A menopausa é o final da vida reprodutiva da mulher e pode ter como consequência a perda da massa óssea e desenvolvimento da osteoporose. A sarcopenia decorrente do processo de envelhecimento acarreta na diminuição de massa e força muscular, déficit de desempenho e maior risco de quedas e fraturas. A Ressonância Nuclear Magnética (RNM) é uma ferramenta não invasiva e eficaz para a avaliação quantitativa e da dinâmica metabólica do músculo esquelético. Por meio do mapa T2 é possível captar as alterações musculares agudas causadas pela atividade física. A intensificação do sinal T2 é causada pelo movimento osmótico da água intramuscular, aumento da acidose e do volume do espaço intracelular. O objetivo desta pesquisa foi avaliar a influência da densidade mineral óssea no metabolismo muscular de mulheres pós-menopáusicas. Foram avaliadas 16 pacientes do sexo feminino, no período pós-menopausa há mais de 12 meses, com média de idade de 63 anos, divididas em Grupo-Osteoporose (GO=9) e Grupo Controle (CG=7). Todas foram submetidas ao exame de Ressonância Nuclear Magnética da região da coxa (RNM1) e em seguida fizeram uma dinamometria isocinética na velocidade de 180 graus/segundo (duas séries de 10 contrações voluntárias máximas) e exercícios específicos para ativação do músculo quadríceps (agachamento e \"step\"), e após os exercícios, fizeram a RNM2. Os resultados mostraram aumento do mapa T2, caracterizado pelo maior tempo de relaxamento nos dois grupos avaliados, sem diferença entre eles. Não se observou correlação significativa dos resultados da RNM2 com os parâmetros de força (pico de torque corrigido pela massa corporal) e potência (trabalho total das 10 repetições da segunda série) e com a dosagem de vitamina D. Também não houve correlação entre a dinamometria isocinética e dosagem de vitamina D. A osteoporose não afeta a resposta muscular do quadríceps ao exercício, avaliada pelo mapa T2 da ressonância nuclear magnética. A metodologia é robusta e eficiente, mostrando que a RM é um método sensível para medir mudanças metabólicas no músculo após o exercício / Menopause is the end of woman\'s reproductive life and consequences as loss of bone mass and osteoporosis may emerge. The ageing\'s sarcopenia entails the reduction of muscle mass and strength, deficit of physical performance and increases the risk of falls and fractures, which is also present in postmenopausal women. Magnetic resonance imaging (MRI) is a noninvasive and effective tool for quantitative assessment and metabolic dynamics of skeletal muscle. Through the T2 map is possible to capture acute muscle disorders caused by physical activity. Intensification of T2 sign is caused by osmotic movement of intramuscular water, increase of acidosis and intracellular space volume. The aim of this study was to evaluate bone mineral density in muscle metabolism in postmenopausal women. We evaluated 8 female patients in postmenopausal for more than 12 months, with a mean age of 63 years, divided into osteoporosis-group (GO=9) and control group (CG=7). They were submitted to MRI examination of thigh at rest (RM1), and then the isokinetic dynamometer at the speed of 180 degrees/second, 2 sets of 10 maximal voluntary contractions and specific exercises to activate the quadriceps muscle (squats and step) and then the RM2 to capture the muscle metabolic changes. For perception of fatigue level, samples of lactate were taken at rest (Lac1), after 1 minute (lac2) and 3 minutes (Lac3) from the end of the exercises. In both groups, it was observed variation of lac2 Lac3, confirming that fatigue levels and changes in RM2 compared to RM1 in the uptake of water were achieved due to intramuscular specific physical changes in post-exercise muscle metabolism. The results showed increased T2 map, characterized by the highest relaxation time in both groups and there are no difference between them. There was no significant correlation of the results of the RNM2 with the parameters of force (peak torque corrected by body mass) and potency (total work) and with the dosage of vitamin D. There was also no correlation between the isokinetic dinamometria and dosage of vitamin D. Osteoporosis does not affect the muscle response of the quadriceps to exercise, assessed by the T2 map of magnetic resonance imaging. The methodology proved to be robust and efficient, showing that MRI is a sensitive method to measure metabolic changes in muscle after exercise

成人骨量的更新与维持通过骨重塑来实现。骨重塑包括骨吸收与骨形成两个偶联的过程，其中成骨细胞介导骨形成，破骨细胞介导骨吸收，当偶联的骨吸收超过骨吸收就会导致骨量丢失，进而导致发生骨质疏松症的发生。目前，临床治疗骨质疏松的药物如阿仑膦酸盐、雌激素受体调节剂、活性维生素D、雌激素替代治疗、降钙素、骨化三醇等都是基于针对破骨细胞的调控来抑制骨吸收，但是对于已经丢失的骨量无法恢复。唯一被美国FDA批准用来通过刺激新骨形成来恢复丢失的骨量的治疗药物就是甲状旁腺激素。然而，这种药物在刺激新骨形成的同时也刺激了骨吸收，即：在使用18个月后有明显促进骨吸收的副作用。 / 酪蛋白激酶相互作用蛋白-1（CKIP-1）基因是一个新发现的骨形成的负调控基因，CKIP-1基因敲除小鼠在骨发育和正常骨代谢过程中均未发现激活骨吸收。CKIP-1敲除导致小鼠胫骨近端骨量与胫骨皮质骨形成速率显著高于野生型，且这一差异随着小鼠的增龄而显著，而骨外器官没有发现异常表型，提示CKIP-1是潜在相对安全的治疗骨质疏松的靶向基因。特别是我们最近研发的一种天门冬氨酸－丝氨酸－丝氨酸重复三肽修饰的脂质体递送（(Asp-Ser-Ser)₆-liposome）系统能够实现靶向骨形成表面的小干扰核酸的递送，并明显减少了小干扰核酸在非骨组织的分布。因此，提出本课题的研究假设：特异性静默骨内CKIP-1可以促进骨形成而不刺激骨吸收，从而为骨质疏松的临床治疗提供安全有效的治疗手段。 / 为了确定CKIP-1基因表达在老年绝经后妇女骨骼中与骨形成内在联系，首先，我们通过对发生骨折的老年绝经后妇女的骨痂标本中CKIP-1 mRNA和蛋白表达的测定，发现CKIP-1基因mRNA和蛋白表达水平与骨形成能力负相关。并且，这种相关性在骨质疏松动物模型中进一步得到证实。其次，针对我们研究假设，从一组针对大鼠、小鼠、猴和人类的成骨样细胞的CKIP-1 mRNA的跨种属siRNA序列中筛选出体外静默效率最高CKIP-1小干扰核酸序列si-3。接着，体内外实验证实si-3序列在健康动物体内的静默效率和促进成骨的功能。同时，确定尾静脉注射（Asp-Ser-Ser）₆-liposome 包裹的CKIP-1小干扰核酸在 大鼠和小鼠为的最佳剂量分别为3.75mg/kg和7.5mg/kg以及注射周期为每两周一次。最后，为了检验CKIP-1 小干扰核酸是否可通过促进骨形成从而逆转绝经后骨质疏松症中的骨丢失，我们分别以绝经后骨质疏松大鼠和小鼠为实验动物模型，通过测定骨形态计量学参数、骨量和骨结构等来评价骨靶向递送系统（(Asp-Ser-Ser)₆-liposome）递送的CKIP-1 siRNA对老年绝经后骨质疏松症的治疗效果。动态活体CT分析结果表明，与0周未治疗的基础值相比，经6周治疗骨密度（BMD）, 相对骨体积分数（BV/TV）和骨小梁厚度（Tb.Th）在小干扰核酸治疗组显著增加。此外，在治疗6周后小干扰核酸治疗组骨密度，相对骨体积和骨小梁厚度显示较高于模型对照组。0周与其它检测时间点之间的对比分析较显示，小干扰核酸治疗组的新生骨显著高于模型组或假手术组。组织形态学分析结果表明在治疗6周后，无论是股骨远端或中段的矿化沉积率（MAR）、骨形成速率（BFR） 和组的骨形成表面（Ob.S/ BS）在OVX组和siRNA组均显著高于模型对照组，而模型对照组和小干扰核酸治疗组的骨吸收表面（Oc.S/ BS）之间无显著性差异。 / 结论：CKIP-1基因小核酸干扰治疗在老年绝经后骨质疏松中能够显著促进骨形成并不会加剧骨吸收，该药物具有显著逆转骨丢失的作用。 / Osteoporosis is characterized by an imbalance between bone formation and bone resorption. Therefore, promoting bone formation and inhibiting bone resorption are the two major therapeutic strategies in the treatment of osteoporosis. Currently, the only Food and Drug Administration (FDA)-approved anabolic agent capable of stimulating bone formation is parathyroid hormone (PTH). However, dominant bone resorption after 18-month treatment with PTH is a great concern (Rubin and Bilezikian 2003). Thus, development of alternative bone anabolic agents is highly desirable. / Casein kinase-2 interacting protein-1 (CKIP-1), which is encoded by Plekho1, and thus also known as Plekho1, is a newly discovered negative regulator of bone formation during bone development and subsequent bone maintenance that does not activate bone resorption (Lu, Yin et al. 2008). Specifically, CKIP-1 protein functions as the auxiliary factor of ubiquitin ligase Smad ubiquitylation regulatory factor 1 (Smurf1) to interrupt the bone anabolic BMP-signalling pathway, which has been demonstrated to be a specific suppressor of bone formation (Yamashita, Ying et al. 2005). In a previous study, we found that CKIP-1 expression in female rat bone increases with aging, whereas bone formation decreases with aging (Guo, Zhang et al. 2010). Systemic examination of the tissue distribution of CKIP-1 expression has revealed that is abundantly expressed in the musculoskeletal system but sparingly expressed in the liver, lungs, kidneys, pancreas, and other organs (Zhang, Tang et al. 2007). In addition, an abnormal tissue phenotype in heart, liver, spleen, lung, and kidney tissue has not been observed in CKIP-1 gene knockout mice (KO), even at an advanced age (Lu, Yin et al. 2008). Thus, CKIP-1 gene silencing might be a potential strategy for promoting bone anabolic action in reversing bone loss. / RNA interference (RNAi), a natural cellular process that regulates gene expression by a highly precise mechanism of sequence-directed gene silencing at the stage of translation by degrading specific messenger RNA and then blocking translation of the specific gene, has been employed for gene silencing in vivo (Frank-Kamenetsky, Grefhorst et al. 2008). Accordingly, RNAi should be an appropriate target for CKIP-1 gene silencing in vivo. / We raised the hypothesis that therapeutic RNAi targeting of CKIP-1 might promote bone formation for reversing postmenopausal bone loss. To test the hypothesis, we performed several studies to achieve the following specific aims: (1) To explore the relationship between CKIP-1 expression and bone formation in aged postmenopausal osteoporosis; (2) To Identify a cross-species CKIP-1 siRNA sequence with high knockdown efficiency; (3) To validate of the identified CKIP-1 siRNA in healthy rodents in vivo; (4) To examine the anabolic effect of the identified CKIP-1 siRNA on bone in osteoporotic animal models. / The relationship between CKIP-1 gene expression and bone formation in bone specimens from aged postmenopausal women: To explore the association between CKIP-1 gene expression and bone formation in bone specimens from aged postmenopausal women, the gene expression of CKIP-1 and ALP in the bone specimens from aged female patients were examined. We found the protein expression of CKIP-1 increased during aging and negatively correlate to bone formation as indicated by the mRNA expression of ALP (Guo., Zhang. et al. 2011). Further, we also found the decreased bone formation during aging was partly rescued in Ckip-1 KO mice during aging. / A cross-species CKIP-1 siRNA sequence: Recently, we identified a specific CKIP-1 siRNA sequence (CKIP-1 siRNA si-3) with high knockdown efficiency across rat, mouse, rhesus, and human osteoblast-like cells that does not induce immunostimulatory activity and promotes osteoblast differentiation across the species in vitro and bone formation in rats in vivo (Guo, Zheng et al. 2012). / Validation of the CKIP-1 siRNA si-3 capsulated by bone-targeted siRNA delivery system in healthy rodents in vivo: We developed a bone-targeting siRNA delivery system (tripeptide aspartate-serine-serine linked with liposome, i.e. (Asp-Ser-Ser)₆-liposome) that can remarkably reduce the exposure of non-bone tissue to CKIP-1 siRNA (Zhang, Guo et al. 2012). To validate the identified CKIP-1 siRNA in healthy rodents in vivo, the established continuous CKIP-1 gene silencing protocol is optimized in adult rats and mice in vivo by hydrodynamic tail vein injection of 3.75mg/kg for rats and 7.5 mg/kg for mice every 2 weeks (Guo, Zhang et al. 2010). The osteogenic effects of CKIP-1 siRNA in both rats and mice were further validated in vivo. / Anabolic effect of CKIP-1 siRNA si-3 on bone in aged postmenopausal osteoporosis: For evaluation of the anabolic effect of CKIP-1 siRNA si-3 on reversing bone loss due to osteoporosis in an animal model, we intravenously injected ovariectomized (OVX) rats and mice with CKIP-1 siRNA delivered by the (Asp-Ser-Ser)₆-liposome, a liposome linked with six repeated aspartate-serine-serine moiety, every 2 weeks for 6 weeks. In vivo and ex vivo microCT analysis demonstrated a change over time in the variables examined and different change patterns over time among the groups examined after administration. We found that the siRNA group had experienced a significant increase in bone mineral density (BMD), relative bone volume (BV/TV), and trabecular thickness (Tb.Th) between weeks 0 and 6; had a higher BMD, BV/TV, and Tb.Th compared to the OVX group at week 6; and had a similar Tb.Th to that of the SHAM group at week 6. Registration analysis between week 0 and other time points revealed that the siRNA had a greater number of newly formed bone than the OVX and SHAM groups. Histomorphometric analysis showed that the siRNA group had a significantly higher mineralization rate (MAR), a significantly higher bone-formation rate (BFR), a significantly larger osteoblast surface (Ob.S/BS) at both the distal and mid-shaft femur compared to the OVX group after 6 weeks of treatment but not a significantly different Oc.S/BS. / Significance: Confirmation of our hypothesis by our results helps establish CKIP-1’s role as a pivotal negative regulator of bone formation in the aging skeleton and provides evidence that inhibiting CKIP-1 is a novel anabolic treatment for osteoporosis, indicating great potential for the use of therapeutic RNAi in orthopaedics and traumatology. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Guo, Baosheng. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves [132-150]). / Abstract also in Chinese. / Declaration --- p.i / Acknowledgements --- p.ii / Abstract --- p.iii / 论文摘要 --- p.vii / Table of Content --- p.ix / Abbreviations --- p.xvii / List of Figures --- p.xix / List of Tables --- p.xxii / Chapter CHAPTER 1 --- Review of recent anabolic therapy for osteoporosis --- p.1 / Chapter 1.1. --- Epidemiology of postmenopausal osteoporosis --- p.1 / Chapter 1.1.1. --- Definition of osteoporosis --- p.1 / Chapter 1.1.2. --- Epidemiology and health challenge of postmenopausal osteoporosis --- p.2 / Chapter 1.2. --- General pathophysiological understanding of osteoporosis and current challenge for osteoporosis treatment --- p.3 / Chapter 1.2.1. --- Bone modeling and remodeling --- p.3 / Chapter 1.2.2. --- Pathophysiological process of osteoporosis --- p.4 / Chapter 1.2.3. --- Systemic risk factors in the pathophysiology of osteoporosis --- p.5 / Chapter 1.2.4. --- Local risk factors in the osteoporosis pathophysiology --- p.6 / Chapter 1.2.5. --- Two therapeutic strategies for osteoporosis treatment --- p.7 / Chapter 1.3. --- Current and potential anabolic agents for osteoporosis treatment --- p.8 / Chapter 1.3.1. --- PTH analogues --- p.8 / Chapter 1.3.2. --- Potential concerns regarding PTH administration --- p.9 / Chapter 1.3.3. --- Potential PTH alternatives --- p.10 / Chapter 1.3.4. --- Modulation of Wnt/β-cateinin pathway --- p.10 / Chapter 1.3.5. --- Aptamer-based technology in osteoporosis treatment --- p.14 / Chapter 1.4. --- CKIP-1: A novel negative regulator of bone formation --- p.15 / Chapter 1.4.1. --- TGF-β/BMP signaling pathways involved in regulating bone formation --- p.15 / Chapter 1.4.2. --- CKIP-1 interrupts BMP signaling pathway --- p.16 / Chapter 1.4.3. --- CKIP-1 negatively regulates bone formation without activating bone resorption --- p.17 / Chapter 1.5. --- RNA interference strategy in anabolic therapy of osteoporosis --- p.18 / Chapter 1.5.1. --- siRNA-mediated gene silencing in osteoporosis treatment --- p.18 / Chapter 1.5.2. --- MicroRNAs as potential therapeutic targets in the anabolic treatment of osteoporosis --- p.20 / Chapter 1.5.3. --- Bone targeted RNAi-based anabolic-agents delivery --- p.23 / Chapter 1.6. --- Summary --- p.24 / Chapter CHAPTER 2 --- The relationship between CKIP-1 expression and bone formation in aged postmenopausal osteoporosis --- p.26 / Chapter 2.1 --- Introduction --- p.26 / Chapter 2.2 --- Materials and methods --- p.28 / Chapter 2.2.1 --- Bone specimen collection from aged postmenopausal women --- p.28 / Chapter 2.2.2 --- Total RNA extraction, reverse transcription and quantitative real-time PCR --- p.28 / Chapter 2.2.3 --- Total protein extraction and western blot analysis --- p.30 / Chapter 2.2.4 --- CKIP-1 expression in bone and other tissues --- p.31 / Chapter 2.2.5 --- Relationship between CKIP-1 expression and bone formation in aged ovariectomized rats --- p.31 / Chapter 2.2.6 --- Role of CKIP-1 in regulating bone formation in aged ovariectomized mice --- p.32 / Chapter 2.2.7 --- Statistics --- p.32 / Chapter 2.3 --- Results --- p.33 / Chapter 2.3.1 --- Correlation analysis between CKIP-1 expression and bone formation-related gene expression in bone specimens from agedd postmenopausal women across age --- p.33 / Chapter 2.3.2 --- CKIP-1 gene expression pattern in bone and other tissues --- p.37 / Chapter 2.3.3 --- Correlation between CKIP-1 expression and bone formation in rat bone --- p.38 / Chapter 2.3.4 --- CKIP-1 negatively regulates bone formation in aged ovariectomized mice by using CKIP-1 knockout mice --- p.39 / Chapter 2.4 --- Summary --- p.41 / Chapter CHAPTER 3 --- Identification of a cross-species CKIP-1 siRNA sequence --- p.43 / Chapter 3.1 --- Introduction --- p.43 / Chapter 3.2 --- Materials and methods --- p.44 / Chapter 3.2.1 --- Design rationale and modification for cross-species CKIP-1 siRNA --- p.44 / Chapter 3.2.2 --- In vitro screening for cross-species CKIP-1 siRNA sequences --- p.45 / Chapter 3.2.3 --- Investigation of the effects of the identified CKIP-1 siRNA on the expression of osteoblast phenotype genes --- p.47 / Chapter 3.2.4 --- Total RNA extraction, reverse transcription and quantitative real-time PCR --- p.47 / Chapter 3.2.5 --- Western blot analysis --- p.51 / Chapter 3.2.6 --- Evaluation of calcium deposition --- p.51 / Chapter 3.2.7 --- BMP-2 reporter activity assay in MC3T3-E1 cells --- p.52 / Chapter 3.2.8 --- Isolation of the primary human blood monocytes and IFN-α and TNF-α measurement --- p.53 / Chapter 3.2.9 --- Statistics --- p.54 / Chapter 3.3 --- Results --- p.54 / Chapter 3.3.1 --- Bio-informatic analysis of the designed CKIP-1 siRNA sequences --- p.54 / Chapter 3.3.2 --- Identified the cross-species CKIP-1 siRNA sequences by In vitro screening --- p.56 / Chapter 3.3.3 --- Effects of the identified CKIP-1 siRNA on the expression of osteoblast phenotype genes --- p.60 / Chapter 3.3.4 --- Effects of the identified CKIP-1 siRNA on matrix mineralization --- p.65 / Chapter 3.3.5 --- Effect of the identified CKIP-1 siRNA on BMP signaling --- p.67 / Chapter 3.3.6 --- Effects of the identified CKIP-1 siRNA on the ratio of RANKL/OPG --- p.67 / Chapter 3.3.7 --- Effects of the identified CKIP-1 siRNA on immunostimulatory activity --- p.68 / Chapter 3.4 --- Summary --- p.71 / Chapter 3.4.1 --- CKIP-1 siRNA si-3 as the identified sequence --- p.71 / Chapter 3.4.2 --- CKIP-1 siRNA si-3 promoted osteoblast differentiation in vitro --- p.72 / Chapter CHAPTER 4 --- Validation of the identified CKIP-1 siRNA in healthy rodents in vivo --- p.74 / Chapter 4.1 --- Introduction --- p.74 / Chapter 4.2 --- Materials and methods --- p.74 / Chapter 4.2.1 --- Localization of intraosseous siRNA delivered by (Asp-Ser-Ser)₆-liposome --- p.75 / Chapter 4.2.2 --- Cell-selective delivery in vivo of CKIP-1 siRNA --- p.76 / Chapter 4.2.3 --- Dose-response study of CKIP-1 siRNA --- p.77 / Chapter 4.2.4 --- Time-course study of CKIP-1 siRNA --- p.77 / Chapter 4.2.5 --- Examination of the effect of the identified siRNA on the expression of osteoblast phenotype genes --- p.78 / Chapter 4.2.6 --- Measurement for serum PINP and urinary DPD --- p.80 / Chapter 4.2.7 --- 5’-RACE Analysis --- p.81 / Chapter 4.2.8 --- Laser captured micro-dissection (LCM) --- p.82 / Chapter 4.2.9 --- Evaluation the anabolic effect of the identified siRNA on healthy rat bone --- p.82 / Chapter 4.2.10 --- Evaluation the anabolic effect of the identified siRNA on healthy mouse bone --- p.84 / Chapter 4.2.11 --- Micro CT analysis --- p.84 / Chapter 4.2.12 --- Dynamic bone histomorphometric analysis --- p.85 / Chapter 4.2.13 --- Statistics --- p.86 / Chapter 4.3 --- Results --- p.87 / Chapter 4.3.1 --- Rationale of bone targeted delivery of CKIP-1 siRNA by (Asp-Ser-Ser)₆-liposome --- p.87 / Chapter 4.3.2 --- Intraosseous distribution of siRNA delivered by (Asp-Ser-Ser)₆-liposome --- p.89 / Chapter 4.3.3 --- Optimal dosage and duration for CKIP-1 siRNA administration in vivo --- p.92 / Chapter 4.3.4 --- Knockdown efficiency of CKIP-1 siRNA in osteoblasts by LCM in combination with Q-PCR --- p.94 / Chapter 4.3.5 --- Examination of the effect of the identified siRNA on the expression of osteoblast phenotype genes --- p.96 / Chapter 4.3.6 --- RNAi mechanism of CKIP-1 siRNA action in vivo --- p.99 / Chapter 4.3.7 --- Anabolic effect of the identified siRNA on healthy rat bone --- p.101 / Chapter 4.3.8 --- Anabolic effect of the identified siRNA on healthy mouse bone . --- p.104 / Chapter 4.4 --- Summary --- p.107 / Chapter 4.4.1 --- Intraosseous localization of CKIP-1 siRNA after systemic administration --- p.107 / Chapter 4.4.2 --- Evidence of RNAi in bone tissue from systemic administration of CKIP-I siRNA --- p.107 / Chapter 4.4.3 --- CKIP-1 siRNA si-3 promots bone formation in rats and mice in vivo --- p.108 / Chapter CHAPTER 5 --- Anabolic effect of the identified CKIP-1 siRNA on bone in postmenopausal osteoporostic animal models --- p.110 / Chapter 5.1. --- Introduction --- p.110 / Chapter 5.2. --- Materials and Methods --- p.110 / Chapter 5.2.1. --- Evaluation of anabolic effect of CKIP-1 siRNA on osteoporotic mouse bone --- p.111 / Chapter 5.2.2. --- Evaluation of anabolic effect of CKIP-1 siRNA on osteoporotic rat bone --- p.112 / Chapter 5.2.3. --- In vivo micro-CT analysis and registration of proximal tibia from osteoporotic rats --- p.112 / Chapter 5.2.4. --- Ex vivo micro-CT analysis of the distal femur and 5th lumbar vertebrae body of osteoporotic rats --- p.115 / Chapter 5.2.5. --- Ex vivo micro-CT analysis of distal femur from osteoporotic mice --- p.115 / Chapter 5.2.6. --- Bone histomorphometric analysis --- p.116 / Chapter 5.2.7. --- Mechanical testing --- p.117 / Chapter 5.2.8. --- Statistics --- p.118 / Chapter 5.3. --- Results --- p.116 / Chapter 5.3.1. --- Anabolic effect of CKIP-1 siRNA si-3 on osteoporotic mouse bone --- p.118 / Chapter 5.3.2. --- In vivo microCT data of proximal tibia from aged osteoporotic rats --- p.121 / Chapter 5.3.3. --- Ex vivo microCT data of distal femur from aged osteoporotic rats --- p.124 / Chapter 5.3.4. --- Ex vivo microCT data of 5th LV body from aged osteoporotic rats --- p.126 / Chapter 5.3.5. --- Bone histomorphometric analysis of aged osteoporotic rats --- p.129 / Chapter 5.3.6. --- Mechanical testing of the mid-shaft femur of aged osteoporotic rats --- p.132 / Chapter 5.4. --- Summary --- p.134 / Chapter CHAPTER 6 --- Discussions --- p.134 / Chapter 6.1 --- CKIP-1 siRNA design rationale and further modification --- p.135 / Chapter 6.1.1 --- Specificity design rationale of the CKIP-1 siRNA --- p.135 / Chapter 6.1.2 --- Stability enhancing modification of CKIP-1 siRNA --- p.136 / Chapter 6.1.3 --- Safety concerns with CKIP-1 siRNA therapy --- p.136 / Chapter 6.2 --- Development of bone-targeted siRNA delivery --- p.136 / Chapter 6.3 --- Prospects for and limitation of application of study findings to clinical therapeutics --- p.137 / References --- p.139 / Publications --- p.159

Para elaboração deste estudo foram observadas e avaliadas 112 mulheres na pós-menopausa sem reposição hormonal, com e sem depressão. As características pessoais quantitativas são descritas com uso de medidas resumo (média, desvio padrão, mediana, mínimo e máximo) e as características qualitativas pessoais descritas com uso de frequências absolutas e relativas. O objetivo do estudo foi verificar se as mulheres com diagnóstico de depressão apresentavam diferenças nos resultados dos testes mnésticos e atencionais, quando comparadas às mulheres sem depressão. Verificar se os sintomas fogachos, sudorese noturna, funções mnésticas e atencionais interferiam nos resultados dos testes nas mulheres com e sem depressão, que foram realizados em quatro tempos: (T0) avaliação inicial, (T1) segunda avaliação, (T2) terceira avaliação, (T3) quarta avaliação, que foi efetuada seis meses após o término da terapia cognitiva comportamental. Acrescentou-se a nota de corte na Escala Climatérica Greene no tempo inicial obtendo-se assim, o coeficiente de correlação de Pearson e a validade de critério ? de Cronback, com índice geral de sensibilidade 0.91 e especificidade de 0.82, com nível de significância de 5% com poder de confiança de 95%. Os resultados dessa pesquisa demonstraram a eficácia da Terapia Cognitiva Comportamental, nos sintomas de ansiedade, depressão, fogachos, sudorese noturna, funções mnésticas e atencionais, em mulheres com e sem depressão na pós-menopausa, sem reposição hormonal / For this study, we observed and evaluated 112 postmenopausal women without hormonal reposition, with or without depression. Personal quantitative characteristics are described using summary statistics (average, standard deviation, median, minimum, maximum) and the personal qualitative characteristics described using absolute and relative frequencies. The main goal of this study was to verify if women diagnosed with depression show different results in mnestics and attentional tests when compared to women without depression. The work also verified if symptoms of hot flashes, night sweats, mnestics and attentional functions were associated with tests results of women with and without depression. The tests were applied four times: (T0) initial evaluation, (T1) second evaluation, (T2) third evaluation, and (T3) last evaluation, performed six months after the end of Cognitive Behavioral Therapy. Passing score was correlated with the Greene Climacteric Scale initial time to obtain the Pearson correlation coefficient and validation of Cronbach\'s criteria, with 0.91 as general index of sensitivity and 0.82 of specificity, significance level of 5%, with a confidence level power of 95%.This research showed the efficacy of Cognitive Behavioral Therapy for symptoms of anxiety, depression, hot flashes, night sweats, memory and attention functions in postmenopausal women with and without depression, without hormonal reposition

Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 4 uppsatser. Även tryckt utgåva.

