<p>This thesis examined the biochemical role of skeletal muscle mitochondria and metabolic consequences of mitochondrial adaptations to exercise in individuals with poor glycemic control. Mitochondrial dysfunction and/or ectopic lipid accumulation has been implicated in the pathogenesis of metabolic-related diseases such as obesity and type 2 diabetes (T2D). However, whether mitochondrial dysfunction is the cause of insulin resistance and T2D or is a consequence of this disorder remains controversial. Alternatively, pro-inflammatory stress signals initiated through altered secretion of adipocytokines and oxidative stress may be a unifying mechanism underlying insulin resistance and T2D. Furthermore, the impact of exercise on muscle adaptation in insulin-resistant states is not well defined. At rest and prior to exercise training, no evidence of mitochondrial dysfunction or disproportionate intramyocellular lipid (IMCL) accretion was detected in obese, insulin-resistant skeletal muscle biopsy samples <em>vs.</em> healthy, lean age-, and fitness-matched men. In response to exercise training (12 weeks, consisting of 32 sessions of 30-60 min @ 50-70% maximal oxygen uptake [VO₂peak]), there was an increase in mitochondrial oxidative phosphorylation (OXPHOS) capacity, mitochondrial content, and IMCL deposition with sub-cellular specificity. Exercise training also reduced both skeletal muscle and systemic oxidative damage, already elevated in the obese. The improved adipocytokine profile associated with obesity after training also coincided with improvements in glycemic regulation. Patients with genetic mitochondrial mutations, resulting in skeletal muscle mitochondrial dysfunction have an increase prevalence of dysglycemia/T2D. However, when evaluated against age- and activity-matched normoglycemic myopathy controls, no differences in mitochondrial electron transport chain protein subunits, mitochondrial or IMCL density, or level of whole-body insulin resistance was detected. In fact, dysglycemic mitochondrial myopathy patients demonstrated <em>higher </em>skeletal muscle OXPHOS capacity and Akt activation, a key step in insulin-stimulated glucose transport activity as compared with normoglycemic mitochondrial myopathy patients. Interestingly, a significant impairment in β-cell function (defective insulin secretion), in the dysglycemic patients was observed coincident with elevated glucose levels during the oral glucose tolerance test (OGTT). These findings indicate that insulin resistance does not cause skeletal muscle mitochondrial dysfunction/IMCL accumulation or <em>vice versa</em> and provides evidence against a direct link between mitochondrial dysfunction and the development of insulin resistance/T2D. Perhaps, oxidative stress/inflammation and pancreatic β-cell erosion mediate the observed obesity-induced insulin resistance and mitochondrial myopathy-associated T2D, respectively? Twelve weeks of moderate endurance exercise is an effective strategy to improve mitochondrial capacity, oxidative damage, inflammation, and glycemic regulation in insulin-resistant, obese individuals, but an improvement in muscle insulin sensitivity did not appear to be required.</p> / Doctor of Philosophy (Medical Science)

<p>The merits of low-volume high-intensity interval exercise (HIT) have been established in healthy populations; however, no studies have examined this exercise prescription in patients with coronary artery disease (CAD). The present thesis examined the acute and chronic effects of HIT in patients with CAD.</p> <p>The first study demonstrated transient improvements in brachial artery endothelial-dependent function, assessed using flow-mediated dilation (FMD), 60-minutes following a single bout of either HIT or moderate-intensity endurance exercise (END) in habitually active patients. The second study demonstrated no effects of training status on the acute endothelial responses to exercise; following 12-weeks of either HIT or END training. However, there was a significant reduction in endothelial-independent function immediately post-exercise, at both pre- and post-training, which requires further examination. The third study demonstrated comparable increases in fitness and resting FMD following 12-weeks of END and HIT, lending support to the notion that favorable adaptations are obtainable with a smaller volume of exercise. Lastly, the fourth study demonstrated no change in heart rate recovery following 12-weeks of END and HIT. However, pre-training heart rate recovery values reported by our sample were in a low risk range, which suggests training induced improvements may only be achievable in populations with attenuated pre-training values.</p> <p>The results of this thesis provide preliminary evidence supporting the use of HIT in patients with CAD. The findings of favorable transient and chronic improvements following HIT are notable, especially given the HIT protocol involves less time and work than END, which was modeled after the current exercise prescription in cardiac rehabilitation. Further investigations are necessary, including the assessment of additional physiological indices, the feasibility and adherence to HIT, the inclusion of CAD populations with co-morbidities including heart failure and diabetes, as well as other forms of HIT training including HIT combined with resistance training.</p> / Doctor of Philosophy (PhD)

