A síndrome da dor patelofemoral (SDPF) é o diagnóstico mais comum em populações fisicamente ativas. A SDPF está relacionada com o mau alinhamento dos membros inferiores durante tarefas de descarga de peso, causando maior estresse e dor na articulação patelofemoral. Esse mau alinhamento está relacionado com um aumento da inclinação ipsilateral do tronco, adução do quadril, abdução do joelho e maior grau de rotação interna da tíbia durante atividades dinâmicas, como agachamento unipodal, corrida, salto e subir e descer escadas. Fatores anatômicos e biomecânicos estão relacionados a alterações ao redor da articulação femoropatelar, como menor força de extensão do joelho, atraso na ativação do vasto medial em relação ao vasto lateral e atrofia do músculo quadríceps. Recentemente, alterações do quadril (fatores proximais), tornozelo e pé (fatores distais) têm sido propostas como fatores contribuintes da SDPF. No entanto, as evidências sobre ativação e alteração da morfologia muscular dos membros inferiores, principalmente nos fatores proximais e distais, são escassas. Esta tese teve como objetivo verificar as alterações neuromusculares dos membros inferiores e determinar se algum parâmetro neuromuscular explicava a cinemática durante tarefas unipodais. Após a apresentação dos motivos para realização deste estudo (Capítulo I), no Capítulo II objetivamos verificar as alterações neuromusculares (ativação muscular e morfologia muscular) relacionadas aos fatores proximais e distais na SDPF por meio de uma revisão sistemática. As buscas foram realizadas nas bases de dados Medline (via PubMed), Scielo, Scopus, PEDro, Cochrane Central, Embase e ScienceDirect databases até abril de 2018 para estudos avaliando ativação muscular ou parâmetros de morfologia muscular das articulações do tronco, quadril e tornozelo/pé. Dois revisores independentes avaliaram cada trabalho para inclusão e qualidade. Dezenove estudos foram identificados (SDPF, n = 319; GC, n = 329). Três estudos investigaram os músculos ao redor das articulações do tronco e tornozelo/pé. Quinze estudos investigaram os músculos ao redor da articulação do quadril. As evidências foram inconclusivas sobre a ativação do transverso do abdome/oblíquo interno (TrA/OI) na SDPF durante atividades de alta velocidade. Os níveis de ativação, duração e atraso na ativação de Glúteo Médio (GMed), glúteo máximo (GMax), biceps femoral (BF) and semitendinoso (ST) foram inconclusivos nos estudos incluídos. Não foram observadas diferenças na ativação de gastrocnêmio lateral (GL), gastrocnêmio medial (GM), sóleo (SOL), tibial anterior (TA) e fibular longo (FIB). Apenas um estudo incluído avaliou parâmetros da morfologia muscular, sem alterações na espessura muscular e na intensidade do eco GMed e GMax. Com base na falta de evidências sobre alterações na ativação muscular em torno das articulações do quadril, tornozelo e pé durante tarefas dinâmicas, e no fato de que um único estudo avaliou os resultados da morfologia muscular (GMed e GMax) na SDPF, propusemos um artigo original (Capítulo III) que teve como objetivo comparar os parâmetros neuromusculares dos membros inferiores e a cinemática no plano frontal durante tarefas unipodais de descarga de peso em mulheres com SDPF e determinar se algum resultado neuromuscular explicava o índice dinâmico de valgo (IVD) durante as tarefas. As buscas foram realizadas nas bases de dados Medline (via PubMed), Scielo, Scopus, PEDro, Cochrane Central, Embase e ScienceDirect databases até abril de 2018 para estudos avaliando ativação muscular ou parâmetros de morfologia muscular das articulações do tronco, quadril e tornozelo/pé. Dois revisores independentes avaliaram cada trabalho para inclusão e qualidade. Dezenove estudos foram identificados (SDPF, n = 319; GC, n = 329). Três