Obesity increases breast cancer risk and progression in postmenopausal women. The Akt/mTOR signaling pathway is activated in tumors in response to increased levels of obesity-related growth factors, including insulin-like growth factor (IGF)-1. Hence, we evaluated energy balance modulation as a mechanism for breast cancer prevention through modulation of Akt/mTOR. Studies suggest that dietary calcium can decrease weight gain, although an exact mechanism is not yet identified. Therefore, we investigated the effects of low-fat (10 kcal % fat) or high-fat (45 kcal % fat) diets containing either calcium phosphate (dairy) or calcium carbonate (supplement) on body weight in ovariectomized (OVX) C57BL/6 mice to determine if dietary calcium could overcome the effects of a high-fat diet. We showed that dairy decreased body weight, with no effect on food consumption. However, it is not known if restoration of normal weight can reverse mammary tumor progression and/or Akt/mTOR pathway activation. To evaluate this, mice were fed a control diet, a calorie restricted regimen, or a diet-induced obesity (DIO) regimen for 17 weeks, after which the DIO mice were switched to the control diet, and this resulted in a 20% weight loss and mice of equal weight to control mice. MMTV-Wnt-1 mammary tumor cells were orthopically injected at week 20, following weight loss. At week 22, mice began placebo or RAD001, an mTOR inhibitor, treatment by oral gavage. Tumor growth and Akt/mTOR signaling were enhanced in formerly obese mice, despite reduction in weight, adiposity and serum hormone levels. RAD001 decreased tumor growth in the CR and control group, but was less effective in the formerly obese mice. In an additional study, we added a DIO gourp which was not switched to the control diet, and found that circulating IGF-1 levels remained significantly elevated in formerly obese mice relative to control and were comparable to levels in the DIO mice. We found that the mechanism of tumor progression was through enhanced Akt/mTOR signaling in both obese and formerly obese mice. Based on the Akt/mTOR activation in MMTV-Wnt-1 tumor growth and progression, we next investigated the anticancer effects of ursolic acid (UA), a pentacyclic triterpene. It was previously shown that UA can affect Akt signaling. Our results showed that UA was effective decreasing tumor growth and Akt/mTOR signaling. Taken together, our findings show that the growth-enhancing effects of obesity on mammary tumor may persist even after weight loss and suggest that a combination of dietary and pharmacologic interventions targeting IGF-1/Akt/mTOR may be an effective strategy in the treatment of postmenopausal breast cancer. / text

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Agradecemos a compreensão on 2016-05-30T18:33:22Z (GMT) / Submitted by TIEGO APARECIDO DINIZ null (tiegodiniz@gmail.com) on 2016-06-16T15:22:21Z No. of bitstreams: 1 20 - DEFESA.pdf: 4027170 bytes, checksum: 5d80e6b779588d24d06e4f27aa4bee6e (MD5) / Approved for entry into archive by Ana Paula Grisoto (grisotoana@reitoria.unesp.br) on 2016-06-16T16:12:44Z (GMT) No. of bitstreams: 1 diniz_ta_me_rcla.pdf: 4027170 bytes, checksum: 5d80e6b779588d24d06e4f27aa4bee6e (MD5) / Made available in DSpace on 2016-06-16T16:12:44Z (GMT). No. of bitstreams: 1 diniz_ta_me_rcla.pdf: 4027170 bytes, checksum: 5d80e6b779588d24d06e4f27aa4bee6e (MD5) Previous issue date: 2016-03-15 / Introdução: O período pós-menopausa é caracterizado por 12 meses ininterruptos de ausência de ciclo menstrual. Mulheres nesse período apresentam aumento da gordura corporal total, especialmente abdominal. Sabe que a gordura dessa região está relacionada com o desenvolvimento de diversas doenças, sendo assim, estratégias que visem tratar ou prevenir esse desfecho se fazem importante. Nesse contexto se destaca o treinamento combinado (associação de treinamento de força e aeróbio na mesma sessão de treino), por favorecer o aumento da massa corporal magra e a diminuição da gordura corporal. Estudos vêm mostrando que após um período de investigação clinica a reposta individual ao treinamento para variáveis metabólicas apresenta grande variação em relação à média. Entretanto, até a presente data nenhum estudo objetivou investigar as características das participantes que responderam positivamente e negativamente na composição corporal e no perfil metabólico após 16 semanas de treinamento combinado. Objetivo: Analisar as variáveis da composição corporal e metabólicas que podem interferir na resposta a 16 semanas de treinamento combinado em mulheres pós-menopausa. Materiais e métodos: Participaram do estudo mulheres com idade entre 50 a 77 anos, todas na pósmenopausa (FSH > 30mUI/ml). As avaliações foram realizadas em dois momentos: pré-intervenção e após 16 semanas de treinamento combinado. Foram realizadas medidas antropométricas, de composição corporal por meio da densitometria radiológica de dupla energia e análises bioquímicas (colesterol total e frações, triacilglicerol e glicemia de jejum. O treinamento foi composto de três sessões semanais com duração de, aproximadamente, 80 minutos. A prescrição do treinamento aeróbio foi realizada de acordo com a velocidade crítica (VC), e prescrita com volume de 30 minutos diários com intensidade fixada em 100% da VC. O treinamento de força foi prescrito de acordo com a zona de repetição máxima ou do teste de uma repetição máxima (RM) dependendo do exercício. O número de series foram fixadas em três, entretanto, os números de repetições foram decrescente (15 para 8 repetições) e a intensidade crescente (65 para 80% do RM). As cargas de treinamento do aeróbio e de força foram ajustadas a cada quatro semanas. O grupo treinamento foi dividido em tercis de responsividade para as alterações percentuais de lipoproteína de alta densidade (HDL), bem como distribuição de gordura inicial. Todas as análises estatísticas foram realizadas utilizando o programa SPSS, versão 13.0 (SPSS Inc, Chicago, IL) e a significância estabelecida em 5%. Resultados: As participantes responsivas positivas para HDL apresentaram valores inferiores de triacilglicerol e lipoproteína de muito baixa densidade (VLDL) após 16 semanas de treinamento combinado. As participantes com gordura corporal predominantemente abdominal apresentaram menor responsividade ao treinamento combinado. Conclusão: Variáveis da composição corporal e metabólicas interferem na responsividade à 16 semanas de treinamento combinado em mulheres pós-menopausa. / Introduction: Postmenopausal is characterized by 12 months of amenorrhea. Women in this period show increase in total and segmental body fat, especially, abdominal adiposity. It is know that such adiposity is related with the development of chronic disease, therefore, strategies to treat or prevent this outcome becomes important. In this view, the combined training stands out, since it can stimulate increase lean body mass and decrease body fat. Studies has been shown that there is heterogeneity in the response of aerobic training regarding metabolic variables. However, to date no study aimed to investigate the characteristics of menopausal women who responded positively and negatively on body composition and metabolic profile after 16 weeks of combined training. Objective: To analyze the variables of body composition and metabolic that may interfere with the response to 16 weeks of combined training in postmenopausal women. Materials and methods: Sample consisted of women aged 50 to 77 years, all postmenopausal. The evaluations were performed twice: baseline and post-16 weeks of combined training. Body composition were assessed by Dual Energy X-ray Absorptiometry (DEXA), total and segmental, and analysis of the biochemical profile: total cholesterol, Low Density Lipoprotein (LDL-c) and High Density Lipoprotein (HDL-c), triacylglycerol and fasting glucose. The combined training was performed three times per week on nonconsecutive days, during 80 minutes (50 minutes of resistance training followed by 30 minutes of aerobic training) per section. The training group was divided into tertile of responsiveness to HDL-c percentage changes, as well as baseline fat distribution. All statistical analyzes were performed using SPSS version 13.0 (SPSS Inc, Chicago, IL) and statistical significance set at 5 %. Results: The positive responders to HDL showed lower triacylglycerol and VLDL after 16 weeks of combined training. Participants with predominantly abdominal body fat had lower responsiveness to combined training. Conclusion: Body composition and metabolic variables interfere with responsiveness to 16 weeks of combined training in postmenopausal women.

Orientador: Lucia Helena Simões da Costa Paiva / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-06T03:23:51Z (GMT). No. of bitstreams: 1 LazarJunior_Felipe_D.pdf: 154939 bytes, checksum: 9790b7b84c0e5eb21859931d78316ca3 (MD5) Previous issue date: 2006 / Resumo: O objetivo deste estudo foi avaliar o conhecimento e as repercussões sobre a atitude e prática dos médicos ginecologistas três anos após a publicação dos resultados do estudo Women¿s Health Initiative. Sujeitos e Método: Um questionário auto-administrado e anônimo com 19 questões foi enviado aos 6000 ginecologistas da Associação de Obstetrícia e Ginecologia do Estado de São Paulo (SOGESP). Os questionários foram postados em novembro de 2005 com recepção concluída em dezembro de 2005. Resultados: O índice de resposta foi de 24,2% (1453 questionários preenchidos) com erro amostral de 2,23% e intervalo de confiança de 95%. Apesar de 95,9% dos ginecologistas referirem conhecer o estudo WHI, apenas 24,4% tinham conhecimento dos outros estudos (HERS I, HERS II, e Million Women Study) além do WHI. Apesar de 84,6% referirem que os resultados obtidos no estudo WHI não poderiam ser extrapolados para outros tipos de TH, 23,1% e 25,2% abandonaram o uso de EEC ou AMP, 63,7% diminuíram a dose, 55,2% passaram a prescrever drogas como bifosfonatos, tibolona e serms, e 46,3% passaram a utilizar calmantes, isoflavonas e drogas naturais. Além disso, 59,2% concordaram que o tempo ideal de TH deveria ser diminuído para 4-5 anos. Houve queda significativa nas prescrições para todas as indicações de TH (p<0.0001). Para os médicos, a causa mais importante de descontinuação da TH foi o maior risco de câncer de mama (62,3%), no entanto, segundo os médicos, o fator mais importante para as pacientes foi o medo da TH (80,3%) Conclusão: Os ginecologistas têm elevado conhecimento do estudo WHI e seguiram suas recomendações com relação à prevenção de doença cardiovascular, consequentemente, mudaram sua forma de abordar o tratamento das mulheres na pós-menopausa, restringindo as indicações, tempo de uso e dose da TH / Abstract: The objective of this study was to evaluate gynecologists¿ knowledge of the Women¿s Health Initiative study, and its repercussions on their attitudes and practice three years after publication. Design: A self-administered, anonymous questionnaire containing 19 questions was sent to 6000 gynecologists, members of the São Paulo Society of Obstetrics and Gynecology. Results: The response rate was 24.2% (1453 completed questionnaires) with a sample error of 2.23% and confidence level of 95%. Although 95.9% of gynecologists were aware of the WHI study, only 24.4% had knowledge of all the other studies mentioned (HERS I, HERS II and Million Women Study). Although 84.6% stated that the results of the WHI study could not be extrapolated to other forms of HT, 23.1% and 25.2%, respectively, stopped prescribing CEE or MPA, 63.7% decreased the dose, 55.2% opted for drugs such as bisphosphonates, tibolone and SERMS, and 46.3% began to prescribe tranquilizers, isoflavone and other natural medications. Moreover, 59.2% agreed that HT should be used for only 4-5 years. Prescriptions decreased significantly for all indications (p<0.0001). The principal reason for physicians to discontinue HT in a patient was increased risk of breast cancer (62.3%), whereas, according to the physicians, the most important factor for the patients was fear of HT (80.3%). Conclusion: A high percentage of gynecologists in this study knew of the WHI study and followed its recommendations concerning cardiovascular prevention; consequently they changed their management of the treatment of postmenopausal women by restricting indications for HT and decreasing its duration of use and dose / Doutorado / Tocoginecologia / Doutor em Tocoginecologia

