Spinal muscular atrophy (SMA) is a neuromuscular disease caused by reduced levels of the survival motor neuron (SMN) protein. SMA results in degeneration of motor neurons, progressive muscle atrophy, and death in severe forms of the disease. Currently, there is a lack of inexpensive, readily accessible, accurate biomarkers to study the disease. Furthermore, the current FDA approved therapeutic is neither 100 % effective nor accessible for all patients, thus more research is required. Tiny cell derived vesicles known as exosomes have been evaluated in an attempt to identify novel biomarkers for many disease states and have also shown therapeutic promise through their ability to deliver protein and nucleic acid to recipient cells. The research presented herein investigates whether (1) the level of SMN protein in exosomes isolated from the medium of cells, and serum from animal models and patients of SMA is indicative of disease, to serve as a biomarker for monitoring disease progression and therapeutic efficacy; (2) SMN-protein loaded exosomes can be utilized to deliver SMN protein to SMN-deficient cells; (3) adenoviral vectors are effective at creating SMN protein-loaded exosomes in situ for body wide distribution of SMN protein. This research has shown SMN protein is naturally released in extracellular vesicles, and the level of exosomal SMN protein is reflective of the disease state. Exosomes can also be modified to hold enhanced levels of SMN protein and deliver them to both the cytoplasm and nucleus of SMN-deficient cells. Furthermore, adenoviral vectors expressing luciferase-tagged SMN1 cDNA, targeted to the liver, results in SMN protein-loaded exosomes and detectable luciferase activity, body-wide. Thus, exosomes present as an effective biomarker and potentially a novel approach to treat SMA.

This is a study of muscle function in Juvenile Idiopathic Arthritis (JIA). Rheumatoid arthritis (RA) is a disease that primarily affects the synovial membrane of joints. Muscle weakness, atrophy and pain occur in adult RA. This may be a consequence of joint pain, stiffness and immobility. Muscle inflammation and neuropathy occur as complications in adults. Muscle function in JIA has been much less studied. The aim of the study was to examine whether muscle weakness and atrophy also occur in children with JIA. This was a longitudinal study over a two-year period, where muscle strength and thickness were measured repeatedly in a group of 20 children and teenagers with JIA. Muscle strength was measured using different methods and in several muscle groups. Muscle biopsies were obtained and nerve conduction velocity studies performed. The study concludes that, compared to healthy people, children and teenagers with JIA have as a group reduced muscle strength and muscle thickness. For most of these children and teenagers, muscle strength is only slightly lower than expected, but a few have marked muscle weakness. This is most apparent in patients with severe polyarthritis where the weakness seems to be widespread. Patients with isolated arthritis may also have greatly reduced strength and thickness of muscles near the inflamed joint. There is a risk of decreasing strength in patients with polyarthritis and in muscles near an active arthritis. Minor changes are common in muscle biopsies, and findings may indicate immunological activity in the muscles. Atrophy of type II fibres, as in adult RA, was not found in JIA. No patient had signs of neuropathy. / On the day of the public defence the status of article IV was: Submitted.

Spinal Muscular Atrophy (SMA) is a neuronal degenerative disease caused by the mutation or loss of the Survival Motor Neuron (SMN) gene. The cause for the specific motor neuron susceptibility in SMA has not been identified. The high axonal transport/localization demand on motor neurons may be one potentially disrupted function, more specific to these cells. We therefore used a large-scale immunoprecipitation (IP) experiment, to identify potential interactors of SMN involved in neuronal transport and localization of mRNA targets. We identified KH-type splicing regulatory protein (KSRP), a multifunctional RNA-binding protein that has been implicated in transcriptional regulation, neuro-specific alternative splicing, and mRNA decay. KSRP is closely related to chick zipcode-binding protein 2 and rat MARTA1, proteins involved in neuronal transport/localization of beta-actin and microtubule-associated protein 2 mRNAs, respectively. We demonstrated that KSRP is arginine methylated, a novel SMN interactor (specifically with the SMN Tudor domain; and not with SMA causing mutants). We also found this protein to be misregulated in the absence of SMN, resulting in increased mRNA stability of KSRP mRNA target, p21cip/waf1. A role for SMN as an axonal chaperone of methylated RBPs could thus be key in SMA pathophysiology.

