No description available.

<p>Neck braces and head supports used today do not allow wearers to rotate their head while maintaining the support they need. For people with chronic muscle diseases, such as ALS, DHS, Myasthenia Gravis, and Muscular Dystrophy, this inconvenience greatly affects their quality of life in that it hinders their abilities to perform activities of daily living, such as nonverbal communication and knowing their surroundings outside without having to move their entire body. There is a need for a head support device that allows individuals with chronic muscle diseases to rotate their heads, so they may better perform daily activities of living and thus live a more fulfilling life. </p> <p>The purpose of this study was to assess the basic stance of safety of a dynamic head support device that allows individuals with chronic muscle diseases to rotate their heads left and right. The assessment includes an experimental procedure that will conclude whether this device can withstand the load equivalent to an average adult’s head in a stationary position and a dynamic movement.</p> <p>This research proposed a procedure that has a testing apparatus that will place a predetermined load onto the dynamic head support device to stabilize it and then continuously add weight that was checked incrementally. This load was placed on the device while it was centered and static first. The next step in this procedure is to assess whether or not the load on the device can be carried while dynamically moving on the race of the radial sliding track of the device. The data recorded from this experiment will provide the necessary information to determine whether the basic safety requirement of load capacity for a medical device such as the one in this proposed research is met. </p>

M.Tech. / OBJECTIVE: An association between cervicogenic headache, cervical joint dysfunction and the presence of myofascial trigger points in the sternocleidomastoid muscle exists. This study is aimed at determining the most effective Chiropractic treatment protocol in the management of cervicogenic headache by comparing the objective and subjective measurements gained in delivering Chiropractic spinal manipulative therapy to the upper cervical spine, myofascial dry needling therapy to myofascial trigger points in the sternocleidomastoid muscle and/or a combination of both therapies. DESIGN: Forty-eight participants suffering from cervicogenic headache were allocated into one of three groups of equal male to female ratio. Each patient was examined and cleared for participation in a clinical trial in which Diversified Chiropractic techniques and/or myofascial dry needling therapy were delivered. Group 1 received Chiropractic spinal manipulative therapy to the upper cervical spine. Group 2 received myofascial dry needling therapy to myofascial trigger points in the sternocleidomastoid muscle. Group 3 received a combination of the mentioned therapies. DURATION AND MEASUREMENTS: Participants were consulted seven times in a four week period. They were treated twice per week for three weeks and a final, follow-up assessment was performed at the start of the fourth week. Subjective and objective measurements were taken and recorded on the first, fourth and seventh consultations. Subjective measurements were taken via the Vernon-Mior Neck Pain and Disability Questionnaire, Triple Visual Analogue Scale and the Headache Disability Index. Objective measurements included cervical spine ranges of motion which were measured using the Cervical Range of Motion Instrument (CROM). The data was statistically analysed using the Shapiro-Wilk, Kruskal-Wallis, Mann-Whitney, Friedman and Wilcoxon Signed Ranks tests. RESULTS: Clinically and statistically significant improvements in all three groups were noted over the course of the study, with regards to perception of pain, disability and cervical spine range of motion. Statistically significant changes in ranges of motion were demonstrated in Group 1 for flexion, extension, lateral flexion (right and left) and right rotation; in Group 2 for right lateral flexion and left rotation and in Group 3 for all cervical ranges of motion. The comparison between the groups (intergroup analysis) showed no statistically significant changes except for right lateral flexion at the first consultation (pre-treatment). CONCLUSION: The results show that Chiropractic spinal manipulative therapy and dry needling are both effective treatment protocols in decreasing pain and dysfunction and increasing cervical range of motion in patients suffering from cervicogenic headache. This was demonstrated clinically, and to a lesser degree, statistically. The results carry a possible suggestion that although the different treatment options are effective individually, no treatment option proves to be statistically superior.

