Endothelial cells (ECs) and smooth muscle cell (SMC) play a key part during development of fibrosis in the intima being partly responsible for synthesis of matrix metalloproteinase (MMPs) and various regulators and substrates of these enzymes. Omega-3 (n-3) polyunsaturated fatty acids (PUFA) consumption, mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), has beneficial effects on atherosclerosis but its effect on the development of fibrosis is relatively unknown. <i>Objective:</i> Determine the effects of EPA and DHA, alone or in combination, on fibrosis-related factors in aortic SMCs (AoSMCs) and human umbilical vein ECs (HUVECs) and human aortic ECs (HAECs). <i>Results:</i> Treatment of cells with/without 10 μM DHA, EPA, oleic acid (OA) or vehicle control (VC) altered expression of MMPs, regulators and substrates of MMPs and inflammatory cytokines. EPA increased the α-actin:β-actin ratio indicative of a more contractile SMC phenotype and gelatinase (MMP-2 and -9) activity in HUVECs. In aortic cells, EPA and DHA decreased uPAR mRNA and protein expressions. DHA, EPA and DHA: EPA (at 3:1 and 1:1) decreased SMC migration, this did not involve uPA/plasmin activity. <i>Conclusion:</i> EPA and DHA could decrease inflammatory cytokines and the fibrogenic environment in atherosclerotic lesions by decreasing MMP expression and activity. These fatty acids may also reduce SMC migration and proliferation, independently of uPA/plasmin activity, potentially reducing SMC build up in the intima. This could possibly prevent and/or show plaque progression and increase the stability of advanced plaques.

Estudos têm mostrado que o treinamento de força de baixa intensidade com oclusão vascular (TFOV) tem apresentado resultados similares nos ganhos de força e hipertrofia comparado ao treinamento de força (TF) de alta intensidade. O objetivo deste estudo foi comparar os efeitos de três diferentes programas de TF nos ganhos de força e hipertrofia musculares e na expressão da miostatina (MSTN) e seus antagonistas. Para isso, vinte e nove jovens do sexo masculino, sem experiência em TF, foram recrutados e divididos randomicamente nos grupos: treinamento de força de baixa intensidade sem oclusão (BI), treinamento de força de baixa intensidade com oclusão (BIO) e treinamento de força de alta intensidade sem oclusão (AI). Os grupos BIO e BI treinaram com intensidade de 20% 1RM, enquanto o grupo AI treinou com intensidade de 80% 1RM. A ANOVA one way foi utilizada para testar as diferenças percentuais nos ganhos de força (1RM) e na área de secção transversa (AST) do músculo quadríceps femoral. O modelo misto para análise das medidas repetidas foi utilizado para testar as diferenças nas variáveis miostatina (MSTN), folistatina-3 (FLST-3), SMAD-7 e GASP-1 nos grupos BI, BIO e AI nas condições pré e pós-treinamento. Os resultados mostraram que os aumentos de força e hipertrofia musculares nos grupos BIO e AI foram similares, entretanto superiores ao grupo BI. Esses resultados podem ser atribuídos a maior diminuição na expressão da MSTN nos grupos BIO (45%) e AI (41%) comparados com o grupo BI (16%) e o aumento na expressão dos genes que antagonizam sua atividade (SMAD-7, FLST-3 e GASP-1). Podemos concluir que a inibição na atividade da MSTN dos grupos BIO e AI podem responder em parte a similaridade nos ganhos de força e hipertrofia entre os grupos e a diferença para o grupo BI / It has been demonstrated that low intensity training associated to vascular occlusion (LIO) promotes similar gains in strength and muscle mass when compared to high intensity strength training (HI). The aim of the present study was to evaluate the effect of three different training programs on skeletal muscle hypertrophy and atrophy related gene expression. Twenty nine young male, with no previous experience in strength training were randomly allocated in three groups: low intensity strength training (i.e. 20% - 1-RM) (LI); low intensity strength training associated to vascular occlusion (i.e. 20% - 1-RM) (LIO); high intensity strength training (HI) (i.e. 80% - 1-RM). One-way ANOVA was used to assess differences in % delta change values of 1-RM and cross sectional area (CSA) of the quadriceps femoris. Mixed model analysis was used to compare myostatin (MSTN), folistatyn-3 (FLST-3), SMAD-7 e GASP-1 changes between groups pre and post training. Results demonstrated similar increases in strength and muscle hypertrophy for LIO and HI groups. Moreover, such increases were significantly greater when compared to LI. These results may be, at least in part, explained by a significant decrease in MSTN mRNA expression in LIO (45%) and HI (41%) when compared to LI (16%); additionally, SMAD-7; FLST-3 and GASP-1 mRNA expression were significantly increased. In conclusion, LIO training promotes similar gains than HI training. The results may be explained by changes in MSTN and related genes mRNA expression