Spinal Muscular Atrophy (SMA) is a neuronal degenerative disease caused by the mutation or loss of the Survival Motor Neuron (SMN) gene. The cause for the specific motor neuron susceptibility in SMA has not been identified. The high axonal transport/localization demand on motor neurons may be one potentially disrupted function, more specific to these cells. We therefore used a large-scale immunoprecipitation (IP) experiment, to identify potential interactors of SMN involved in neuronal transport and localization of mRNA targets. We identified KH-type splicing regulatory protein (KSRP), a multifunctional RNA-binding protein that has been implicated in transcriptional regulation, neuro-specific alternative splicing, and mRNA decay. KSRP is closely related to chick zipcode-binding protein 2 and rat MARTA1, proteins involved in neuronal transport/localization of beta-actin and microtubule-associated protein 2 mRNAs, respectively. We demonstrated that KSRP is arginine methylated, a novel SMN interactor (specifically with the SMN Tudor domain; and not with SMA causing mutants). We also found this protein to be misregulated in the absence of SMN, resulting in increased mRNA stability of KSRP mRNA target, p21cip/waf1. A role for SMN as an axonal chaperone of methylated RBPs could thus be key in SMA pathophysiology.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Estudos anteriores de nosso laboratório demonstraram que a estimulação aguda dos receptores 2-adrenérgicos (2-AR) atenua a perda de massa muscular induzida pela desnervação motora (DEN) por meio de uma via dependente de AMPc/PKA. No entanto os mecanismos moleculares envolvidos na ativação crônica destes receptores ainda são pouco conhecidos. Por outro lado, a ativação desta via de sinalização também está envolvida no controle da estabilidade dos receptores nicotínicos (AChR) na junção neuromuscular (JNM), sugerindo que a densidade dos AChR possa estar sob controle neuro-humoral. Desta forma, aventou-se a possibilidade de que além dos efeitos protetores na massa muscular, a ativação dos receptores 2-AR pudesse mediar a estabilização dos AChR na placa motora. Para testar essa hipótese, camundongos foram submetidos à DEN através da secção do nervo ciático, um protocolo clássico de indução de atrofia muscular e desestabilização dos AChR, e tratados com salina ou clembuterol (CB), um 2-agonista seletivo, por até 14 dias. Após 3 dias de DEN, observou-se redução da massa muscular e aumento do conteúdo proteico e expressão do RNAm de genes relacionados à ativação do sistema Ubiquitina-Proteassoma (atrogina-1 e MuRF1) e do sistema autofágico/lisossomal (catepsina L e LC3). A DEN também promoveu aumento no turnover dos AChR, no número de vesículas endocíticas e na expressão do RNAm para a subunidade 1 dos AChR. Após 7 dias, a DEN reduziu a expressão dos genes relacionados à atrofia e aumentou a atividade da via do AMPc/PKA independentemente do tratamento com CB. Na tentativa de elucidar os sinais extracelulares que produziam esta resposta adaptativa, foi demonstrado que neurônios catecolaminérgicos trafegam ao longo do nervo ciático e sua ablação pela DEN reduziu o conteúdo de noradrenalina muscular. Baseados nestes resultados, foi postulado a existência de uma hipersenbilidade às catecolaminas em músculos desnervados cronicamente. O tratamento com CB por 3 dias aboliu o aumento da expressão dos atrogenes induzido pela DEN e este efeito foi associado ao maior conteúdo de AMPc e de substratos fosforilados pela PKA. Além disso, o CB diminuiu a hiperexpressão do RNAm para catepsina L e LC3 induzida pela DEN de 7 dias. Embora o CB não tenha alterado a meia-vida dos AChR em músculos inervados e desnervados, houve um total bloqueio do aumento do número de vesículas endocíticas contendo o AChR em músculos desnervados e tratados com CB. Corroborando estes dados, o CB aumentou a incorporação de AChR novos nas JNM e este efeito foi também associado à maior expressão do RNAm para a subunidade 1-AChR em músculos desnervados. Esta ação do CB no turnover dos AChR parece ser direta uma vez que neuroniôs catecolaminérgicos presentes no nervo ciático ativam receptores 2-ARe a produção de AMPc especificamente na JNM. Em estudos in vitro, foi demonstrado que a estimulação colinérgica produzida pelo carbacol (10-4M) diminuiu a velocidade de síntese de proteínas, aumentou a proteólise total e a atividade do sistema proteolítico Ca2+-dependente em músculos soleus de ratos por meio da ativação dos receptores nicotínicos. Este efeito catabólico do carbacol foi completamente bloqueado pela adição