estudos investigaram os músculos ao redor das articulações do tronco e tornozelo/pé. Quinze estudos investigaram os músculos ao redor da articulação do quadril. As evidências foram inconclusivas sobre a ativação do transverso do abdome/oblíquo interno (TrA/OI) na SDPF durante atividades de alta velocidade. Os níveis de ativação, duração e atraso na ativação de Glúteo Médio (GMed), glúteo máximo (GMax), biceps femoral (BF) and semitendinoso (ST) foram inconclusivos nos estudos incluídos. Não foram observadas diferenças na ativação de gastrocnêmio lateral (GL), gastrocnêmio medial (GM), sóleo (SOL), tibial anterior (TA) e fibular longo (FIB). Apenas um estudo incluído avaliou parâmetros da morfologia muscular, sem alterações na espessura muscular e na intensidade do eco GMed e GMax. Com base na falta de evidências sobre alterações na ativação muscular em torno das articulações do quadril, tornozelo e pé durante tarefas dinâmicas, e no fato de que um único estudo avaliou os resultados da morfologia muscular (GMed e GMax) na SDPF, propusemos um artigo original (Capítulo III) que teve como objetivo comparar os parâmetros neuromusculares dos membros inferiores e a cinemática no plano frontal durante tarefas unipodais de descarga de peso em mulheres com SDPF e determinar se algum resultado neuromuscular explicava o índice dinâmico de valgo (IVD) durante as tarefas. Quinze mulheres com SDPF e quinze mulheres saudáveis pareadas por 5 idade (grupo controle - GC) foram comparadas com os seguintes testes: (1) questionário funcional; (2) espessura muscular ao redor do quadril (GMed e tensor da fáscia lata - TFL), joelho (VL e VM) e tornozelo/pé (TA e FIB); (3) IVD e ativação muscular durante agachamento e salto vertical unipodais; (4) torque isométrico máximo para abdução do quadril, extensão do joelho e eversão/ inversão do pé; e (5) ativação muscular durante testes isométricos e funcionais. Uma regressão linear múltipla (modelo Stepwise) foi usada para verificar se alguma variável neuromuscular explicava o IVD durante as tarefas unipodais. O tamanho de efeito (ES) foi usado para determiner a magnitude da diferença entre os grupos. Comparado ao GC, o grupo SDPF apresentou: (1) menor espessura do GMed (-10.02%; ES = -0.82) e maior espessura do TFL (+18.44%; ES = +0.92) e do FIB (+14.23%; ES = +0.87); (2) menor ativação do TA durante o agachamento unipodal (-59,38%; ES = -1.29); (3) menor ativação do GMed durante o salto vertical unipodal (-28.70%; ES = -1.35) e (4) maior ativação do GMed durante o teste isométrico de abdução de quadril (+34.40%; ES = +0.77). IVD durante o agachamento unipodal foi explicado pela ativação do VL durante a tarefa somente no GC, enquanto a espessura do TA no GC e o torque de eversores do pé no SDPF explicou o IVD durante o salto vertical unipodal. Com base em nossos resultados, as mulheres com SDPF apresentaram alterações neuromusculares significativas nas articulações do quadril e tornozelo/pé. No entanto, apenas fatores distais explicaram o IVD no grupo SDPF. / Patellofemoral pain syndrome (PFPS) is the most common diagnoses in physically active populations. PFPS is related with lower limbs poor alignment during weight-bearing tasks, causing higher patellofemoral joint stress and pain. This poor alignment is related with an increase of ipsilateral trunk lean, hip adduction, knee abduction and greater tibial internal rotation during dynamic activities such as single-leg squat, running, jumping, and stepping tasks. Anatomical and biomechanical factors are related with unwanted changes around the patellofemoral joint, such as lower knee extension strength, delayed onset of vastus medialis activation relative to vastus lateralis and quadriceps muscle atrophy (knee joint muscles intrinsic changes). Recently, hip (proximal), ankle and foot (distal) changes have been proposed as PFPS contributing factors. However, the evidences about lower limb muscle activation and morphology changes, mainly in proximal and distal factors, are scarce. This thesis aimed to create clinical subgroups based in lower limb neuromuscular changes and determine if some neuromuscular outcome explained kinematics during single-leg tasks. After displaying the reasons to perform this study (Chapter I), in Chapter II we aimed to verify neuromuscular changes (muscle activation and muscle morphology) related to proximal and distal factors in PFPS through a systematic review. Medline (via PubMed), Scielo, Scopus, PEDro, Cochrane Central, Embase and ScienceDirect databases were searched until April 2018 only for retrospective studies evaluating muscle activation or muscle morphology parameters of trunk, hip and ankle/foot joints. Two independent reviewers assessed each paper for inclusion and quality. Twenty retrospective studies were identified (PFPS, n=319; CG, n=329). Three studies investigated muscles around trunk and ankle/foot joints. Fifteen studies investigated muscles around the hip joint. Evidences were inconclusive about transversus abdominis/internal oblique (TrA/IO) activation in PFPS during high-speed activities. Gluteus medius (GMed), gluteus maximus (GMax), bíceps femoris (BF) and semitendinous (ST) activation level, activation duration and activation onset were inconclusive in the included studies. No differences were observed in gastrocnemius lateralis (GL), gastrocnemius medialis (GM), soleus (SOL), tibialis anterior (TA) and fibularis (FIB) muscle activation. Only one included study evaluated muscle morphology parameters, without changes in the GMed and GMax muscle thickness and echo intensity. Based in the lack of evidences about muscle activation changes in PFPS patients’ muscles around hip, ankle and foot joints during dynamic tasks, and in the fact that a single study evaluated muscle morphology outcomes (GMed), we proposed an original article (Chapter III) that aimed to compare lower limb neuromuscular parameters and frontal plane kinematics during single-leg tasks in women with PFPS, and determine if some neuromuscular outcome explained dynamic valgus index (DVI) during tasks. Fifteen PFPS women and fifteen healthy age-matched women (control group - CG) were compared with the following tests: (1) functional questionnaire; (2) hip (GMed and tensor fasciae latae - TFL), knee (VL and VM) and ankle/foot (TA and FIB) muscle thickness; (3) DVI and muscle activation during single-leg squat and vertical jump; (4) maximal isometric torque for hip abduction, knee extension and foot eversion/inversion; and (5) muscle activation during isometric and functional tests. A multiple- 7 stepwise regression analysis was used to test if neuromuscular outcomes explained DVI during single-leg tasks. Effect sizes (ES) were used to determine the magnitude of between-groups differences. Compared to the CG, PFPS showed: (1) smaller GMed (-10.02%; ES = -0.82) and greater TFL (+18.44%; ES = +0.92) and FIB muscle thickness (+14.23%; ES = +0.87); (2) lower TA muscle activation during single-leg squat (-59,38%; ES = -1.29); (3) lower GMed muscle activation during single-leg jump (-28.70%; ES = -1.35) and (4) greater GMed muscle activation during hip abduction isometric test (+34.40%; ES = +0.77). DVI during single-leg squat was explained by VL activation during this task only in CG, whereas lower TA muscle thickness in the CG and higher foot eversion torque in PFPS explained DVI during single-leg vertical jump. Based in our results, females with PFPS showed significant neuromuscular changes at the hip and ankle/foot joints. However, only distal factors explained DVI in the PFPS group.