A atrofia está associada ao aumento da degradação protéica em doenças sistêmicas, sendo o sistema proteolítico ubiquitina proteassoma (SUP) uma das principais vias envolvidas. Contudo, pouco é conhecido sobre a contribuição do SUP à atrofia desencadeada pela insuficiência cardíaca (IC). Sabendo dos benefícios do treinamento físico aeróbico (TFA) e que os mecanismos moleculares envolvidos na atrofia na IC ainda não estão esclarecidos, nessa dissertação investigamos: 1) a contribuição do SUP para a atrofia associada à IC em 2 modelos experimentais: um modelo genético de camundongos com hiperatividade simpática (HS), e um modelo de infarto do miocárdio (IM) em ratos e 2) o efeito do TFA sobre a atrofia associada à IC e sobre o SUP. Na HS verificamos aumento da expressão das E3 ligases, da deubiquitinase USP28, das proteínas ubiquitinadas e da atividade do proteassoma no sítio quimiotripsina, sendo que o TFA reduziu a expressão dos componentes alterados. No IM, observamos disfunção cardíaca não associada à IC, porém, com aumento da expressão de Atrogin-1; enquanto o TFA não produziu efeitos significantes. Dessa forma, os dados sugerem a participação do SUP na atrofia desencadeada pela IC na HS e, que o TFA previne a atrofia por reduzir a expressão/atividade de alguns componentes do SUP; e, que no IM, o aumento da expressão de Atrogin-1 precedeu a perda de massa muscular / Skeletal muscle atrophy is associated with increased protein degradation in systemic diseases, which seems to be mainly related to ubiquitin-proteasome system (UPS). However, little is known about UPS contribution to the heart failure-induced muscle atrophy (HF-MA). Likewise, aerobic exercise training (AET) has been established as an adjuvant therapy for HF and molecular mechanisms underlying HF-MA has not been clarified yet. The objectives of the study were: 1) to verify UPS contribution for HF-MA in 2 experimental models: sympathetic hyperactivity-induced HF (&#945;2A/&#945;2CARKO) in mice, and myocardial infarction model (MI) in rats and 2) AET effects on HF-MA and UPS. In &#945;2A/&#945;2C ARKO mice, we observed activation of UPS characterized by increased mRNA levels of E3 ligases Atrogin-1 and E3-a, deubiquitinating enzyme USP28, increased levels of ubiquitinated proteins and chymotrypsin-like proteasome activity. AET prevented HF-MA in the &#945;2A/&#945;2C ARKO by reducing of UPS activity. In MI model, rats displayed cardiac dysfunction and exercise intolerance with no signs of atrophy. However, Atrogin-1 mRNA and protein levels were increased. Therefore, alterations in Atrogin-1expression might precede atrophy and HF in this model. In conclusion, our data provide evidence for skeletal muscle anti-atrophic effect upon AET in &#945;2A/&#945;2C ARKO that is related, at least in part, to a reduced UPS

Background - Regular exercise reduces the risk of cardiovascular disease and subsequent sudden cardiac death (SCD). However, a small, but notable proportion of athletes die suddenly due to inherited or congenital disorders of the heart that predispose to malignant ventricular arrhythmias. Such tragedies are highly publicised, particularly when high-profile athletes are involved. To date, limited evidence for the efficacy of cardiovascular pre-participation screening exists outside of the Italian experience. Furthermore, limited data exists examining the impact of ethnicity on cardiac adaptations to physical training. Whilst the cardiovascular benefits of exercise are well known, the impact of life-long endurance exercise is less well understood. Long term high-intensity endurance exercise is associated with changes in cardiac morphology together with electrocardiographic alterations that are believed to be physiologic in nature. Recent data however, has suggested a number of deleterious adaptive changes in cardiac structure, function and electrical activity in response to life-long endurance activity. Aims and Objectives - The aims of this PhD were; 1) To find an effective preparticipation screening method that would successfully identify pre-existing cardiovascular abnormalities, 2) To identify the prevalence of hypertrophic cardiomyopathy and Long QT syndrome in elite UK athletes; 3) To examine the impact and significance of ethnicity upon left ventricular remodelling in elite athletes, and 4) To examine the acute and chronic impact of ultra-endurance exercise across the life-span in male endurance athletes. Major Results and Conclusions – 1) Study 2 