase (GPx) na musculatura esquelética. No músculo gastrocnêmio, fígado, rins e cérebro foi determinada a peroxidação lipídica (TBARS). A concentração de magnésio foi determinada no eritrócito, soro e músculos gastrocnêmio e sóleo, fígado, rins e cérebro. A atividade de enzimas antioxidantes foi menor no grupo EXMARG (p< 0,05), especialmente na fração citossólica. Provavelmente, estes animais ficaram mais suscetíveis a danos oxidativos, mais propensos a realizar com dificuldade o exercício físico proposto, levando o seu esforço próximo à anaerobiose. Entretanto, o grupo EXMARG não apresentou concentrações significativas de TBARS no músculo. O cérebro apresentou maior risco para a ação pró-oxidativa na deficiência de magnésio. O nível de ingestão de magnésio não apresentou o efeito significativo esperado para os parâmetros, exceto no soro (p<0,05). A deficiência marginal de magnésio associada ao treinamento físico regular levou à maior ação pró-oxidativa sobre o organismo, especialmente sobre a musculatura esquelética. / This study aimed to verify if the ingestion of a diet poor in magnesium alters the oxidative metabolism in rats submitted to moderate physical activity. Male Wistar rats (initial body mass of 280 g) were divided into 4 groups: control (CON, n=9), exercised control (CONEX, n=9), deficient in Mg (MARG, n=9), and exercised and deficient in Mg (EXMARG, n=9). The control diet presented 500 mg of Mg/ Kg diet and the deficient diet contained 200 mg of Mg/ Kg diet. The animals were submitted to 6 weeks of swimming exercise, 1 hour/day, 5 time/week. Serum creatine kinase (CK) and lactate dehydrogenase (LDH) activity was obtained. Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities were determined in skeletal muscles. Lipid peroxidation level (TBARS) was assayed in gastrocnemius and soleus muscles, liver and brain. Magnesium concentration was assayed in erythrocyte, serum, gastrocnemius and soleus muscles, liver, kydney and brain. Antioxidant enzyme activity was smaller on EXMARG group (p<0,05), especially in the citossol. possibly, these animals were more susceptible to oxidative damage, being difficult to execute the exercise, leading their effort near anaerobic level. However, the EXMARG group did not presented significant muscle TBARS concentration. The brain presented increased risk to magnesium deficiency pro-oxidative action. In summary, marginal magnesium deficiency in association with regular physical training led to a greater pro-oxidative action in the organism, specially over skeletal muscle.

Devido ao constante aumento na prevalência de obesidade e doenças relacionadas é sugerido que indivíduos obesos sejam submetidos a programas educativos para redução da massa corporal. Objetivos: avaliar os efeitos de um programa de Educação em Saúde (Educação nutricional e Educação física) voltado a um grupo de mulheres obesas. Métodos: 50 mulheres obesas foram submetidas a um programa de quatro meses envolvendo educação nutricional (1 vez/semana) e exercício físico (aeróbio e contra-resistência - 3 vezes/semana). Foram avaliadas variáveis antropométricas, metabólicas e alimentares: peso, estatura, circunferência da cintura e do quadril, composição corporal por raios X de dupla energia (DEXA), teste ergoespirométrico e gasto energético de repouso (VO2000-Imbrasport&#174;), hemograma, leucograma, perfil lipídico, glicemia, leptina, IGF-1 (Fator de crescimento semelhante à insulina-1, TSH (Hormônio estimulante da tireóide), albumina e pré albumina, 3 diários alimentares e de atividade física. Para análise dos resultados, as participantes foram distribuídas em G1 (IMC inicial < IMC final) e G2 (IMC inicial &#8805; IMC final). Resultados: No G1 houve redução de: massa corporal, IMC, CC, CQ, RCQ, gordura corporal (kg), massa corporal magra (kg) e glicemia. No G2 não foram encontradas alterações significativas nestas variáveis. Não foram encontradas diferenças significativas no GER e ambos os grupos apresentaram aumento