de CB (10-4M) ao meio de incubação. Os dados obtidos no presente estudo permitem sugerir que a estimulação crônica dos 2-AR no músculo esquelético induz um efeito anti-catabólico pela supressão dos sistemas proteolíticos proteassomal e lisossomal, provavelmente através da via de sinalização do AMPc/PKA. A inibição destes sistemas pode estar relacionada ao aumento do turnover dos AChR, uma vez que a velocidade de incorporação destes receptores na JNM foi aumentada pelo CB. Além disso, os achados que mostram a associação entre neurônios noradrenérgicos e colinérgicos no nervo ciático, que conjuntamente inervam as JNM, e a co-localização de receptores 2-AR e AChR na sinapse permitem sugerir a existência de uma interação funcional entre o sistema colinérgico e adrenérgico na manutenção da massa muscular e da placa motora. / Previous studies from our laboratory have shown that the acute stimulation of 2-adrenergic receptor (2-AR) attenuates the muscle loss induced by motor denervation (DEN) through a cAMP/PKA dependent pathway. However, the molecular mechanisms involved in the chronic activation of these receptors are poorly understood. Furthermore, the activation of this signaling pathway is also involved in controlling the stability of nicotinic receptors (AChR) at the neuromuscular junction (NMJ), suggesting that the density of AChR may be under neurohumoral control. Thus, we postulated that besides the protective effects on muscle mass the activation of 2-AR receptors could mediate the stabilization of AChR in the motor plate. To test this hypothesis, mice were submitted to DEN through of the sciatic nerve section, a classical protocol of induction muscle atrophy and destabilization of AChR, and were treated with saline or clenbuterol (CB), a selective 2-agonist for 14 days. DEN decreased the muscle mass and increased the protein content and mRNA expression of genes related to the activation of the ubiquitin-proteasome system (atrogin-1 and MuRF1) and autophagic/lysosomal system (cathepsin L and LC3). DEN also promoted an increase in the turnover of AChR, number of endocytic vesicles and the expression of mRNA for the 1 subunit of AChR. Interestingly, chronic DEN induced down-regulation of atrophy related-genes, and increased the activity of cAMP/PKA pathway independently of CB treatment. In an attempt to elucidate the extracellular signals that produced this adaptive response, it was demonstrated that catecholaminergic neurons travels along the sciatic nerve and its ablation by DEN reduces muscle norepinephrine content. Based on these results, it was postulated the existence of a muscle adrenergic hypersensitivity to circulating catecholamines induced by chronic DEN. CB treatment for 3 days completely abolished the higher expression of atrogenes and this effect was associated with increased Camp content and PKA phosphorylated substrates. Furthermore, CB decreased the DEN-induced hyperexpression of cathepsin L and LC3 mRNA at 7 days. Although CB has not altered the half-life of AChR in innervated and denervated muscles, it produced a total blockage of the increased number of endocytic vesicles containing the AChR in denervated muscles. Consistently, CB increased the incorporation of new AChR and this effect was associated with an increased expression of the 1-subunit AChR mRNA in denervated muscles. This action of CB on AChR turnover appears to be direct, since catecholaminergic neurons are present in the sciatic nerve stimulating 2-AR and cAMP production specifically in the NMJ. Furthermore, in vitro studies demonstrated that cholinergic stimulation produced by carbachol (10-4M) decreased the rate of protein synthesis and increased the proteolytic activity of Ca2+-dependent system in rat soleus muscle through activation of nicotinic receptors. This catabolic effect of carbachol was completely blocked by the addition of CB (10-4M) to the incubation medium. These data suggest that chronic stimulation of 2-AR in skeletal muscle induces an anti-catabolic effect by suppressing proteasomal and lysosomal proteolytic systems, probably through the cAMP/PKA signaling. The inhibition of these systems seems to be related to the increased AChR incorporation into NMJ induced by CB treatment. Moreover, the association between noradrenergic and cholinergic neurons in the sciatic nerve, both of which innervate the motor endplates, and the co-localization of AChR and 2-ARat the synapse suggest the existence of a functional interaction between cholinergic and adrenergic systems in the maintenance of muscle mass and motor endplate.