sought to confirm the efficacy of resting 12-Lead ECG ‘alongside’ personal/family history questionnaires and physical examinations as collective tools to identify diseases that have the potential of causing sudden death within a cohort of elite junior athletes (n=1074) and physically active school children (n=1646). Nine participants were identified with a positive diagnosis of a disease associated with SCD. None of those diagnosed with a disease associated with SCD were symptomatic or had a family history of note. Thus, personal symptoms and family history questionnaires alone are inadequate in the identification of individuals with diseases associated with SCD. In conclusion, resting 12-Lead ECG is paramount when screening for diseases that have the potential of causing sudden death in the young. 2) Study 3 examined 3,500 asymptomatic elite athletes (75% male) with a mean age of 20.5 ± 5.8 years with 12-lead ECG and 2-dimensional echocardiography. None had a known family history of HCM. Of the 3,500 athletes, 53 (1.5%) had LVH (mean 13.6 ± 0.9mm, range 13 to 16mm), and of these 50 had a dilated LV cavity with normal diastolic function to indicate physiological left ventricular hypertrophy. Three (0.08%) athletes with LVH had a non-dilated LV cavity and associated deep T-wave inversion that could have been consistent with HCM. However, none of the 3 athletes had any other phenotypic features of HCM on further non-invasive testing and none had first-degree relatives with features of HCM. In conclusion, the prevalence of HCM in elite athletes is significantly less than in the general population; with the demands of strenuous exercise on the cardiovascular system selecting out most individuals with HCM. Study 4 examined 2000 elite athletes in order to identify the prevalence of Long QT syndrome. Three athletes had a QTc value of >500 ms and all exhibited one of: paradoxical prolongation of QTc during exercise, a confirmatory genetic mutation, or prolonged QTc in a first-degree relative. In contrast, none of the athletes with a QTc value of <500 ms had any other features to indicate LQTS. Accordingly, the prevalence of a prolonged QTc interval in elite British athletes is 0.4%. 3) Study 6 examined 300 nationally ranked UK black male athletes (mean age 20.5 years) in comparison to 150 black and white sedentary individuals and 300 highly-trained white male athletes. Black athletes exhibited greater LV wall thickness and cavity size compared with sedentary black and white individuals. Black athletes had greater LV wall thickness compared with white athletes. A minority of black athlete’s exhibit LVH ≥15 mm; proposing that in the absence of cardiac symptoms or a family history of HCM, an LV wall thickness ≥15 mm in black athletes may represent physiologic LVH when the LV cavity is enlarged and diastolic indexes are normal. 7 black athletes (12%) with LVH displaying deep T-wave inversions in leads V1 to V4. In conclusion, in the absence of obvious pathology, these electrical anomalies in black athletes likely represent a normal spectrum of ECG changes in response to physical training. 4) Study 8 examined 17 male participants (age 33.5 ± 6.5 years, 26–40 years) using cardiac magnetic resonance (CMR) and echocardiography before and after a marathon to investigate the relationship between systolic function and diastolic function against biomarkers of cardiac damage. Results demonstrates biomarkers of myocardial cell damage following an acute bout of prolonged exercise are not associated with either systolic or diastolic functional measures, and do not seem to be associated with any detectable myocardial inflammation, oedema, or scarring using either gold standard techniques of gadolinium enhanced CMR or echocardiography respectively. The impact of multiple episodes of prolonged exercise, as experienced by highly trained veteran endurance athlete is not fully understood. 5) Study 10 examined the cardiac structure and function of 12 life-long, competitive endurance veteran athletes (> 50 yrs, mean ± SD marathons 178 ± 209 (range 20 – 650)) against 17 young male endurance athletes (<40 yrs) using echocardiography and CMR with late gadolinium enhancement (LGE) to assess myocardial fibrosis. Lifelong veteran athletes had smaller LV and RV end-diastolic and end-systolic volumes (p<0.05) but maintained LV and RV systolic function compared with young athletes. In 6 (50%) of the veteran athletes LGE of CMR indicated the presence of myocardial fibrosis; no LGE in the young athletes. The prevalence of LGE in veteran athletes was not associated with the number of competitive marathons or ultra-endurance marathons (>50 miles) completed, age, LV and RV end-diastolic volumes or LV mass (p>0.05). In conclusion, there is limited evidence at present demonstrating that cardiovascular re-modelling following lifelong endurance exercise leads to long-term disease progression, cardiovascular disability or SCD.