O dano muscular induzido pelo exercício (DMIE) e os diferentes elementos envolvidos em seu processo têm sido amplamente estudados. A doença periodontal (DP), por sua vez, tem sido indicada como um possível fator de risco para várias condições sistêmicas, como diabetes, doenças cardiovasculares, partos prematuros, obesidade, entre outros. Tais associações têm sido atribuídas à possibilidade de que a DP possa induzir um processo de inflamação sistêmica de baixa intensidade, caracterizado pela elevação de biomarcadores sanguíneos que também estão envolvidos no mecanismo de dano muscular induzido pelo exercício (DMIE). O objetivo do presente estudo é investigar se a doença periodontal pode atuar como um modificador do DMIE em homens saudáveis. Foram avaliados 40 indivíduos, com idade entre 25 e 45 anos, que buscaram atendimento na faculdade de odontologia da UFRGS ou eram praticantes de atividades físicas. Questionário estruturado para obtenção de dados demográficos e comportamentais e o IPAQ (International Physical Activity Questionnaire) foram aplicados. Dois periodontistas examinaram perda de inserção (PI), profundidade de sondagem, sangramento à sondagem e índices de placa e sangramento gengival no exame basal, juntamente com avaliações antropométricas. Os participantes então realizaram um protocolo de indução de dano muscular que incluiu cinco séries de 15 contrações excêntricas máximas dos quadríceps de uma perna, em um dinamômetro isocinético. Força muscular (contrações isométricas voluntárias máximas - CIVM), espessura e ecogenicidade muscular (ultrassonografia) e dor (escala visual analógica) foram avaliadas em diferentes momentos em relação ao protocolo. Modelos de regressão logística multivariados foram ajustados para idade, educação, índice de massa corporal, fumo, consumo de álcool, proteína C reativa e nível de atividade física. Nessa amostra, PI esteve associada a maiores reduções de força muscular após o protocolo, com um aumento de 1 mm na média de PI representando 7% a mais de redução na CIVM. Pode-se concluir, a partir dessa análise preliminar, que a doença periodontal pode ser considerada um modificador do processo de dano muscular, aumentando a deterioração da força muscular. / Exercise-induced muscle damage (EIMD) and the different elements involved in it´s process has been largely studied. Periodontal diseases (PD) has been pointed out as a possible risk fator for a number of systemic conditions, like diabetes, cardiovascular diseases, preterm birth, obesity, and others. Such associations has been atribbuted to the fact that PD can lead to a low-grade inflammatory process, characterized by elevated blood concentrations of biomarkers that are also involved in the EIMD mechanisms. The aim of this study is to assess whether PD can act as a EIMD modifier in healthy men. This study included 40 healthy males with 25-45 yrs that seek for treatment at Dentistry Faculty or are physical activiy practitioners. A structured questionnaire to obtain demographic and comportamental data and the IPAQ (International Physical Activity Questionnaire) were applied. Two periodontists assessed attachment loss (AL), probing depth (PD), bleeding on probing (BOP), plaque and bleeding index in the baseline exam, together with anthropometrical evaluation. The participants then performed a muscle damage protocol comprising five sets of 15 maximum eccentric contractions of the quadriceps muscles of one leg in a isokinetic dynamometer. Evaluations of muscle strength (maximal voluntary isometric contraction), muscle thickness and echo intensity (ultrasonography images) and soreness (visual analogue scale) were made at different periods in relation to the protocol. Multivariable logistic models were fitted adjusting for age, education, body mass index (BMI), smoking, alcohol consumption, C-reactive protein (CRP) and physical activiy level. In this sample, AL was associated with higher reductions of muscle force, with a 1- mm increment in AL mean significantly decreased CIVM by 7%. It can be concuded, based on this preliminar analysis, that PD may be considered as a modifier of EIMD, increasing muscle strenght deterioration.