Indiana University-Purdue University Indianapolis (IUPUI) / Under normal conditions, smooth muscle cells do not replicate, or proliferate, and provide a means of contraction for many internal organs, including blood vessels and the gut. However, under abnormal or disease conditions, such as congenital heart disease and cancer, smooth muscle cells acquire the ability to replicate, to make extracellular matrix proteins and to migrate. Thus, determining how smooth muscle cells regulate these processes is crucial to understanding how the cells can switch between normal and diseased states. Serum response factor (SRF) is a widely expressed protein that plays a key role in the regulation of smooth muscle differentiation, proliferation and migration. It is generally accepted that one way that SRF can distinguish between these functions is through pathway-specific co-factor interactions. A novel SRF co-factor, chromodomain helicase DNA binding protein 8 (CHD8), was originally isolated from a yeast two-hybrid assay. CHD8 is widely expressed in adult tissues including smooth muscle. Data from in vitro binding assays indicate that the N-terminus of CHD8 can interact directly with the MADS domain of SRF. Co-immunoprecipitation assays verified the ability of these two proteins to interact within cells. Adenoviral-mediated shRNA knockdown of CHD8 in smooth muscle cells resulted in statistically significant 10-20% attenuation of expression of SRF-dependent, smooth muscle-specific genes. Similar experiments revealed that knockdown of CHD8 did not affect the SRF-dependent induction of immediate early genes required to promote proliferation. In contrast, knockdown of CHD8 in A10 vascular smooth muscle cells resulted in a marked induction in of apoptosis, characterized by increases in apoptotic markers such as phospho-H2A.X, cleaved PARP and activated caspase-3. These data suggest that CHD8 may play a specific role in modulating SRF’s activity toward anti-apoptotic genes, thereby regulating smooth muscle cell survival.

Introdução: Até o presente momento, há escassez de estudos que avaliem os níveis séricos de citocinas angiogênicas em pacientes com dermatomiosite (DM), uma miosite autoimune sistêmica que tem como fisiopatogênese a vasculopatia. Portanto, os objetivos do presente estudo foram: (a) analisar sistematica e simultaneamente os níveis séricos de angiogenin (ANG), angiopoietin (ANGPT) -1, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) -1 e -2 e platelet derived growth factor (PDGF) -AA e -BB em pacientes com DM; (b) correlacionar o nível sérico destas citocinas com as características clínico-laboratoriais, alterações metabólicas e atividade da DM. Pacientes e métodos: Estudo transversal, único centro, no qual foram incluídos, no período de 2012 a 2014, 48 pacientes consecutivos com DM definida (Bohan e Peter, 1975), entre 18 e 45 anos de idade, e em seguimento regular na nossa Instituição. Foram excluídos pacientes com condições clínicas relacionadas à DM (como sequelas de doença e tratamento prolongado) ou secundárias a outras causas que poderiam influenciar na interpretação dos resultados das citocinas avaliadas, seja por apresentarem variações hormonais ou por estarem relacionados ao mecanismo de inflamação e/ou angiogênese. Os pacientes foram pareados por sexo, idade e etnia com 48 indivíduos saudáveis (grupo controle). A análise das citocinas séricas foi realizada por imunoensaio multiplex. Os parâmetros da atividade da DM foram baseados nos escores estabelecidos por International Myositis Assessment & Clinical Studies Group (IMACS). Resultados: A distribuição de sexo e a etnia foram comparáveis entre os grupos DM e controle assim como a média de idade (33,3±7,6 vs. 35,8±8,2 anos, respectivamente), e a mediana de duração de doença foi de 1 ano. No grupo DM, os níveis séricos de FGF-1 e FGF-2 (P < 0,001, P < 0,001, respectivamente) estavam elevados, enquanto os níveis de VEGF e PDGF-AA (P=0,009 e P=0,022, respectivamente) estavam reduzidos. Os níveis de ANG, ANGPT-1 e PDGFBB foram semelhantes em ambos os grupos. Houve uma tendência para correlação positiva entre as citocinas (com exceção de VEGF e PDGF-BB) e os parâmetros de atividade da DM, enquanto FGF-2 apresentou correlação negativa. Além disso, o FGF-1 correlacionou-se fortemente com manifestações cutâneas da dermatomiosite. Conclusões: Os dados atuais reforçam a importância das citocinas angiogênicas nos mecanismos de vasculopatia da DM, especialmente em condições de atividade cutânea e adequado