do VO2 pico, redução da leptina plasmática e da albumina sérica. Conclusões: O programa de perda de peso realizado neste estudo foi eficiente para resultar em redução da massa corporal em 50% das participantes, apresentando também melhoras em fatores de risco para doenças cardiovasculares. Independentemente da redução da massa corporal e na massa corporal magra, programas de exercício físico sem o controle individualizado da ingestão alimentar, principalmente de proteínas, pode resultar em prejuízos para o estado nutricional de mulheres obesas. / Because of the high prevalence of obesity and its associated comorbities all over the world, it is suggested to submmit obese people to edicational weight reduction programs. Objectives: to evaluate the effects of an educational program (nutrition and physical education) in obese women. Methods: 50 obese women were submitted to a four months program of nutritional education (once a week) and exercise training (aerobic and resistance -3 times/week). They were evaluated variables related to anthropometry, metabolic and eating behavior: weight, height, waist and hip circumferences, body composition by dual X-ray energy (DEXA), aerobic power and resting energy expenditure (VO2000-lmbrasport&#174;); hemogram, leucogram, lipid profile, glucose level, leptin, IGF-1 (Insulin like growth factor-1), TSH (Tireoid stimulating hormone), albumin and pré-albumin, 3 days of food and physical activity records. The participants were distributed into the follow groups for the analysis: G1 (initial BMI < final BMI) and G2 (initial BMI &#8805; final BMI). Results: In G1 they were reduced: body mass, body mass index (BMI), waist circumference, hip circumference, waist/hip relation, fat mass (kg), lean body mass (kg) and glucose. No statistical differences were found in these parameters in G2. No statistical differences were found in resting energy expenditure in both groups and there was an increase in VO2peak, decrease in leptin and albumin concentration in both groups. Conclusions: The weight reduction program realized in this study was efficient to result weight loss in 50% of the participants, with improvements in cardiovascular risk factors. Independent of reductions on body mass and lean body mass, exercise training programs without individualized control of protein intake, especially of proteins, can jeopardize nutritional status of obese women.

Introdução: A Poluição do ar é um dos principais fatores de risco de morte no mundo. Estudos têm demonstrado que o exercício regular pode retardar o aparecimento de doenças. Por outro lado, o exercício físico aumenta o volume de ar inalado, resultando em uma maior deposição de poluentes nos pulmões. Objetivos: Avaliar a variabilidade da frequência cardíaca (VFC) durante a realização de exercícios físicos de moderado a intenso, em ambientes com diferentes concentrações de poluentes, em jovens saudáveis que praticam exercícios regularmente. Métodos: 58 indivíduos jovens e saudáveis foram submetidos a avaliação da VFC antes, durante e após a atividade física (7,5 km), em dias diferentes, em um circuito na via pública (CVP) e um circuito em um parque arborizado (CPq). O Polar RS800 foi o equipamento usado para registrar a frequência cardíaca (FC) e VFC, durante 15 minutos em repouso, durante os 45 minutos de corrida e durante os 15 minutos de recuperação. O MP2.5, temperatura (°C) e umidade relativa do ar, em porcentagem, foram monitorados durante as corridas. Resultados: Cinquenta e oito voluntários completaram o protocolo em ambos os circuitos. A idade média dos participantes foi de 19,2 (± 1,1) anos. A concentração média de MP2,5 foi 24,5 (± 12,9) ug/m3 no CPq e 74,8 (± 41,5) ug/m3 no CVP. A FC média observada durante o exercício foi menor no CVP (p = 0,0017). Correr no circuito CVP foi associado com uma maior redução no índice SDNN index em relação ao circuito CPq. Conclusão: A atividade física no CVP foi associada a um efeito adverso na FC e na