Recent research suggests that adding protein (PRO) to a carbohydrate (CHO) supplement can have substantial benefits for endurance exercise performance and recovery beyond that of CHO alone. CHO+PRO supplements are often commercially available formulations consisting of carbohydrates (dextrose, maltodextrin) and whey protein. The effects of a supplement containing moderate protein and a low-CHO mixture on endurance performance has not been investigated. Also, the effects of CHO+PRO supplementation in the form of a natural food, flavored milk, on measures of recovery from acute endurance exercise, as well as on chronic aerobic exercise training adaptations, have not been characterized. Therefore, in this series of four studies, the effects of CHO+PRO supplementation on the following areas of endurance exercise performance, recovery, and adaptation are investigated: acute endurance exercise performance, inflammatory and muscle damage markers, muscle glycogen resynthesis, activation of signaling proteins involved in the initiation of protein synthesis and degradation, subsequent endurance exercise performance, and chronic aerobic training adaptations (maximal oxygen consumption, oxidative enzyme activity, body composition, immune cell levels, and inflammatory markers). Study 1 demonstrated that a supplement containing a low-CHO mixture plus moderate protein significantly improved aerobic endurance when cycling at or below the ventilatory threshold, despite containing 50% less CHO and 30% fewer calories relative to a higher CHO beverage. Study 2 demonstrated that CHO+PRO supplementation in the form of chocolate milk (CM) is an effective post-exercise supplement that can improve subsequent performance and provide a greater intracellular signaling stimulus for protein synthesis compared to CHO and placebo. Study 3 found that post-exercise CM supplementation during 4.5 wks of aerobic exercise training improves the magnitude of cardiovascular adaptations more effectively than isocaloric CHO or placebo, while the fourth study demonstrated that post-exercise CM supplementation during 4.5 wks of aerobic training improves body composition more effectively than isocaloric CHO or placebo. The fourth study also demonstrated that 4.5 wks of training does not appear to perturb resting immune cell concentrations or markers of inflammation and muscle damage. Taken together, the results of this research series suggest that CHO+PRO supplementation extends endurance performance, improves recovery, and increases training adaptations more effectively than CHO or placebo. / text

A atrofia está associada ao aumento da degradação protéica em doenças sistêmicas, sendo o sistema proteolítico ubiquitina proteassoma (SUP) uma das principais vias envolvidas. Contudo, pouco é conhecido sobre a contribuição do SUP à atrofia desencadeada pela insuficiência cardíaca (IC). Sabendo dos benefícios do treinamento físico aeróbico (TFA) e que os mecanismos moleculares envolvidos na atrofia na IC ainda não estão esclarecidos, nessa dissertação investigamos: 1) a contribuição do SUP para a atrofia associada à IC em 2 modelos experimentais: um modelo genético de camundongos com hiperatividade simpática (HS), e um modelo de infarto do miocárdio (IM) em ratos e 2) o efeito do TFA sobre a atrofia associada à IC e sobre o SUP. Na HS verificamos aumento da expressão das E3 ligases, da deubiquitinase USP28, das proteínas ubiquitinadas e da atividade do proteassoma no sítio quimiotripsina, sendo que o TFA reduziu a expressão dos componentes alterados. No IM, observamos disfunção cardíaca não associada à IC, porém, com aumento da expressão de Atrogin-1; enquanto o TFA não produziu efeitos significantes. Dessa forma, os dados sugerem a participação do SUP na atrofia desencadeada pela IC na HS e, que o TFA previne a atrofia por reduzir a expressão/atividade de alguns componentes do SUP; e, que no IM, o aumento da expressão de Atrogin-1 precedeu a perda de massa muscular / Skeletal muscle atrophy is associated with increased protein degradation in systemic diseases, which seems to be mainly related to ubiquitin-proteasome system (UPS). However, little is known about UPS contribution to the heart failure-induced muscle atrophy (HF-MA). Likewise, aerobic exercise training (AET) has been established as an adjuvant therapy for HF and molecular mechanisms underlying HF-MA has not been clarified yet. The objectives of the study were: 1) to verify UPS contribution for HF-MA in 2 experimental models: sympathetic hyperactivity-induced HF (&#945;2A/&#945;2CARKO) in mice, and myocardial infarction model (MI) in rats and 2) AET effects on HF-MA and UPS. In &#945;2A/&#945;2C ARKO mice, we observed activation of UPS characterized by increased mRNA levels of E3 ligases Atrogin-1 and E3-a, deubiquitinating enzyme USP28, increased levels of ubiquitinated proteins and chymotrypsin-like proteasome activity. AET prevented HF-MA in the &#945;2A/&#945;2C ARKO by reducing of UPS activity. In MI model, rats displayed cardiac dysfunction and exercise intolerance with no signs of atrophy. However, Atrogin-1 mRNA and protein levels were increased. Therefore, alterations in Atrogin-1expression might precede atrophy and HF in this model. In conclusion, our data provide evidence for skeletal muscle anti-atrophic effect upon AET in &#945;2A/&#945;2C ARKO that is related, at least in part, to a reduced UPS