by Lanyi Xu. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (p. [175]-186). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

Doctor of Philosophy (PhD) / The BCNU + O6benzylguanine (O6BG) driven selective enrichment strategy was first established for enhanced transplantation of hematopoietic stem cells. This study describes a novel application of this BCNU + O6BG driven selective enrichment strategy in skeletal muscle stem cell transplantation. Furthermore, this study addresses the three main limitations observed in previously reported skeletal muscle stem cell transplantation strategies. Limitation of ineffective donor cells which lack the ability for successful engraftment was overcome by using a heterogeneous population of donor cells which are present during a normal skeletal muscle regeneration response. The limitation of donor cell death upon transplantation as a result of competition from the endogenous stem cells of the host muscles was overcome by elimination of host muscle stem cells with BCNU + O6BG treatment. Efficiency of elimination of host muscle stem cells was further demonstrated by the complete inhibition of a regeneration response up to 3 months in injured, BCNU + O6BG treated muscles. The limitation of localised engraftment as a result of intramuscular injection of donor cells was also addressed. The transplanted donor cells demonstrated the ability to migrate via systemic circulation. This characteristic of the donor cells would allow the transplantation of cells via intraarterial or intravenous delivery which would overcome the limitation of localised engraftment. Finally, application of the BCNU + O6BG driven selective enrichment strategy in skeletal muscle stem cell transplantation demonstrated enhanced engraftment. This is the first reported attempt of enhanced stem cell transplantation in a solid tissue achieved upon application of the BCNU + O6BG driven selective enrichment strategy. This study provides the basis for application of the BCNU + O6BG driven selective enrichment strategy in other tissues where stem cell transplantation is considered.

Recovery after prolonged or high-intensity exercise is characterised by a substantial increase in adipose tissue lipolysis, resulting in elevated rates of plasma-derived fat oxidation. Despite the large increase in circulating fatty acids (FAs) after exercise, only a small fraction of this is taken up by exercised muscle in the lower extremities. Indeed, the predominant fate of non-oxidised FAs derived from post-exercise lipolysis is reesteriflcation hi the liver. During recovery from endurance exercise, a number of changes also occur hi skeletal muscle that allow for a high metabolic priority towards glycogen resynthesis. Reducing muscle glycogen during exercise potentiates these effects, however the cellular and molecular mechanisms regulating substrate oxidation following exercise remain poorly defined. The broad arm of this thesis was to examine the regulation of fat metabolism during recovery from glycogen-lowering exercise hi the presence of altered fat and glucose availability. In study I, eight endurance-trained males completed a bout of exhaustive exercise followed by ingestion of carbohydrate (CHO)-rich meals (64-70% of energy from CHO) at 1, 4, and 7 h of recovery. Duplicate muscle biopsies were obtained at exhaustion and 3, 6 and 18 h of recovery. Despite the large intake of CHO during recovery (491 ± 28 g or 6.8 + 0.3 g • kg-1), respiratory exchange ratio values of 0.77 to 0.84 indicated a greater reliance on fat as an oxidative fuel. Intramuscular triacylglycerol (IMTG) content remained unchanged in the presence of elevated glucose and insulin levels during recovery , suggesting IMTG has a negligible role in contributing to the enhanced fat oxidation after exhaustive exercise. It appears that the partitioning of exogenous glucose towards glycogen resynthesis is of high metabolic priority during immediate post-exercise recovery, supported by the trend towards reduced pyruvate dehydrogenase (PDH) activity and increased fat oxidation. The effect of altering plasma FA availability during post-exercise recovery was examined in study II. Eight endurance-trained males performed three trials consisting of glycogen-lowering exercise, followed by infusion of either saline (CON), saline + nicotinic acid (NA) (LFA) or Intralipid and heparin (HFA). Muscle biopsies were obtained at the end of exercise (0 h) and at 3 and 6 h in recovery. Altering the availability of plasma FAs during recovery induced changes in whole-body fat oxidation that were unrelated to differences in skeletal muscle malonyl-CoA. Furthermore, fat oxidation and acetyl-CoA carboxylase (ACC) phosphorylation appear to be dissociated after exercise, suggesting mechanisms other than phosphorylation-mediated changes in ACC activity have an important role in regulating malonyl-CoA and fat metabolism in human skeletal muscle after exercise. Alternative mechanisms include citrate and long-chain fatty acyl-CoA mediated changes in ACC activity, or differences in malonyl-CoA decarboxylase (MCD) activity. Reducing plasma FA concentrations with NA attenuated the post-exercise increase in MCD and pyruvate dehydrogenase kinase 4 (PDK4) gene expression, suggesting that FAs and/or other factors induced by NA are involved hi the regulation of these genes. Despite marked changes hi plasma FA availability, no significant changes in IMTG concentration were detected, providing further evidence that plasma-derived FAs are the preferential fuel source contributing to the enhanced fat oxidation post-exercise during recovery. To further examine the effect of substrate availability after exercise, Study III investigated the regulation of fat metabolism during a 6 h recovery period with or without glucose infusion. Enhanced glucose availability significantly increased CHO oxidation compared with the fasted state, although no differences in whole-body fat oxidation were apparent. Consistent with the similar rates of fat metabolism, no difference hi AMPK or ACCβ phosphorylation were observed between trials. In addition, no significant treatment or time effects for IMTG concentration were detected during recovery. The large exercise-induced PDK4 gene expression was attenuated when plasma FAs were reduced during glucose infusion, supporting the hypothesis that PDK4 is responsive to sustained changes in lipid availability and/or changes in plasma insulin. Furthermore, the possibility exists that the suppression of PDK4 mRNA also reduced PDK activity and thus maintained PDH activity to account for the higher rates of CHO oxidation observed during glucose infusion compared with the control trial.