Spinal Muscular Atrophy (SMA) is a neuronal degenerative disease caused by the mutation or loss of the Survival Motor Neuron (SMN) gene. The cause for the specific motor neuron susceptibility in SMA has not been identified. The high axonal transport/localization demand on motor neurons may be one potentially disrupted function, more specific to these cells. We therefore used a large-scale immunoprecipitation (IP) experiment, to identify potential interactors of SMN involved in neuronal transport and localization of mRNA targets. We identified KH-type splicing regulatory protein (KSRP), a multifunctional RNA-binding protein that has been implicated in transcriptional regulation, neuro-specific alternative splicing, and mRNA decay. KSRP is closely related to chick zipcode-binding protein 2 and rat MARTA1, proteins involved in neuronal transport/localization of beta-actin and microtubule-associated protein 2 mRNAs, respectively. We demonstrated that KSRP is arginine methylated, a novel SMN interactor (specifically with the SMN Tudor domain; and not with SMA causing mutants). We also found this protein to be misregulated in the absence of SMN, resulting in increased mRNA stability of KSRP mRNA target, p21cip/waf1. A role for SMN as an axonal chaperone of methylated RBPs could thus be key in SMA pathophysiology.

A atrofia muscular espinhal (AME) é uma doença rara e neurodegenerativa, que afeta crianças e adultos. Gera atrofia muscular, prejudica os movimentos voluntários e, em muitos casos, dificulta a comunicação oral. Esta dissertação é composta por dois artigos. O Estudo 1 objetivou revisar a literatura sobre o desenvolvimento cognitivo de pessoas com AME. O Estudo 2 objetivou avaliar o desempenho visual, cognitivo e motor de crianças com AME tipo 1 (AME-I). O primeiro estudo foi uma revisão sistemática, com levantamento dos últimos 25 anos (de 1992 a 2017) nas bases de dados PUBMED/Medline, Web of Science e Scielo. Os descritores utilizados foram: spinal muscular atrophy e cognition. O estudo 2 consistiu na avaliação de 24 crianças, divididas em dois grupos: 12 crianças com AME-I (3 a 9 anos, 9 meninos e 3 meninas) e 12 crianças saudáveis, pareadas por idade e sexo. As 24 crianças responderam a quatro tarefas de associação de figuras, com dificuldade crescente. As respostas foram detectadas por meio de um rastreador de olhar. Para o primeiro estudo foram localizados 43 artigos, desses, nove foram selecionados, de acordo com os critérios de inclusão e exclusão. O estudo apontou que o desempenho cognitivo de crianças com AME é heterogêneo. Três artigos indicaram que essas crianças têm desempenho cognitivo normal, três artigos indicaram que há atraso e outros três estudos relataram desempenho acima da média. De modo geral, as crianças com maior fraqueza muscular (AME-I) apresentaram maior comprometimento e estudos mais recentes detectaram esse atraso. O segundo estudo descreveu pior desempenho do grupo AME-I, em relação ao grupo controle (maior número de erros e maior tempo para execução das tarefas). Concluímos que, até o momento, poucos estudos investigaram aspectos cognitivos em crianças e adolescentes com AME. O desenvolvimento cognitivo de crianças com AME deve ser acompanhado, principalmente em crianças com AME-I. É necessário avaliar o desempenho cognitivo e, se necessário, propor intervenções