Neste trabalho, avaliamos os efeitos da suplementação crônica de leucina e do treinamento de força sobre a miopatia diabética. 40 ratos machos da linhagem Wistar Hannover foram distribuídos em 5 grupos: controle, não diabético (C), diabético não tratado (D), diabético treinado (DT), diabético suplementado com leucina e treinado (DLT). O início das intervenções ocorreu na 4ª semana de vida dos animais, e perdurou por 8 semanas. Foram avaliados: massa corporal, consumo de ração e água, concentrações sanguíneas de glicose, insulina e perfil lipídico; capacidade funcional muscular voluntária através de testes de força de preensão e de ambulação; conteúdo intracelular de proteínas relacionadas à via anabólica mTOR e p70S6K, totais e fosforiladas, no músculo extensor longo dos dedos. Os ratos diabéticos não tratados (grupo D) apresentaram hiperglicemia e hipoinsulinemia moderada, menor massa corporal, maior consumo de ração e água, menor peso absoluto dos músculos extensor longo dos dedos e gastrocnêmio, menor força de preensão, menor capacidade de ambulação e menor atividade das proteínas mTOR e p70S6K comparado ao grupo C, o que caracteriza o quadro de miopatia diabética. O peso relativo do músculo gastrocnêmico (peso absoluto/100g de peso do animal) foi maior nos grupos DT e DLT comparado com o grupo D, e maior no grupo DLT comparado com o grupo DL (p < 0,05). Não houve diferença estatística entre os grupos DL e D sobre os pesos relativos dos músculos, ou seja, a suplementação crônica de leucina não afetou este parâmetro nos ratos diabéticos. Interessantemente, houve diferença estatística entre os grupos DL e D sobre a força muscular (p < 0,05), sem haver diferença entre grupos DL e C quanto à glicemia; ou seja, a dieta suplementada com leucina foi capaz de controlar a glicemia e atenuar a perda de força muscular. O treinamento de força também controlou a glicemia, recuperou a força muscular e melhorou a capacidade de ambulação, bem como a regulação da via mTOR-p70S6K. A fosforilação da via mTOR-p70S6K foi maior nos grupos DT e DLT comparado com o grupo D (p < 0,05), e sem diferença entre estes grupos treinados e o grupo C, sugerindo que o treinamento de força combinado com a suplementação de leucina recuperou a atividade da via do mTOR-p70S6K nos animais diabéticos, que pode refletir em maior síntese proteica muscular. O colesterol total do grupo D foi maior comparado com o do grupo C; e nos grupos diabéticos treinados (DT e DLT), este parâmetro foi menor do que no grupo D (p < 0,05). Adicionalmente, o HDL-c aumentou nos grupos treinados (DT e DLT) quando comparado com o grupo D, mas não alterou no grupo que recebeu apenas a suplementação de leucina (grupo DL). Portanto, neste estudo, a suplementação crônica de leucina por si só normalizou a glicemia e melhorou a força muscular dos animais diabéticos. Além disso, o treinamento de força foi responsável pelo maior aumento de força e da massa muscular, bem como pela normalização da glicemia, pela elevação da concentração de HDL-c e pela redução do colesterol total dos animais diabéticos e ambas foram capaz de recuperar a via mTOR-p70S6K. / In this study, we evaluated the effects of chronic supplementation with leucine and resistance training on diabetic myopathy. 40 Wistar Hannover rats were divided into 5 groups: control, non-diabetic (C), untreated diabetic (D), trained diabetic (DT), diabetic supplemented with leucine and trained (DLT). The beginning of the interventions occurred in the 4th week of life of the animals, and lasted for 8 weeks. Were evaluated: body weight, food and water intake, blood concentrations of glucose, insulin and lipid profile; voluntary muscle functional capacity through grip strength and ambulation test; intracellular content of proteins related to the anabolic mTOR and p70S6K pathway, total and phosphorylated in the extensor digitorum longus muscle. Diabetics untreated mice (group D) had hyperglycemia and moderate hypoinsulinemia, lower body mass, food and water intake, reduced absolute weights of the muscles of the long extensor digitorum, and gastrocnemius, the lower grip strength, lower ambulation capacity and lower activity of mTOR and p70S6K protein compared the C group, featuring diabetic myopathy. The relative weight of the gastrocnemius muscle (absolute weight / 100g of body weight) was greater in DT and DLT groups compared with group D, and higher in the DLT group compared to the DL group (P < 0.05). No statistical difference between the DL and D groups on the relative weights of the muscles, that is, chronic supplementation of leucine did not affect this parameter in diabetic rats. Interestingly, there was statistical difference between the DL and D groups on muscle strength (P < 0.05), with no difference between groups DL and C on the blood glucose; that is, the diet supplemented with leucine was able to control glycemia and avoid loss of muscle strength of diabetic animals. Resistance training also controlled glycemia, recovered muscle strength and improved the capacity of ambulation of diabetic animals and the regulation of the mTOR-p70S6K pathway. The phosphorylation of mTOR-p70S6K pathway was higher only in the DT and DLT groups compared with the D group (P < 0.05), and no difference between the DT and C groups, suggesting that the training recovered muscle mass in diabetic animals. Total cholesterol was greater in Group D compared to the group C; and trained diabetic groups (DLT and DT), this parameter was lower than that of the D group (P < 0.05). In addition, HDL-C increased in trained groups (DT and DLT) as compared to group D, but had no effect the group that received only leucine supplementation (DL group). Therefore, in this study, chronic supplementation of leucine alone normalized glucose and improved muscle strength of diabetic animals. In addition, resistance training was responsible for the largest increase in strength and muscle mass, as well as the normalization of glucose, elevated concentrations of HDL-C and reduction in total cholesterol of animals diabetics and both were able to recover mTOR- p70S6K pathway.