Imaging based muscle density (MD) is associated with poor lower extremity performance, the development of mobility impairments, frailty, and hip fracture. These associations are all related to falls, yet no studies have investigated MD in community dwelling fallers. The primary objective of this study was to determine whether lower leg MD differed between community dwelling elderly women who do and do not report falls. The secondary objective was to determine if lower leg muscle cross sectional area (MCSA), timed up & go (TUG) test, and relative grip strength (RGS; as a ratio to body mass) differed between fallers and non-fallers. Women (N = 135), 60 years or older (mean age 74.1, SD 7.6) were recruited from a random sample of Saskatoon residents. Fallers (n = 36) and Non-fallers (n = 99) were grouped based on 12-month retrospective falls survey response. A peripheral quantitative computed tomography (pQCT) scan of the non-dominant lower leg was acquired to determine MD and MCSA. Participant age, height, weight, TUG test result and RGS were recorded. Between-group differences in mean age, body mass index (BMI), MD, MCSA, TUG and RGS were compared using independent t-tests (P < 0.05). MD and TUG results were transformed to meet the assumption of normality for parametric analysis. Age, BMI, MCSA and RGS did not differ (P > 0.5). Fallers had 3.2% lower MD (P = 0.01) and 15.1% slower TUG scores (P = 0.02), than non-fallers. Muscle density may serve as a physiological marker for the assessment of muscular health and fall risk in community dwelling elderly women.

Early strength increase with training is normally attributed to neural adaptations but recent evidence suggests that muscle hypertrophy occurs earlier than previously thought. The purpose of this study was to examine the time course of adaptation through 20 days of training and 5 days of detraining. Twenty-two untrained subjects trained one arm every 2nd day for 20 days. Subjects performed isokinetic eccentric biceps training at 90°/s (6 sets of 8 reps). Muscle thickness (reported in cm) via ultrasound, strength (reported in Nm) and muscle activation (electromyography) were measured before, during and after training (9 time points). Muscle thickness increased after 8 days of training (3.66±0.11 to 3.90±0.12; p<0.05) and remained above baseline until the end of training (3.97±0.12). After 5 days of detraining muscle thickness decreased (3.97±0.12 vs. 3.85±0.11; p<0.05), but remained higher than baseline (p<0.05). Muscle thickness did not change significantly in the untrained arm at any time point. Strength in the trained arm decreased after 8 days of training (65.6±4.1 to 57.5±3.5; p<0.05) and remained suppressed throughout the study. Muscle activation amplitude increased after 14 days of training (p<0.05) and remained elevated throughout the study. In conclusion, biceps muscle thickness increases very rapidly with frequent intense eccentric training although this type of training appears to impair strength. These findings provide additional evidence that muscle hypertrophy may occur much faster than has been generally accepted.