para pessoas com AME. O desenvolvimento cognitivo adequado facilita a autonomia e interação. Os rastreadores de olhar podem estimular e aprimorar esse repertório / Spinal muscular atrophy (SMA) is a rare and neurodegenerative disease, affecting children and adults. SMA causes muscular atrophy and weakness, and, in many cases, impairs the development of oral communication. This dissertation is composed of two articles. Study 1 aimed to review the literature about the cognitive development of people with SMA. Study 2 aimed to evaluate the visual, cognitive and motor performance of children with SMA type 1 (SMAI). Study 1 reviewed the findings of the last 25 years (1992 to 2017), in PUBMED/Medline, Web of Science and Sicelo databases. The descriptors were: spinal muscular atrophy and cognition. Study 2 consisted of the evaluation of 24 children divided into two groups: 12 children with SMA-I (3 to 9 years of age, 9 boys and 3 girls) and 12 healthy children, matched by age and sex. The 24 children performed four figure-association tasks, with increasing difficulty. Responses were detected by an eye tracking device. For the first study, 43 articles were identified and nine were selected because they met the inclusion and exclusion criteria. The study pointed out that the cognitive performance of children with SMA is heterogeneous. Three articles indicated that children with SMA had normal cognitive performance, three observed delayed performance and three studies described cognitive performance as above average. In general, samples with children with more severe muscular weakness (SMA-I) showed some cognitive impairment and more recent studies detected this delay. The second study described poorer performance of the SMA-I group, compared to the control group (more errors and longer times). In conclusion, few studies investigated cognitive outcomes in children and adolescents with SMA. The cognitive development of children with SMA should be followed, especially children with SMA-I. More studies should evaluate and, if necessary, intervene to prevent cognitive impairment in people with SMA. The proper cognitive development facilitates autonomy and interaction. The eye tracker can stimulate and improve their repertoire

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder, which causes dysfunction/loss of lower motor neurons and muscle weakness as well as atrophy. While SMA is primarily considered as a motor neuron disease, recent data suggests that survival motor neuron (SMN) deficiency in muscle causes intrinsic defects. We systematically profiled secreted proteins from control and SMN deficient muscle cells with two combined metabolic labeling methods and mass spectrometry. From the screening, we found lower levels of C1q/TNF-related protein 3 (CTRP3) in the SMA muscle secretome and confirmed that CTRP3 levels are indeed reduced in muscle tissues and serum of an SMA mouse model. We identified that CTRP3 regulates neuronal protein synthesis including SMN via mTOR pathway. Furthermore, CTRP3 enhances axonal outgrowth and protein synthesis rate, which are well-known impaired processes in SMA motor neurons. Our data revealed a new molecular mechanism by which muscles regulate the physiology of motor neurons via secreted molecules. Dysregulation of this mechanism contributes to the pathophysiology of SMA.