A menopausa é o final da vida reprodutiva da mulher e pode ter como consequência a perda da massa óssea e desenvolvimento da osteoporose. A sarcopenia decorrente do processo de envelhecimento acarreta na diminuição de massa e força muscular, déficit de desempenho e maior risco de quedas e fraturas. A Ressonância Nuclear Magnética (RNM) é uma ferramenta não invasiva e eficaz para a avaliação quantitativa e da dinâmica metabólica do músculo esquelético. Por meio do mapa T2 é possível captar as alterações musculares agudas causadas pela atividade física. A intensificação do sinal T2 é causada pelo movimento osmótico da água intramuscular, aumento da acidose e do volume do espaço intracelular. O objetivo desta pesquisa foi avaliar a influência da densidade mineral óssea no metabolismo muscular de mulheres pós-menopáusicas. Foram avaliadas 16 pacientes do sexo feminino, no período pós-menopausa há mais de 12 meses, com média de idade de 63 anos, divididas em Grupo-Osteoporose (GO=9) e Grupo Controle (CG=7). Todas foram submetidas ao exame de Ressonância Nuclear Magnética da região da coxa (RNM1) e em seguida fizeram uma dinamometria isocinética na velocidade de 180 graus/segundo (duas séries de 10 contrações voluntárias máximas) e exercícios específicos para ativação do músculo quadríceps (agachamento e \"step\"), e após os exercícios, fizeram a RNM2. Os resultados mostraram aumento do mapa T2, caracterizado pelo maior tempo de relaxamento nos dois grupos avaliados, sem diferença entre eles. Não se observou correlação significativa dos resultados da RNM2 com os parâmetros de força (pico de torque corrigido pela massa corporal) e potência (trabalho total das 10 repetições da segunda série) e com a dosagem de vitamina D. Também não houve correlação entre a dinamometria isocinética e dosagem de vitamina D. A osteoporose não afeta a resposta muscular do quadríceps ao exercício, avaliada pelo mapa T2 da ressonância nuclear magnética. A metodologia é robusta e eficiente, mostrando que a RM é um método sensível para medir mudanças metabólicas no músculo após o exercício / Menopause is the end of woman\'s reproductive life and consequences as loss of bone mass and osteoporosis may emerge. The ageing\'s sarcopenia entails the reduction of muscle mass and strength, deficit of physical performance and increases the risk of falls and fractures, which is also present in postmenopausal women. Magnetic resonance imaging (MRI) is a noninvasive and effective tool for quantitative assessment and metabolic dynamics of skeletal muscle. Through the T2 map is possible to capture acute muscle disorders caused by physical activity. Intensification of T2 sign is caused by osmotic movement of intramuscular water, increase of acidosis and intracellular space volume. The aim of this study was to evaluate bone mineral density in muscle metabolism in postmenopausal women. We evaluated 8 female patients in postmenopausal for more than 12 months, with a mean age of 63 years, divided into osteoporosis-group (GO=9) and control group (CG=7). They were submitted to MRI examination of thigh at rest (RM1), and then the isokinetic dynamometer at the speed of 180 degrees/second, 2 sets of 10 maximal voluntary contractions and specific exercises to activate the quadriceps muscle (squats and step) and then the RM2 to capture the muscle metabolic changes. For perception of fatigue level, samples of lactate were taken at rest (Lac1), after 1 minute (lac2) and 3 minutes (Lac3) from the end of the exercises. In both groups, it was observed variation of lac2 Lac3, confirming that fatigue levels and changes in RM2 compared to RM1 in the uptake of water were achieved due to intramuscular specific physical changes in post-exercise muscle metabolism. The results showed increased T2 map, characterized by the highest relaxation time in both groups and there are no difference between them. There was no significant correlation of the results of the RNM2 with the parameters of force (peak torque corrected by body mass) and potency (total work) and with the dosage of vitamin D. There was also no correlation between the isokinetic dinamometria and dosage of vitamin D. Osteoporosis does not affect the muscle response of the quadriceps to exercise, assessed by the T2 map of magnetic resonance imaging. The methodology proved to be robust and efficient, showing that MRI is a sensitive method to measure metabolic changes in muscle after exercise

Abstract Osteoporotic hip fractures are associated with high mortality and morbidity rates as well as significant costs. Low-frequency (LF) axial transmission ultrasound is a promising modality for assessing mineral density and geometrical properties. Thus, it may yield additional information on the risk of osteoporotic fractures. This study aimed to evaluate the ability of LF ultrasound to assess osteoporotic status and the risk of fracture in postmenopausal women. Also, lifestyle-related risk factors of hip fractures and the additional discrimination value of combining lifestyle-related risk factors and LF ultrasound velocity were assessed. Two study populations were used. The first consisted of 1,222 older women. Lifestyle-related risk factors and mobility were assessed at baseline. The women were followed for 13 years and the fractures that occurred were recorded. A subgroup of the women was later measured with LF ultrasound and dual-energy x-ray absorptiometry (DXA). The other study population included 95 postmenopausal women whose fracture history was gathered and bone status assessed with LF ultrasound, DXA and peripheral quantitative computed tomography (pQCT). Low body mass and impaired mobility predicted hip fractures. In addition, the risk of cervical hip fracture was increased by low physical activity and decreased by moderate coffee consumption and hypertension. Smoking and old age increased the risk of trochanteric hip fracture. The LF ultrasound velocity reflected to some degree the geometry and bone mineral density of the proximal femur. Decreased low-frequency ultrasound velocity was a significant risk factor of hip fracture even when combined with lifestyle-related risk factors. The LF ultrasound method showed similar fracture discrimination ability compared to DXA and pQCT, especially on the radius. In conclusion, the LF ultrasound method showed promising results in bone characterization and fracture discrimination. Further prospective studies with larger population are needed to confirm the combined effect of clinical risk factors and LF ultrasound. / Tiivistelmä Osteoporoottisiin lonkkamurtumiin liittyy korkean