VFC, acentuando o desequilíbrio autonômico / Introduction: Air pollution is one of major death risks factors on worldwide. Studies have shown that regular exercise can slow down the emergence of diseases. On the other hand, physical exercise increases the volume of air inhaled and, as a result, greater deposition of pollutants in the lungs. Aims: To evaluate the heart rate variability (HRV) during moderate to intense exercise, in environments with different concentrations of pollutants, in healthy young people who practice exercises regularly. Methods: 58 young, healthy individuals underwent HRV assessment before, during, and after physical activity (7.5 km), on different days, which consisted of running a circuit on a public street (PS) and running a circuit in a wooded park (PK). Polar RS800 equipment was used to record the heart rate (HR) and HRV, after 15 minutes at rest, after 45 minutes of running, and after 15 minutes of recovery. MP2.5, temperature (°C), and Percent relative air humidity were monitored during the races. Results: Fifty-eight volunteers completed the protocol in both circuits. Age of participants was 19.2 (± 1.1) years. The average concentration of MP2.5 was 24.5 (± 12.9) ug/m3 in the PK circuit and 74.8 (± 41.5) ug/m3 in the PS circuit. The HR average observed during the exercise was smallest in the PS circuit (p=0.0017). Running in the PS circuit was associated with a greater reduction in the SDNN index regarding PK circuit. Conclusion: Physical activity in PS was associated with an adverse effect in HR and HRV, accentuating the autonomic imbalance

INTRODUÇÃO: A Peroxisome Proliferator Activated Receptor- - Coactivator 1 ( PGC-1 e ) é proteína responsável pela conexão entre estímulos ambientais e resposta metabólica celular. Sua presença é importante em tecidos adiposo, hepático e muscular esquelético e, em animais, em tecido adiposo marrom. Interage com receptores nucleares modulando a biogênese mitocondrial e mantendo o equilíbrio termo energético celular com o meio ambiente. A redução da expressão de PGC-1 e da oxidação fosforilativa tem sido associada à resistência à insulina em doenças como Diabetes Mellitus tipo 2 e Síndrome Metabólica. OBJETIVOS: Avaliar o efeito do exercício na expressão da PGC-1 em tecidos alvos da insulina, como o fígado e músculos esquléticos soleus ( SOL ) e plantaris ( PLA ) de ratos machos Wistar e correlacioná-lo com a sensibilidade à insulina. METODOLOGIA: Ratos machos Wistar 190±15 g, n = 24, randomizados em 2 grupos: Ex ( exercício físico ) e Sd ( sedentário ) colocados respectivamente, em roda de atividade ou gaiolas comuns durante cinco semanas. Ao final do período, após jejum de quatro horas, foi colhido sangue para dosagens de glicose ( GLI ), insulina ( INS ) e ácidos graxos livres ( AGL ) e, em seguida, foram submetidos ao Teste de Supressão da Glicose e Insulina Endógenas com infusão durante 180 minutos de solução GLI ( 20mg/kg/min ) + INS ( 5 mU/kg/min ); amostras de sangue foram colhidas aos 140, 150, 160, 170 e 180 minutos. Terminado o teste e ainda sob anestesia, foram retirados os tecidos: fígado ( FG ) e músculos esquléticos ( PLA e SOL ), os quais foram imediatamente congelados e mantidos a -70ºC para posteriores análises. A expressão da PGC-1 foi avaliada pelo Western Blot com anticorpo policlonal anti- PGC-1. Análise estatística por teste t Student não-pareado e nível de significância 5%. RESULTADOS: Os dados se referem à média e erro padrão médio dos valores individuais das amostras. A distância percorrida na última semana ( km/dia ) pelo grupo Ex foi eficaz ( 5,61 ± 0,67 ). Não houve diferença no peso ( g ) dos ratos entre os grupos Ex e Sd ( 355,85 ± 9,51 x 375,68 ± 5,30 ) NS. Os valores de GLI jejum ( mg/dl ) foram semelhantes entre os grupos ( 117,6 ± 3,7 x 122,4 ± 2,6 ) NS. Entretanto, INS e AGL foram menores no grupo Ex: INS ( ng/ml ) ( 0,68 ± 0,12 x 1,45 ± 0,14 ) p < 0,001 e AGL ( mEq/L ) ( 1,12 ± 0,11 x 1,60 ± 0,11 ) p < 0,006. Durante o teste de