The risk of having a disability increases with advancing age and as the life expectancy is growing worldwide, the number of people living with disability is expected to increase, as well as the number of years lived with disability. Low back pain and sarcopenia are health problems that present a higher prevalence with aging. While low back pain is a symptom, sarcopenia is considered a geriatric syndrome. However, both issues constitute a significant health burden in older adults. Although there are many research studies investigating low back pain, the participation of older adults is often missing from these studies, preventing the generalization of the findings to this population, and leaving some questions unanswered. On the other hand, sarcopenia is a new research field with gaps to fill and flaws to correct. Questions related to low back pain management in older adults, the inclusion of this population in clinical trials, the presence of association between sarcopenia and low back pain and questions pertaining the diagnosis and measurement of sarcopenia have yet to be fully addressed by researchers. The broad aim of this thesis therefore was to contribute to a better understanding concerning low back pain and sarcopenia in older adults by performing studies in these key research areas. Different interventions are presented in clinical practice guidelines for the treatment of low back pain. However, these recommendations are based on clinical trials investigating young and middle-aged adults and as a result, the recommendations do not encompass older adults. Therefore, a systematic review was performed with the objective of assessing the effectiveness of interventions for low back pain in older adults ≥ 60 years (Chapter 3). Eligible studies were identified via searches in Medline, EMBASE, CINAHL, LILACS, PEDro, and Cochrane CENTRAL. A total of 18 randomized controlled trials fulfilled the eligibility criteria and the results from eight trials were pooled in a meta-analysis to test the effectiveness of complementary health approaches (i.e., manual therapy, acupuncture, mindfulness, yoga). Evidence about interventions to manage non-specific low back pain in older adults was found to be weak. Very low to moderate quality evidence showed that complementary health approaches, percutaneous electrical nerve stimulation, education, exercise, or pharmacological agents did not produce a clinically significant reduction in pain and disability at short and intermediate terms compared to sham, usual care, or minimal intervention. Interventions were often not well described and the risk of bias was moderate (average of 6.4 on the 10-point PEDro Scale (SD = 1.44)). Evidence about interventions for non-specific low back pain in older adults is limited and new studies are highly likely to change these results. Participation of older adults in clinical trials pertaining to the management of low back pain has been limited. Usually, the exclusion of older adults from clinical trials is based solely on an arbitrary age limit. Therefore, an investigation concerning the potential increased inclusion of older adults in upcoming clinical trials was conducted (Chapter 4). Chapter four presents an analysis of the International Clinical Trial Registry Platform database from the World Health Organization performed to verify the participation of older adults in registered clinical trials. A total of 167 clinical trial protocols for low back pain with registration dates from January 2015 through November 2018 were planning to recruit participants older than 65 years. However, only five registered trials (2.99%; pooled sample = 169 participants) were designed to target this population specifically. The exclusion of older participants was not formally justified and imposed through an arbitrary upper-age limit in 93.6% of the protocols. Most studies planning to include older adults were interested in pharmacologic interventions, devices/technology, and physical rehabilitation, and were to be carried out in developed regions. However, older adults with low back pain will continue to be under-investigated in clinical trials for low back pain in the near future. Although a slight increase in the participation of older adults in clinical trials was observed, the improvement is small and some questions still need an answer. Therefore, a survey investigating whether researchers recognize the exclusion of older adults from clinical trials, its impact, and justifications to support this exclusion was realized (Chapter 5). All attendees of the 2017 International Back Forum were invited by email to answer an electronic survey about their opinions regarding participation of older adults in clinical trials for low back pain. Approximately 90% of those who answered the questionnaire were engaged with back research, with more than a half having done or doing a clinical trial for low back pain. Most of the respondents believed that older people are excluded from clinical trials for low back pain and that exclusion based solely on age is not justifiable. About two thirds of the respondents reported that the exclusion of older people from clinical trials can impose a barrier in offering evidence-based interventions to this population. More researchers are planning to include older adults in their current/future trials compared to their previous work. An increase in the investigation of older adults in clinical trials is expected