Background: The patient's prerequisites form the basis for the pre-and postoperative care period. One of the aspects that affect health care is the patient's physical activity where immobilizing surgery involves atrophy of muscle mass. A low preoperative activity level, perioperative immobilization and postoperative immobilization increase the risk of postoperative complications. Aim: The purpose was to investigate how much skeletal muscle mass patients lose related to immobilizing surgery and how immobilization affects the patient's care time postoperatively. Method: A literature study that reviewed 12 original articles. The articles were reviewed according to Forsberg and Wengström (2016) where article’s contents and results were compared with the aim of this literature study. Results: After examination, no general loss of muscle mass after immobilized surgery could be identified. The muscle mass's ability to atrophy varies depending on the area of surgery and individual-based conditions. However, muscle mass and its quality were identified as a potential prognostic marker for how post-operative care time will play out where lower levels of muscular quality imply increased risk of complications and mortality. Care time for patients with a low muscle grade has been identified as prolonged related to immobilizing surgery. A care period that can be shortened by muscular activation in the form such as electrical stimulus or resistance exercises. Conclusion: The conclusion of this literature study is that the muscle mass lost in immobilized surgery and how postoperative care is affected is individual-based and influenced by preoperative muscle size and type of surgical procedure. Further research is needed on preoperative and postoperative skeletal muscle mass measurement and a routine for measuring muscle mass, since muscle atrophy has been identified as an important marker for postoperative care and survival. / Bakgrund: Patientens förutsättningar ligger till grund för hur den pre- och postoperativa vårdtiden kommer att fortlöpa. En av aspekterna som påverkar vården är patientens fysiska aktivitet där immobiliserande kirurgi innebär atrofi av muskelmassa. En låg preoperativ aktivitetsnivå, perioperativ immobilisering och postoperativ immobilisering ökar risken för postoperativa komplikationer relaterade till muskelatrofi. Syfte: Syftet var att undersöka hur mycket skelettmuskulatur patienter förlorar i samband med immobiliserande operation samt hur immobiliseringen påverkar patientens vårdtid postoperativt. Metod: En litteraturstudie som granskade 12 originalartiklar. Artiklarna granskades enligt Forsberg och Wengström (2016) där innehåll och resultat jämfördes med denna litteraturstudies syfte. Resultat: Efter granskning har ingen generell förlust av muskelmassa efter kirurgi kunnat identifieras. Muskelmassans förmåga att atrofiera varierar beroende på operationsområde och individbaserade förutsättningar. Muskelmassan och dess kvalitet kunde dock identifieras som en prognostisk markör för hur den postoperativa vårdtiden kommer att fortlöpa där lägre grad av muskulär kvalitet innebär ökad risk för komplikationer och mortalitet. Vårdtiden för patienter med muskelgrad av låg kvalitet har kunnat identifieras som förlängd i samband med immobiliserande kirurgi. En vårdtid som kan förkortas genom muskulär aktivering i form av t.ex. elektrisk stimulans eller motståndsövningar. Slutsats: Konklusionen av denna litteraturstudie är att den muskelmassa som förloras vid immobiliserande kirurgi samt hur den postoperativa vårdtiden påverkas är individbaserat och påverkas av preoperativ muskelgrad och typ av kirurgiskt ingrepp. Efter genomförd granskning eftersöks vidare forskning gällande preoperativ och postoperativ mätning av skelettmuskelmassa och en standardiserad rutin för att mäta muskelmassa, detta då muskelatrofi har identifierats som en viktig markör för postoperativ vård och överlevnad.