supressão, os valores de GLI e INS na fase de estabilidade foram semelhantes entre grupos ( expressos em área sob a curva ): AUC GLI ( mg/dl/min ) ( 2,77 ± 0,12 x 2,95 ± 0,07 ) NS; AUC INS ( ng/ml/min ) ( 0,81 ± 0,15 x 0,99 ± 0,09 ) NS. A expressão da PGC-1 foi maior no PLA de ratos do grupo Ex e, em FG e SOL foi semelhante entre os grupos. CONCLUSÃO: O exercício físico durante 5 semanas em roda de atividade voluntária, aumentou a sensibilidade à insulina e a oxidação de ácidos graxos livres no jejum. A melhora da sensibilidade à insulina esteve associada à maior expressão da PGC-1 somente em músculo PLA. Estes dados sugerem que o aumento da sensibilidade à insulina no jejum não se relacionou com o aumento da expressão da PGC-1 em outros tecidos alvos da ação insulínica, como FG e SOL, neste modelo de estudo. / INTRODUCTION: The Peroxisome Proliferator-Activated Receptor- - Coactivator 1 ( PGC-1 e ) is a protein responsible for the connection between environmental stimuli and cell metabolic response. Its presence is important in fat tissue, hepatic and skeletal muscle and in animals on brown fat tissue. Interact with nuclear receptors modulating the mitochondrial biogenesis and maintain thermal energy balance with the environment. Diminished of PGC-1 expression and oxidative phophorylation has been associated to insulin resistance in diseases like Type 2 Diabetes and Metabolic Syndrome. OBJECTIVES: To evaluate the effects of exercise on the PGC-1 expression in target tissues of insulin, such as liver and skeletal muscles soleus (SOL) and plantaris (PLA) of male Wistar rats and correlates with insulin sensitivity. METHODOLOGY: Male Wistar rats 190±15g, n = 24, divided randomly into 2 groups: Ex ( physical exercise ) and Sd ( sedentary ), respectively placed in a voluntary running wheel cage or a standard cage for five weeks. At the end of study, after fasting for 4 hours, blood was collected for measurements of glucose ( GLU ), insulin ( INS ) and free fatty acids ( FFA ) then the animals were submitted to Test of Suppression Endogenous Glucose and Insulin, with infusion during 180 minutes of solution GLU ( 20mg/kg/min ) + INS ( 5mU/kg/min ); blood samples was collected at 140, 150, 160, 170 and 180 minutes. Finished the test and still anesthetized, the tissues were removed: liver ( LIV ), skeletal muscle ( SOL and PLA ) that were immediately frozen in liquid nitrogen and stored at -70ºC until analysis. The PGC-1 expression was evaluated by Western Blotting with polyclonal antibody anti-PGC-1. Statistical analysis by unpaired Students t test with significance level 5%. RESULTS: the data refer to the mean and standard error of individual values. The distance covered per day during last week ( km / day ) by Ex group was efficient ( 5,61 ± 0,67 ). There was no difference in weight ( g ) of rats between Ex and Sd groups ( 355,85 ± 9,51 x 375,68 ± 5,30 ) NS. The values of fasting GLU were similar between groups ( mg/dl ) ( 117,6 ± 3,7 x 122,4 ± 2,6 ) NS. However INS and FFA were lower in group Ex: INS ( ng/ml ) ( 0,68 ± 0,12 x 1,45 ± 0,14 ) p < 0,001 and FFA ( mEq/L ) ( 1,12 ± 0,11 x 1,60 ± 0,11 ) p < 0,006. During the suppression test the values of GLU and INS on stability step were similar between groups ( expressed in area under curve ): AUC GlU ( mg/dl/min ) ( 2,77 ± 0,12 x 2,95 ± 0,07 ) NS; AUC INS ( ng/ml/min ) ( 0,81 ± 0,15 x 0,99 ± 0,09 ) NS. The PGC-1 expression was greater in PLA of rats Ex than Sd group, and there was no difference in LIV and SOL between groups. CONCLUSION: The physical exercise during five weeks in voluntary running wheel increased the insulin sensitivity and fasting free fatty acids oxidation. The improvement of insulin sensitivity was associated with higher PGC-1 expression on PLA muscle only. These data suggest that increasing insulin sensibility on fasting is not associated with increasing of the PGC-1 expression in others targets tissues of insulin action, such as LIV and SOL, in this study model.