Animals rely on lipids as a major fuel for endurance exercise because they pack more joules per gram than any other fuel. However, in contrast to mammals, information on how the mobilization of lipids from endogenous stores is managed to meet the needs of energy metabolism in swimming fish is sparse. Information on in vivo rates of lipid mobilization in swimming fish has been limited to relatively low exercise intensities and has only been investigated in a single species. Therefore, the goal of my thesis was to address this paucity of information by quantifying lipolytic rate in rainbow trout during graded exercise and fatty acid mobilization in Atlantic salmon during prolonged endurance exercise. In the first part of my work, I hypothesized that like mammals, rainbow trout stimulate lipolysis above resting levels to a peak with increasing work intensity, but subsequently lower its rate at high intensities when ATP production from carbohydrates becomes dominant. To test this hypothesis, I measured the rate of appearance of glycerol (Ra glycerol) in the blood (resulting from the breakdown of triacylglycerol (TAG)) of trout at rest (control) and during graded exercise from rest to Ucrit. Results showed that Ra glycerol in trout averaged 1.24 ± 0.10 µmol kg -1 min-1 and that this rate was unaffected by exercise of any intensity. These experiments revealed that rainbow trout do not modulate lipolysis during exercise. Furthermore, I calculated that baseline lipolytic rate was much higher in trout than in mammals and that this rate is in constant excess of the requirements of energy metabolism. My second investigation focused on measuring fatty acid mobilization in Atlantic salmon. To date, the majority of studies on energy metabolism in salmonids have used rainbow trout as the ubiquitous model for salmonids. I postulated that domesticated rainbow trout may be far less impressive athletes than their wild anadromous form and other salmonids. In this regard, I proposed that studying energy metabolism in Atlantic salmon (even those from aquaculture) may help to deepen our understanding of the physiology of true long-distance migrant fish. To study the effects of prolonged endurance exercise on the mobilization of fatty acids from endogenous stores in these fish, I monitored the rate of appearance of fatty acids (Ra NEFA calculated from Ra Palmitate) in the blood during 72 hours of sustained swimming. I found that contrary to what has been previously described in rainbow trout, Ra Palmitate (and by proxy, Ra NEFA) is reduced by approximately 64% (from 0.75 ± 0.12 µmol kg-1min-1 to 0.27 ± 0.06 µmol kg-1min-1 and from 19.3 ± 7.8 µmol kg-1min-1 to 6.9 ± 2.0 µmol kg-1min-1 for Ra Palmitate and Ra NEFA, respectively) during prolonged endurance exercise in Atlantic salmon. However, like in trout, even this reduced rate of fatty acid mobilization exceeds the requirements of energy metabolism at rest and during swimming. While further experiments will be necessary, I speculated that this reduction in Ra NEFA may be caused by a partial inhibition of lipolysis to reduce the energetic cost of TAG:FA cycling and optimize fuel budgets during prolonged endurance exercise. This thesis provides the first in vivo measurements of lipolysis during graded exercise in salmonids and the first in vivo measurements of fatty acid mobilization in Atlantic salmon. From the results mentioned above, I concluded that salmonids mobilize lipids in constant excess of the requirements for energy metabolism, possibly to allow for rapid reorganization of membrane phospholipids in response to changing environmental conditions. However, more anadromous and migratory phenotypes may rely on a tighter control of lipolysis to minimize the costs of substrate cycling and conserve energy on limited fuel stores.

Globally, cancer is one of the leading causes of mortality, with an estimated 18.1 million cancer cases, 10 million deaths, and 1.9 million new cases diagnosed in 2020 (Sung et al., 2021). However, during the past several decades, cancer survival has improved such that 82% of children and >2/3 of adults diagnosed with cancer will survive beyond five years (World Health Organization (WHO) - Childhood Cancer, 2021). Skeletal muscle atrophy and fibrosis are long-term adverse effects experienced by 80% of cancer survivors for which there is no available therapy (Paulino, 2004). These long-term consequences are related to the toxicity from the cancer treatment, leading to alterations in skeletal muscle function which can lead to comorbidities and increased mortality among cancer survivors (Paulino, 2004; Williams et al., 2016). Thus, novel approaches to address the long-term effects of cancer therapy on skeletal muscle are critically needed. Exercise training is a potential non-pharmacological strategy that improves common cancer- and treatment-related side effects (Mustian et al., 2012). Specifically, exercise programs that combine resistance and endurance training (RET) have been shown to improve muscle strength and cardiovascular fitness in cancer survivors (Tong et al., 2020). The mechanisms responsible for these effects remain unknown. The remarkable plasticity of skeletal muscle relies primarily on muscle stem (satellite) cells (MuSCs) (Lepper et al., 2011) that are regulated, in part, by muscle-resident stromal cells (Bentzinger et al., 2013). These different stromal cell types, including: vascular endothelial cells (ECs), immune cells, and mesenchymal progenitors, also known as fibro-adipogenic progenitors (FAPs), create the muscle stem cell niche (Yin et al., 2013). FAPs possess a dual role as they are involved in skeletal muscle maintenance and regeneration by secreting pro-myogenic trophic factors (Biferali et al., 2019; Joe et al., 2010; Uezumi et al., 2010; Wosczyna et al., 2019), but also contribute to fibrotic and fatty tissue accumulation in chronic degenerative conditions (Uezumi et al., 2010). The divergent features of FAPs highly depend on signals they receive from their microenvironment (Giuliani et al., 2021); however, FAP's contribution to cancer treatment-induced muscle pathology in cancer survivors remains unknown. The overall objective of this thesis is to begin to develop an understanding of the role of FAPs in cancer treatment-induced muscle pathology and to determine if RET represents an effective therapy to prevent the long-term muscle defects of juvenile cancer plus therapy.