tratamento medicamentoso. Estudos adicionais serão necessários para validar os dados obtidos no presente trabalho / Introduction: Until now, there are few studies evaluating serum levels of angiogenic cytokines in patients with dermatomyositis (DM), a systemic autoimmune myositis that has vasculopathy as its physiopathogenesis. Therefore, the aims of the present study were: (a) to analyze systematically and simultaneously serum levels of angiogenin (ANG), angiopoietin (ANGPT) -1, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) -1 and -2, and platelet derived growth factor (PDGF) -AA and -BB in patients with DM; (b) to correlate the serum level of these cytokines with the clinical and laboratory features, metabolic alterations and DM activity. Patients and methods: This is an one-center cross sectional study, in which 48 consecutive patients with defined DM (Bohan and Peter, 1975) aged 18 to 45 years and regularly followed up at our Institution were included from 2012 to 2014. Patients with clinical conditions related to DM (as sequelae of disease and prolonged treatment) or secondary to other causes that could influence the results interpretation of the evaluated cytokines were excluded, either because of hormonal variations or relationship with inflammation mechanism and/or angiogenesis. Patients were gender-, age- and ethnicity-matched with 48 healthy individuals (control group). The serum levels of cytokines analyses were performed by multiplex immunoassay. The parameters of DM activity were based on the scores established by the International Myositis Assessment & Clinical Studies Group (IMACS). Results: The gender and ethnicity were comparable between DM and control groups as soon as the mean age (33.3±7.6 vs. 35.8±8.2 years, respectively), and the median disease duration was 1 year. The serum levels of FGF-1 and FGF-2 (P < 0.001 and P < 0.001, respectively) were higher in DM group, whereas the levels of VEGF and PDGF-AA (P=0.009 and P=0.022, respectively) were lower in DM group. The levels of ANG, ANGPT-1 and PDGF-BB were similar in both groups. There was a tendency for cytokines (with the exceptions of VEGF and PDGF-BB) to correlate positively with DM activity parameters, whereas FGF-2 correlated inversely. Moreover, FGF-1 strongly correlated with the cutaneous manifestations of DM. Conclusion: The current data reinforce the importance of angiogenic cytokines in DM vasculopathy mechanisms, especially in conditions of cutaneous activity and adequate drug treatment. Additional studies will be needed to validate the data obtained in this work

Introdução: Até o presente momento, há escassez de estudos que avaliem os níveis séricos de citocinas angiogênicas em pacientes com dermatomiosite (DM), uma miosite autoimune sistêmica que tem como fisiopatogênese a vasculopatia. Portanto, os objetivos do presente estudo foram: (a) analisar sistematica e simultaneamente os níveis séricos de angiogenin (ANG), angiopoietin (ANGPT) -1, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) -1 e -2 e platelet derived growth factor (PDGF) -AA e -BB em pacientes com DM; (b) correlacionar o nível sérico destas citocinas com as características clínico-laboratoriais, alterações metabólicas e atividade da DM. Pacientes e métodos: Estudo transversal, único centro, no qual foram incluídos, no período de 2012 a 2014, 48 pacientes consecutivos com DM definida (Bohan e Peter, 1975), entre 18 e 45 anos de idade, e em seguimento regular na nossa Instituição. Foram excluídos pacientes com condições clínicas relacionadas à DM (como sequelas de doença e tratamento prolongado) ou secundárias a outras causas que poderiam influenciar na interpretação dos resultados das citocinas avaliadas, seja por apresentarem variações hormonais ou por estarem relacionados ao mecanismo de inflamação e/ou angiogênese. Os pacientes foram pareados por sexo, idade e etnia com 48 indivíduos saudáveis (grupo controle). A análise das citocinas séricas foi realizada por imunoensaio multiplex. Os parâmetros da atividade da DM foram baseados nos escores estabelecidos por International Myositis Assessment & Clinical Studies Group (IMACS). Resultados: A distribuição de sexo e a etnia foram comparáveis entre os grupos DM e controle assim como a média de idade (33,3±7,6 vs. 35,8±8,2 anos, respectivamente), e a mediana de duração de doença foi de 1 ano. No grupo DM, os níveis séricos de FGF-1 e FGF-2 (P < 0,001, P < 0,001, respectivamente) estavam elevados, enquanto os níveis de VEGF e PDGF-AA (P=0,009 e