Made available in DSpace on 2016-01-26T12:51:20Z (GMT). No. of bitstreams: 1 marilitafalangolaaccioly_tese.pdf: 2076302 bytes, checksum: 922e6d60d30a7543a522073d3b9c0607 (MD5) Previous issue date: 2007-10-25 / Statins are used to treat dislipidemias with great tolerance, however, several side effects can occur, specially myopathies. The regular practice of physical exercise (PE) produce beneficial alteration in the lipidic profile, however can generate muscle injuries. OBJECTIVE -To evaluate the effect of PE in the lipidic profile; the efficacy of the assocciation between PE and statins in the control of the lipidic profile and evaluate the effect of the association between PE and statins in the muscular function through histological analysis. MATERIAL/METHOD- It was used 80 male Wistar rats , distributed in 8 groups, including animals submitted to a hypercholesterolemic diet (HD), simvastatin with (G1) and without (G2) PE; HD and fluvastatin with (G3) and without PE (G4); fed with comercial ration (CR) in presence (G5) and absence (G6) of PE; HD submitted (G7) or not to PE (G8). The HD was administered for 90 days, statins and practice of PE in the treadmill for 8 weeks. It was measured in the beginning (T0) and at the end (T2) of the experiment the level of total cholesterol (TC) , the fraction of cholesterol of high density lipoprotein (HDLc), triglycerides (TG), piruvic glutamic transaminase (TGP) and the fraction of the cholesterol non-HDLc (non-HDLc) was calculated. The animals were sacrificed, the soleus muscle removed for histological analysis. The paired t test and multivaried analysis were applied with a significance level of p<0,05. RESULTS â The analysis of the groups, at the T2, showed reduction in the TC level when compared G3 with groups G1 (p=0,0414), G6 (p=0,0021) and G8 (p=0,0099) and G7 with group G8 (p<0,0001). However, G1 presented elevated levels in relation to G5 (p=0,0286), G7 (p=0,0192) and G8 (p=0,0196), as well as the G2 in comparison to G7 (p=0,0115). The PE associated with fluvastatin (G3) or simvastatin (G1) has not induced a significant increase in the levels of HDLc, when compared to G4 and G2 (p>0,05). The CR, even with sedentarism (G6) kept the levels of HDLc elevated when compared to the groups remaining. Fluvastatin, independently of the presence of PE (G3 and G4) reduced the fraction of non-HDLc in comparison to G6 (p=0,0201; p=0,0315) and G1 (p=0,0271; p=0,0390, respectively). For the triglycerides levels G1 showed elevated values compared to G3 (p=0,0278), as well as TGP (p=0,0151). The main histological alteration found were fibers of different diameter, atrophics, in degeneration, splitting, edema, inflammatory infiltrate. These alterations were observed in 90% of the animals of G1, 80% of G2, 70% of G3, 30% of G4, 40% of G5 and 30% of G7. In G6 and G8 muscular fibers with preserved morphology were identified. CONCLUSION â PE influenciates in the reduction of TC levels even with DH, becoming the differential in the reduction of TC, non-HDLc and TG with the use of fluvastatin compared to simvastatin, whilst levels of HDLc resist to increase. Conversely, the increase in TGP levels are associated with HD and the use of statins, preferably