sairastavuuden ja kuolleisuuden lisäksi huomattavat taloudelliset kustannukset. Tässä työssä tutkittiin matalataajuisen ultraäänitekniikan soveltuvuutta osteoporoosin ja murtumariskin arviointiin. Matalataajuista luun pituusakselin suuntaista ultraäänitekniikkaa voidaan käyttää luun mineraalitiheyden ja rakenteen tutkimiseen. Lisäksi tutkittiin elintapoihin liittyviä lonkkamurtuman riskitekijöitä sekä näiden yhdistämistä ultraäänimittaustulosten kanssa riskimalliin. Tutkimuksessa käytettiin kahta tutkimuspopulaatiota. Ensimmäisen muodosti 1222 ikääntynyttä naista, joiden elintavat ja liikuntakyky kartoitettiin tutkimuksen alussa. Kolmentoista vuoden seuranta-ajan aikana tapahtuneet murtumat kerättiin potilasarkistoista. Osa naisista osallistui matalataajuisella aksiaalisuuntaisella ultraäänellä tehtyyn mittaukseen ja kaksienergiseen röntgentutkimukseen (DXA). Toinen tutkimuspopulaatio koostui 95 postmenopausaalisesta naisesta. Naisten murtumahistoria kerättiin ja heille tehtiin matalataajuinen ultraäänimittaus sekä DXA- ja perifeerinen tietokonetomografiatutkimus (pQCT). Alhainen painoindeksi ja heikentynyt liikuntakyky lisäsivät lonkkamurtuman riskiä. Vähäinen fyysinen aktiivisuus lisäsi ja kohtalainen kahvinjuonti ja verenpainetauti alensivat reisiluun kaulan murtumariskiä. Tupakointi ja korkea ikä kasvattivat sarvennoisen alueen lonkkamurtuman riskiä. Matalataajuisen ultraäänen nopeus oli yhteydessä reisiluun yläosan geometriaan ja mineraalitiheyteen. Alhainen ultraäänen nopeus oli merkittävä lonkkamurtuman riskitekijä sekä yksin että yhdistettynä elintapamuuttujiin. Lisäksi ultraäänimenetelmä saavutti röntgenmenetelmiin (DXA ja pQCT) verrattavan erottelukyvyn murtumapotilaiden ja kontrollihenkilöiden välillä. Tutkittu ultraäänimenetelmä osoittautui lupaavaksi työkaluksi luun karakterisoinnissa ja murtumariskin arvioinnissa. Laajempia seurantatutkimuksia tulosten vahvistamiseksi tarvitaan erityisesti elintapoihin liittyvien riskitekijöiden ja ultraäänen yhdistämisen osalta.

Orientador: Vera Aparecida Madruga / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Educação Física / Made available in DSpace on 2018-08-18T10:46:08Z (GMT). No. of bitstreams: 1 Conceicao_MiguelSoares_M.pdf: 1532956 bytes, checksum: 8b4cb337b2669a48e0b8c68602a72f25 (MD5) Previous issue date: 2011 / Resumo: O presente estudo analisou as alterações nos marcadores indiretos de dano muscular após uma sessão de ações excêntricas de flexores do cotovelo com diferentes velocidades de movimento, em mulheres jovens e na pós-menopausa. Participaram da pesquisa 37 mulheres, voluntárias, com idade compreendida entre 18 a 65 anos. Essas voluntárias foram divididas em quatro grupos. Grupo de mulheres jovens que executou ações excêntricas com velocidade rápida (n=10) e grupo de jovens que executou ações excêntricas com velocidade lenta (n=9). Grupo de mulheres na pós-menopausa que realizou as ações excêntricas com velocidade rápida (n=10) e grupo de mulheres na pós-menopausa que realizou as ações excêntricas com velocidade lenta (n=8). As ações excêntricas foram realizadas no braço não dominante, utilizando-se um dinamômetro isocinético, e consistiram em 30 ações excêntricas máximas divididas em cinco séries de seis repetições. Para analisar a magnitude do dano muscular foram utilizados marcadores indiretos como a contração isométrica voluntária máxima (CIVM), amplitude de movimento (AM), circunferência de braço, dor muscular, creatina quinase (CK), interleucina-6 (IL-6), fator de necrose tumoral (TNF-?) e prostaglandina (PGE2). A CIVM, AM, dor muscular e circunferência de braço foram avaliadas pré, imediatamente após, 24, 48 e 72h após a execução de ações excêntricas. Para a atividade plasmática da CK, IL-6, TNF-? e PGE2, as coletas aconteceram pré, 24, 48 e 72h após as ações excêntricas. Como resultado desta dissertação é apresentado um artigo original. O objetivo do estudo original apresentado foi comparar as alterações dos marcadores de dano muscular e inflamação entre mulheres jovens e na pós-menopausa após ações excêntricas. Diferenças significantes entre grupos foram encontradas para torque excêntrico e TNF-? na qual, mulheres na pós-menopausa apresentaram maiores valores (p<0,05). Uma correlação positiva significante (p<0,05) se estabeleceu entre idade x dor e idade x PGE2. Concluindo, esses resultados não suportam a hipótese que mulheres na pós-menopausa são mais susceptíveis ao dano muscular induzido por ações excêntricas comparado a mulheres jovens / Abstract: The present study have analyzed the changes in muscle damage and inflammatory markers after an acute bout of elbow flexors eccentric exercise at difference velocities, in young and post menopausal women. 37 women aged between 18 and 65 participated of the study. They were divided into four groups, (1) fast velocity, young women (n = 10); (2) slow velocity, young women (n = 9); (3) fast velocity, postmenopausal women (n = 10) and (4) slow velocity, postmenopausal women (n = 8). Eccentric exercise consisted of five sets of six maximal elbow flexors eccentric repetitions performed with the nondominant arm in an isokinetic dynamometer. It was assessed voluntary isometric contraction (MVIC), range of motion (ROM), arm circumference, muscle soreness, creatine kinase (CK), interleukin-6 (IL-6), tumor necrosis factor (TNF-?) and prostaglandin (PGE2). The MVIC, ROM, muscle soreness and arm circumference were assessed before, immediately after, 24, 48 and 72h after eccentric exercise. For the plasma activity of CK, IL-6, TNF-? and PGE2, the blood samples were made before, 24, 48 and 72 hours after the eccentric protocol. As result of the present dissertation it is presented an original article. The aim of the presented original study was to compare changes in indirect markers of muscle damage and inflammation in young and postmenopausal women after maximal eccentric exercise. Significant differences were found between groups for eccentric torque and TNF-?, with greater values for postmenopausal women (p<0.05). A positive significant correlation (p<0.05) was found between age x muscle soreness and between age x PGE2. In conclusion, these results do not support the hypothesis that postmenopausal women were more susceptible to eccentric exercise-induced muscle damage than young women / Mestrado / Atividade Fisica, Adaptação e Saude / Mestre em Educação Física