Les facteurs de risque des maladies cardiovasculaires, telle, que la détérioration du profil lipidique, deviennent plus prononcés après la ménopause, ce qui fait de la maladie coronarienne, l’une des principales causes de décès chez les femmes ménopausées. Une proportion importante de femmes prennent du poids après la ménopause en particulier dans la région abdominale entraînant par conséquent des perturbations métaboliques. Des données récentes suggèrent également que l’absence des œstrogènes observée à la ménopause favorise le développement de la stéatose hépatique. Cette dernière a été incriminée pour incriminée dans le développement de la résistance à l'insuline, et est de ce fait considérée comme une composante hépatique du syndrome métabolique. Il est impératif d'établir des stratégies visant à contrecarrer l'accumulation de graisse dans le foie et l’accroissement du tissu adipeux chez les femmes ménopausées, en tenant compte que l'utilisation de l'hormonothérapie substitutive est de nos jours moins soutenue. Les quatre études de la présente thèse ont été conduites pour tenter de fournir des informations sur le traitement et la prévention de l’augmentation de la masse graisseuse et de la stéatose hépatique qu’entraîne la suppression des œstrogènes, à travers les modifications du mode de vie (diète et exercice physique) chez la rate ovariectomizée (Ovx); un modèle animal de la ménopause. Dans les deux premières études nous nous sommes concentrés sur l’augmentation de la masse graisseuse et sa reprise suite à une perte de poids. Dans la première étude, nous avons montré que les rates Ovx qui ont suivi un programme de restriction alimentaire (FR) ont diminué significativement (P < 0.01) leur poids corporel, leur contenu en graisses intra-abdominales ainsi que leurs triacylglycérols (TAG) hépatiques, comparativement aux rates Ovx nourries à la diète normale. De plus, l’entraînement en résistance (RT) a prévenu la reprise de poids corporel ainsi que l’accroissement du tissu adipeux et l’accumulation de lipides dans le foie des rates Ovx, après l’arrêt du régime amaigrissant. Les résultats de la deuxième étude ont confirmé l'efficacité de la restriction alimentaire associée à l’entraînement en résistance (FR + RT) dans la réduction du poids corporel, des lipides dans le foie et le tissu adipeux chez les rates Ovx. Tenant compte des résultats de notre première étude, l’entraînement en résistance seulement a constitué un atout pour atténuer le poids corporel et la masse grasse reprise par les rates Ovx suite à un programme de perte de poids (FR + RT); bien que l'impact ait été moindre comparé au maintien seul de la restriction alimentaire. De la même manière que la supplémentation en œstrogènes, les résultats de la troisième étude indiquent que l'entraînement en endurance mené concurremment avec l’ovariectomie a significativement atténué l'accumulation de lipides dans le foie ainsi que dans le tissu adipeux. Toutefois, l’entraînement en endurance effectué avant l'ovariectomie n'a pas protégé contre l'accumulation des graisses qu’entraîne l'ovariectomie, si celui-ci est interrompu après l'ovariectomie. Enfin, pour compléter les résultats antérieurs, nous avons montré dans la quatrième étude que l’expression des gènes impliqués dans la synthèse de lipide; SREBP-1c, SCD-1, ChREBP, et ACC dans le foie a augmenté après le retrait des œstrogènes, tandis qu’une diminution (P < 0.01) des niveaux d'ARNm de PPAR-α a été observée. De plus, l'expression hépatique des gènes des cytokines pro-inflammatoires incluant IKKβ, IL-6 ainsi que le contenu protéinique de NF-кB étaient augmentés (P < 0.01) chez les rates Ovx par rapport aux rates ayant subi une Ovx simulée (Sham). Toutes ces perturbations ont été améliorées avec la supplémentation en œstrogènes seulement, ainsi qu'avec l'entraînement en endurance seulement. Dans l'ensemble, nos résultats indiquent que l'exercice physique (en résistance ou en endurance) a un impact significatif sur la réduction de l'accumulation des lipides dans le foie et dans le tissu adipeux des rates Ovx. De plus, chez les rates Ovx, l’entraînement en endurance mimerait les effets des œstrogènes sur l'expression des gènes impliqués dans l'accumulation de lipides et l’inflammation préclinique dans le foie. / Cardiovascular disease risk factors, such as lipid profile deterioration, become more pronounced after menopause making coronary heart disease a leading cause of death among postmenopausal women. A large proportion of women after menopause gain weight especially in the abdominal region resulting in several metabolic disturbances. Recent evidence also suggests that loss of estrogen function in menopause is associated with the development of a state of hepatic steatosis. Excessive fat accumulation in hepatocytes has been shown to play an important role in the development of insulin resistance and is even considered as a hepatic component of the metabolic syndrome. There is an important need to establish strategies to counteract fat accumulation in adipocyte and liver in postmenopausal women specifically considering the fact that utilization of hormone replacement therapy