Introduction: The effect of electrical stimulation on muscle degeneration and regeneration is largely unknown and it has not been studied in conjunction with telomeres. The consumption of non-steroidal anti-inflammatory drugs (NSAIDs) is widespread in athletes and the general population when faced with muscle soreness or injury. Furthermore, the effect of NSAIDs on muscle regeneration is controversial and its effect on telomere lengths is also unknown. Methods: Young adult males performed 200 electrically stimulated maximal isokinetic contractions with one leg (ES) and the other worked as a control (CON). They received either 1200mg ibuprofen (IBU) per day or placebo (PLA) from 21 days pre- to 30 days post-exercise. Muscle biopsies were obtained from the vastus lateralis of the CON leg at baseline (H0) and ES leg at 2.5h (H2.5) and both legs at 2, 7 and 30 days post-exercise. Blood samples were obtained at the same time points and at day 4 post-exercise. Afterwards the muscle and blood specimen were analysed for skeletal muscle and peripheral blood telomere lengths by Southern blot and signs of muscle degeneration and regeneration were quantified histologically. Results: Histological changes occurred in the ES leg, including; increased proportion of damaged myofibres (2.1±2.8%) and infiltrated myofibres (5.0±6.0%) at day 7, small myofibres (3.0±4.4%) and internally located myonuclei (2.9±3.1%) at day 30. The IBU group had significantly less internally located myonuclei at day 30 compared to PLA (1.7±2.4% vs. 4.1±3.8%). No significant differences were observed in skeletal muscle mean and minimum telomere lengths between ES and CON leg, between IBU and PLA group or between time points. Peripheral blood mean telomere lengths were not significantly different between IBU and PLA group, but between time points; H0 (9.6±1.2kb) and H2.5 (9.1±1.1kb) were significantly shorter than day 4 (10.3±1.6kb) and day 7 (10.1±1.5kb) (P&lt;0.05). Conclusion: Electrically stimulated contractions caused significant muscle degeneration and regeneration in the 30 days post-exercise. Electrical stimulation also appeared to cause fluctuations in peripheral blood telomere lengths, but not skeletal muscle telomeres. The intake of ibuprofen appeared to interfere with muscle regeneration, but did not seem to affect the peripheral blood or skeletal muscle telomeres. However, due to marked individual variations and the small participant group it is difficult to conclude on the effects of electrical stimulation and ibuprofen on proliferative potential. Further studies are warranted to elucidate the effects of electrical stimulation and ibuprofen on blood and skeletal muscle telomeres.

Two studies were conducted to determine if Hsp70 is able to protect human skeletal muscle from muscle mechanical damage and alterations in SERCA activity associated with prolonged concentric exercise. In the first study, one-legged isometric knee extension exercise at 40% MVC and a duty cycle of 50% (5 sec contraction followed by 5 sec of relaxation) was used to induce a heat shock response in one leg only. Participants were followed over six recovery days to determine the time course of Hsp70 induction and decay. Results showed fiber type specific increases in Hsp70 that persisted in one leg only throughout six days of recovery. These increases in Hsp70 occurred with only transient changes in Ca2+ uptake and muscular force. With the exception of minor decreases in low frequency force, there were no apparent reductions in muscular force or SERCA activity by the third recovery day. Therefore an exercise protocol was established which was able to induce a heat shock response with only minor alterations in muscle mechanical function and SERCA activity. In the second study, the same isometric exercise was employed, however, on the day corresponding to recovery day 3 in the first study, participants were asked to complete a one hour cycling protocol at 70% VO2 max. The goal was to cause similar one-legged increases in Hsp70 as the first study and to then challenge SERCA activity and muscular force in the presence of elevated Hsp70 by using cycling exercise. Results showed cycling induced reductions in maximal Ca2+ ATPase activity, muscular force, rates of muscle relaxation, and rates of muscle force development were attenuated by the preconditioning (isometric) exercise. These studies confirm the idea that preconditioning exercise is able to attenuate subsequent exercise induced insults to SERCA activity and muscular force, likely through an Hsp70 mediated mechanism.