simvastatin and PE practice. Moreover, PE seems to potentialize muscle injury induced by statins. / As estatinas são utilizadas no tratamento das dislipidemias, com grande tolerância, no entanto, vários efeitos colaterais podem surgir, destacando-se miopatia. A prática regular do exercício físico (EF) produz modificações favoráveis no perfil lipídico, entretanto, pode gerar lesões musculares. OBJETIVO - Avaliar a influência do EF no perfil lipídico; a eficácia da associação entre EF e estatinas no controle do perfil lipídico e avaliar o efeito da associação entre EF e estatinas na função muscular pela análise histológica. MATERIAL e Mà TODO - Foram utilizados 80 ratos machos Wistar, distribuídos em 8 grupos, incluindo animais submetidos à dieta hipercolesterolêmica (DH), simvastatina com (G1) e sem (G2) EF; DH e fluvastatina, com (G3) e sem EF (G4); alimentados com ração comercial (RC) na presença (G5) e ausência de (G6) EF; DH submetidos (G7) ou não (G8) a EF. A DH foi administrada por 90 dias, as estatinas e prática de EF em esteira rolante por 8 semanas. Foram dosados, no início (T0) e ao final (T2) dos experimentos, os níveis de colesterol total (CT), fração de colesterol da lipoproteína de alta densidade (HDLc), triglicérides (TG), transaminase glutâmico pirúvico (TGP) e calculada a fração de colesterol não-HDLc (não-HDLc). Os animais foram sacrificados, e o músculo sóleo retirado para análise histológica. Aplicaram-se os testes t-teste pareado e análise multivariada, com nível significante para p<0,05. RESULTADOS â A análise entre os grupos, no T2, mostrou redução dos níveis de CT quando comparado G3 aos grupos G1 (p=0,0414), G6 (p=0,0021) e G8 (p=0,0099) e G7 ao grupo G8 (p<0,0001). Entretanto, G1 apresentou níveis aumentados em relação a G5 (p=0,0286), G7 (p=0,0192) e G8 (p=0,0196), assim como, o G2 em comparação ao G7 (p=0,0115). O EF associado à fluvastatina (G3) ou a simvastatina. (G1) não induziu aumento significante nos níveis de HDLc, quando comparado a G4 e G2 (p>0,05). A RC mesmo com o sedentarismo (G6) manteve os níveis de HDLc elevados quando comparados aos demais grupos. A fluvastatina independente da presença de EF (G3 e G4) reduziu a fração não-HDLc em comparação a G6 (p=0,0201; p=0,0315) e a G1 (p=0,0271; p=0,0390, respectivamente). Para os níveis de TG destacou-se G1 com valores elevados em comparação a G3 (p=0,0278), assim como para TGP (p=0,0151). As principais alterações histológicas encontradas foram fibras de diferentes diâmetros, atróficas, em degeneração, splitting, edema, infiltrado inflamatório. Essas alterações foram observadas em 90% dos animais do grupo G1, 80% de G2, 70% de G3, 30% de G4, 40% de G5 e 30% de G7. Nos grupos G6 e G8 identificaram-se fibras musculares com morfologia preservada. CONCLUSà ES â EF influencia na redução dos níveis de CT mesmo com DH, tornando-se o diferencial na diminuição dos níveis de CT, não-HDLc e TG no uso de fluvastatina comparado a simvastatina, enquanto os níveis de HDLc são resistentes a elevação. Por outro lado, o aumento nos níveis de TGP associa-se com DH e uso de estatinas, preferencialmente simvastatina e prática de EF. Além disso, o EF parece potencializar a lesão muscular induzida pelas estatinas.