is now less supported. The four studies of the present thesis have been conducted in an attempt to provide information on the treatment and prevention of estrogen withdrawal-induced fat mass and hepatic steatosis via lifestyle modifications (diet and exercise training) in an ovariectomized (Ovx) rat model of menopause. In the first two studies we focused on fat mass gain and regain following weight loss. In study 1, we showed that food restriction program (FR) decreased (P < 0.01) body mass, intra-abdominal fat pad weight, and liver triacylglycerol (TAG) levels as compared to normally fed Ovx rats. Moreover, resistance training program (RT) was useful in preventing body weight as well as adipose tissue and liver fat regain in Ovx rats, following diet-induced weight loss. Results of study 2 confirmed the efficiency of the FR + RT program in reducing body weight as well as liver and adipocytes fat accretion in Ovx rats. In line with the findings of our first study, continuation of only RT constituted an asset to attenuate body weight and fat mass regain in Ovx rats following a FR + RT weight loss program, although the impact was less than maintaining FR alone. Similar to estrogen supplementation, results of study 3 indicated that endurance exercise training conducted concurrently with the induction of ovariectomy significantly attenuated liver and adipocyte fat accumulation. However, an endurance exercise training state acquired before ovariectomy did not provide any protective effects against ovariectomy-induced fat accumulation if exercise is discontinued after the ovariectomy. Finally, complementing previous findings we showed in study 4 that liver gene expressions of transcription factors SREBP-1c and ChREBP along with downstream lipogenic enzymes SCD-1 and ACC were increased with estrogens withdrawal conversely to reduced PPAR-α mRNA levels (P < 0.01). Furthermore, gene expressions of pro-inflammatory cytokines including IKKβ and IL-6 as well as protein content of NF-кB were higher (P < 0.01) in the liver of Ovx than in Sham animals. All of these responses were corrected with estrogen supplementation alone as well as with endurance exercise training alone in Ovx rats. On the whole, our results indicate that exercise training (resistance or endurance) has a significant impact on reducing fat accumulation in liver and adipocytes in Ovx rats. In addition, it seems that endurance exercise training in Ovx rats stimulates estrogenic-like effects on the expression of genes involved in lipid accumulation and sub-clinical inflammation in the liver.

Les facteurs de risque des maladies cardiovasculaires, telle, que la détérioration du profil lipidique, deviennent plus prononcés après la ménopause, ce qui fait de la maladie coronarienne, l’une des principales causes de décès chez les femmes ménopausées. Une proportion importante de femmes prennent du poids après la ménopause en particulier dans la région abdominale entraînant par conséquent des perturbations métaboliques. Des données récentes suggèrent également que l’absence des œstrogènes observée à la ménopause favorise le développement de la stéatose hépatique. Cette dernière a été incriminée pour incriminée dans le développement de la résistance à l'insuline, et est de ce fait considérée comme une composante hépatique du syndrome métabolique. Il est impératif d'établir des stratégies visant à contrecarrer l'accumulation de graisse dans le foie et l’accroissement du tissu adipeux chez les femmes ménopausées, en tenant compte que l'utilisation de l'hormonothérapie substitutive est de nos jours moins soutenue. Les quatre études de la présente thèse ont été conduites pour tenter de fournir des informations sur le traitement et la prévention de l’augmentation de la masse graisseuse et de la stéatose hépatique qu’entraîne la suppression des œstrogènes, à travers les modifications du mode de vie (diète et exercice physique) chez la rate ovariectomizée (Ovx); un modèle animal de la ménopause. Dans les deux premières études nous nous sommes concentrés sur l’augmentation de la masse graisseuse et sa reprise suite à une perte de poids. Dans la première étude, nous avons montré que les rates Ovx qui ont suivi un programme de restriction alimentaire (FR) ont diminué significativement (P < 0.01) leur poids corporel, leur contenu en graisses intra-abdominales ainsi que leurs triacylglycérols (TAG) hépatiques, comparativement aux rates Ovx nourries à la diète normale. De plus, l’entraînement en résistance (RT) a prévenu la reprise de poids corporel ainsi que l’accroissement du tissu adipeux et l’accumulation de lipides dans le foie des rates Ovx, après l’arrêt du régime amaigrissant. Les résultats de la deuxième étude ont confirmé l'efficacité de la restriction alimentaire associée à l’entraînement en résistance (FR + RT) dans la réduction du poids corporel, des lipides dans le foie et le tissu adipeux chez les rates Ovx. Tenant compte des résultats de notre première étude, l’entraînement en résistance seulement a constitué un atout pour atténuer le poids corporel et la masse grasse reprise par les rates Ovx suite à un programme de perte de poids (FR + RT); bien que l'impact ait été moindre comparé au maintien seul de la restriction alimentaire. De la même manière que la supplémentation en œstrogènes, les résultats de la troisième étude indiquent que l'entraînement en endurance mené concurremment avec l’ovariectomie a significativement atténué l'accumulation de lipides dans le foie ainsi que dans le tissu adipeux. Toutefois, l’entraînement en endurance effectué avant l'ovariectomie n'a pas protégé contre l'accumulation des graisses qu’entraîne l'ovariectomie, si celui-ci est interrompu après l'ovariectomie. Enfin, pour compléter les résultats antérieurs, nous avons montré dans la quatrième étude que l’expression des gènes impliqués dans la synthèse de lipide; SREBP-1c, SCD-1, ChREBP, et ACC dans le foie a augmenté après le retrait des œstrogènes, tandis qu’une diminution (P < 0.01) des niveaux d'ARNm de PPAR-α a été observée. De plus, l'expression hépatique des gènes des cytokines pro-inflammatoires incluant IKKβ, IL-6 ainsi que le contenu protéinique de NF-кB étaient augmentés (P < 0.01) chez les rates Ovx par rapport aux rates ayant subi une Ovx simulée (Sham). Toutes ces perturbations ont été améliorées avec la supplémentation en œstrogènes seulement, ainsi qu'avec l'entraînement en endurance seulement. Dans l'ensemble, nos résultats indiquent que l'exercice physique (en résistance ou en endurance) a un impact significatif sur la réduction de l'accumulation des lipides dans le foie et dans le tissu adipeux des rates Ovx. De plus, chez les rates Ovx, l’entraînement en endurance mimerait les effets des œstrogènes sur l'expression des gènes impliqués dans l'accumulation de lipides et l’inflammation préclinique dans le foie. / Cardiovascular disease risk factors, such as lipid profile deterioration, become more pronounced after menopause making coronary heart disease a leading cause of death among postmenopausal women. A large proportion of women after menopause gain weight especially in the abdominal region resulting in several metabolic disturbances. Recent evidence also suggests that loss of estrogen function in menopause is associated with the development of a state of hepatic steatosis. Excessive fat accumulation in hepatocytes has been shown to play an important role in the development of insulin resistance and is even considered as a hepatic component of the metabolic syndrome. There is an important need to establish strategies to counteract fat accumulation in adipocyte and liver in postmenopausal women specifically considering the fact that utilization of hormone replacement therapy is now less supported. The four studies of the present thesis have been conducted in an attempt to provide information on the treatment and prevention of estrogen withdrawal-induced fat mass and hepatic steatosis via lifestyle modifications (diet and exercise training) in an ovariectomized (Ovx) rat model of menopause. In the first two studies we focused on fat mass gain and regain following weight loss. In study 1, we showed that food restriction program (FR) decreased (P < 0.01) body mass, intra-abdominal fat pad weight, and liver triacylglycerol (TAG) levels as compared to normally fed Ovx rats. Moreover, resistance training program (RT) was useful in preventing body weight as well as adipose tissue and liver fat regain in Ovx rats, following diet-induced weight loss. Results of study 2 confirmed the efficiency of the FR + RT program in reducing body weight as well as liver and adipocytes fat accretion in Ovx rats. In line with the findings of our first study, continuation of only RT constituted an asset to attenuate body weight and fat mass regain in Ovx rats following a FR + RT weight loss program, although the impact was less than maintaining FR alone. Similar to estrogen supplementation, results of study 3 indicated that endurance exercise training conducted concurrently with the induction of ovariectomy significantly attenuated liver and adipocyte fat accumulation. However, an endurance exercise training state acquired before ovariectomy did not provide any protective effects against ovariectomy-induced fat accumulation if exercise is discontinued after the ovariectomy. Finally, complementing previous findings we showed in study 4 that liver gene expressions of transcription factors SREBP-1c and ChREBP along with downstream lipogenic enzymes SCD-1 and ACC were increased with estrogens withdrawal conversely to reduced PPAR-α mRNA levels (P < 0.01). Furthermore, gene expressions of pro-inflammatory cytokines including IKKβ and IL-6 as well as protein content of NF-кB were higher (P < 0.01) in the liver of Ovx than in Sham animals. All of these responses were corrected with estrogen supplementation alone as well as with endurance exercise training alone in Ovx rats. On the whole, our results indicate that exercise training (resistance or endurance) has a significant impact on reducing fat accumulation in liver and adipocytes in Ovx rats. In addition, it seems that endurance exercise training in Ovx rats stimulates estrogenic-like effects on the expression of genes involved in lipid accumulation and sub-clinical inflammation in the liver.