Spinal muscular atrophy is an autosomal recessive genetic disease that results from the loss and/or degeneration of alpha motor neurons in the lower part of the spinal cord. With ~ 1 in 6000 live births per year being affected, this disease is the second leading cause of infant death and is caused by the loss or decrease of the Survival of Motor Neuron protein (SMN). While a lot is known about the role that SMN plays in the cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs), it remains a crucial question in the field to gain a better understanding of what specific/distinct function(s) SMN might have in motor neurons. We have identified novel interactions between SMN and two RNA-binding proteins (RBPs) known to be components of axonal RNA granules. More specifically, we demonstrated that SMN interacts with HuD and SERBP1 in a direct fashion in foci-like structures along neurites of motor neuron-derived cells. We have also demonstrated that the SMN/HuD interaction is required for the localization of HuD into RNA granules in neurites of motor neuron-derived cells. Furthermore, I have shown that SERBP1 is down-regulated in the absence of normal levels of SMN and, most importantly, that over-expression of SERBP1 can rescue SMA-like neuronal defects using a cell culture model of the disease. These findings may help shed light on the non-canonical molecular pathway(s) involving SMN and RBPs in motor neurons and underscores the possible therapeutic benefits of targeting these RBPs in the treatment of SMA.

Trichostatin A (TSA) is a histone deacetylase inhibitor with beneficial effects in spinal muscular atrophy mouse models that carry the human SMN2 transgene. Whether TSA specifically targets the upregulation of the SMN2 gene or whether other genes respond to TSA and in turn provide neuroprotection in SMA mice is unclear. We have taken advantage of the Smn2B/- mouse model that does not harbor the human SMN2 transgene, to test the hypothesis that TSA has its beneficial effects through a non-Smn mediated pathway. Daily intraperitoneal injection of TSA from postnatal day 12 to 25 was performed in the Smn2B/- mice and littermate controls. Previous work from our laboratory demonstrated that treatment with TSA increased the median lifespan of Smn2B/- mice from twenty days to eight weeks. As well, there was a significant attenuation of weight loss and improved motor behavior. Pen test and righting reflex both showed significant improvement, and motor neurons in the spinal cord of Smn2B/-mice were protected from degeneration. Both the size and maturity of neuromuscular junctions were significantly improved in TSA treated Smn2B/- mice. Here, we have shown that TSA treatment does not increase the levels of Smn protein in mouse embryonic fibroblasts or myoblasts obtained from the Smn2B/- mice. Further, qPCR analysis revealed no changes in the level of Smn transcripts in the brain or spinal cord of TSA-treated SMA mice. Similarly, western blot analysis revealed no significant increase in Smn protein levels in the brain, spinal cord, hind limb muscle, heart muscle, or the liver of TSA treated Smn2B/- mice. However, TSA has beneficial effects in the muscles of Smn2B/- mice and improves motor behavior and myofiber size. TSA improves muscle development by enhancing the activity of myogenic regulatory factors independent of the Smn gene. The beneficial effect of TSA is therefore likely through an Smn-independent manner. Identification of these protective pathways will be of therapeutic value for the treatment of SMA.

U5 small ribonucleoprotein particle (U5 snRNP) is a crucial component of the spliceosome, the complex responsible for pre-mRNA splicing. Despite the importance of U5 snRNP, not much is known about its biogenesis. When we depleted one of the core U5 components, protein PRPF8, the other U5-specific proteins do not associate with U5 snRNA and the incomplete U5 was accumulated in nuclear structures known as Cajal bodies. To further clarify the role of PRPF8 in U5 snRNP assembly, we studied PRPF8 mutations that cause an autosomal dominant retinal disorder, retinitis pigmentosa (RP). We prepared eight different PRPF8 variants carrying RP-associated mutations and expressed them stably in human cell culture. We showed that most mutations interfere with the assembly of snRNPs which consequently leads to reduced efficiency of splicing. The mutant PRPF8 together with EFTUD2 are stalled in the cytoplasm in a form of U5 snRNP assembly intermediate. Strikingly, we identified several chaperons including the HSP90/R2TP complex and ZNHIT2 as new PRPF8's interactors and potential U5 snRNP assembly factors. Our results further imply that these chaperons preferentially bind the unassembled U5 complexes and that HSP90 is required for stability of...

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