in the future which may optimize the development of evidence-based interventions for this population. As early evidence suggests an association between sarcopenic markers and low back pain, the association between the diagnosis of sarcopenia and low back pain still needs to be investigated (Chapter 6). Therefore, a study investigating the association between sarcopenia using different diagnosis criteria and low back pain in older adults was performed. Data from 12,646 older adults (50.1% men, 49.9% women) ≥ 65 years of age that participated in the Canadian Longitudinal Study on Aging (CLSA) were analyzed. The prevalence of low back pain in the past 12 months as well the prevalence of sarcopenia assessed through different definitions, and the number of comorbidities and depressive symptoms were included in the analysis. Associations between sarcopenia, comorbidities and lifestyle factors with low back pain were examined using multivariate logistic regressions. Prevalence of low back pain was 16.3% and the prevalence of sarcopenia varied among sarcopenia definitions and the presence of low back pain. Participants with low back pain had higher prevalence of pre-sarcopenia and sarcopenia compared to those without low back pain based on the International Working Group on Sarcopenia (x2 = 20.25, p < 0.001) and the Foundation National Institute of Health definitions (x2 = 13.83, p < 0.001). The odds of having low back pain was higher among those with sarcopenia based on the Foundation National Institute of Health criterion (OR 1.28, 95%CI 1.0-1.64). These results suggest that sarcopenia may influence low back pain in older adults and future studies should consider to test whether the association between sarcopenia and low back pain is causal. Current clinical practice guidelines recommend to divide patients with low back pain in specific subgroups to provide a targeted intervention. However, despite older adults presenting specific age-related characteristics that could classify them as a subgroup, this population has been neglected. Sarcopenia is a muscle disease affecting older adults and is diagnosed with the presence of a reduction in muscle strength and muscle quantity/quality. Although low back pain has been shown to be associated with muscle dysfunction, the role of sarcopenia in relation to low back pain is unknown. An experiment comparing sarcopenic markers (grip strength and gait speed), muscle activity and elasticity between older adults with and without chronic low back pain was conducted (Chapter 7). The anticipatory activity of transversus abdominis muscle during the rapid arm abduction test, transversus abdominis muscle elasticity, grip strength and gait speed were collected from a group of older adults (≥ 60 years) with chronic low back pain (≥ 3 months) and the results compared with a control group of matched older adults without low back pain. Participants with chronic low back pain presented with a reduction in the sarcopenic markers compared with the controls: grip strength (mean difference (MD) = 5.3Kg, 95%CI = 1.5-9.0, p = 0.006), gait speed (MD = 0.21m/s, 95%CI = 0.10-0.31, p<0.001), as well as a delay in activation of transversus abdominis (p = 0.002). A delay in transversus abdominis muscle activation, and a reduction in muscle strength and gait speed were observed in older adults with chronic low back pain compared to subjects without back complaints. These findings show an association between muscle dysfunction and chronic low back pain in older adults. Although the definition of sarcopenia was recently updated establishing muscle strength as the key criteria surpassing the role of muscle mass, there remains confusion regarding its diagnosis and the comparison of estimates is problematic. Therefore, a systematic review assessing how sarcopenia is measured and defined in population-based studies was performed. Chapters 8 and 9 describe the protocol of a systematic review and the full systematic review respectively. The databases Medline, EMBASE, CINAHL, Web of Science (Core Collection), and Google Scholar were searched for observational population-based studies reporting prevalence of sarcopenia in community dwelling older adults. Descriptive statistics were used to present data pertaining to sarcopenia definition and measurement tools, and the quality-effects model for meta-analysis of pooled prevalence. Results found seven different operational definitions of sarcopenia and a variety of measurement tools applied to assess the sarcopenic markers: muscle mass, muscle strength and physical performance. The prevalence of sarcopenia varied between the definitions, with general estimates ranging from 5% based on the European Working Group on Sarcopenia in Older People (EWGSOP1) criterion to 17% with the International Working Group on Sarcopenia criterion. The use of different measurement tools to assess muscle mass, strength and physical performance resulted in variations within definitions ranging from 1 to 7%, 1 to 12% and 0 to 22%, respectively. The criteria used to define sarcopenia, as well as the measurement tools used to assess sarcopenic markers has an influence in the prevalence of sarcopenia. The establishment of a unique definition for sarcopenia, the use of methods that guarantee an accurate evaluation of muscle mass, and the standardization of measurement tools are necessary to allow a proper diagnosis and comparison of sarcopenia prevalence among populations.