P=0,022, respectivamente) estavam reduzidos. Os níveis de ANG, ANGPT-1 e PDGFBB foram semelhantes em ambos os grupos. Houve uma tendência para correlação positiva entre as citocinas (com exceção de VEGF e PDGF-BB) e os parâmetros de atividade da DM, enquanto FGF-2 apresentou correlação negativa. Além disso, o FGF-1 correlacionou-se fortemente com manifestações cutâneas da dermatomiosite. Conclusões: Os dados atuais reforçam a importância das citocinas angiogênicas nos mecanismos de vasculopatia da DM, especialmente em condições de atividade cutânea e adequado tratamento medicamentoso. Estudos adicionais serão necessários para validar os dados obtidos no presente trabalho / Introduction: Until now, there are few studies evaluating serum levels of angiogenic cytokines in patients with dermatomyositis (DM), a systemic autoimmune myositis that has vasculopathy as its physiopathogenesis. Therefore, the aims of the present study were: (a) to analyze systematically and simultaneously serum levels of angiogenin (ANG), angiopoietin (ANGPT) -1, vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) -1 and -2, and platelet derived growth factor (PDGF) -AA and -BB in patients with DM; (b) to correlate the serum level of these cytokines with the clinical and laboratory features, metabolic alterations and DM activity. Patients and methods: This is an one-center cross sectional study, in which 48 consecutive patients with defined DM (Bohan and Peter, 1975) aged 18 to 45 years and regularly followed up at our Institution were included from 2012 to 2014. Patients with clinical conditions related to DM (as sequelae of disease and prolonged treatment) or secondary to other causes that could influence the results interpretation of the evaluated cytokines were excluded, either because of hormonal variations or relationship with inflammation mechanism and/or angiogenesis. Patients were gender-, age- and ethnicity-matched with 48 healthy individuals (control group). The serum levels of cytokines analyses were performed by multiplex immunoassay. The parameters of DM activity were based on the scores established by the International Myositis Assessment & Clinical Studies Group (IMACS). Results: The gender and ethnicity were comparable between DM and control groups as soon as the mean age (33.3±7.6 vs. 35.8±8.2 years, respectively), and the median disease duration was 1 year. The serum levels of FGF-1 and FGF-2 (P < 0.001 and P < 0.001, respectively) were higher in DM group, whereas the levels of VEGF and PDGF-AA (P=0.009 and P=0.022, respectively) were lower in DM group. The levels of ANG, ANGPT-1 and PDGF-BB were similar in both groups. There was a tendency for cytokines (with the exceptions of VEGF and PDGF-BB) to correlate positively with DM activity parameters, whereas FGF-2 correlated inversely. Moreover, FGF-1 strongly correlated with the cutaneous manifestations of DM. Conclusion: The current data reinforce the importance of angiogenic cytokines in DM vasculopathy mechanisms, especially in conditions of cutaneous activity and adequate drug treatment. Additional studies will be needed to validate the data obtained in this work

Objetivos. Alta prevalência de síndrome metabólica (SM) tem sido descrita recentemente em diferentes miopatias inflamatórias idiopáticas, mas não em síndrome antissintetase (SAS). Portanto, avaliamos a frequência de SM em SAS e a associação de SM com os fatores de risco de doenças cardiovasculares e as características da doença relacionada à SAS. Métodos. Trata-se de um estudo transversal, único centro, no qual 42 pacientes consecutivos com SAS foram pareados por sexo, idade, etnia e índice de massa corporal com 84 indivíduos saudáveis, no período de 2012 a 2015. Todos os pacientes apresentavam pelo menos quatro dos cinco itens dos critérios de Bohan e Peter (1975) e também os seguintes sinais e/ou sintomas no início da doença: artrite, acometimento pulmonar, fenômeno de Raynaud, febre, \"mãos de mecânico\" e autoanticorpos antissintetases. O status da SAS foi avaliado, baseando-se nos questionários de International Myositis Assessment and Clinical Studies Group (IMACS). Os dados clínicos, laboratoriais e terapêuticos foram coletados por meio de um protocolo padronizado. A SM foi definida de acordo com a Joint Interim Statement de 2009. A análise de adipocitocinas séricas (adiponectina, leptina e resistina) foi feita através de método padronizado, enquanto que a análise de resistência insulínica foi realizada através do método de Homeostatic Model Assessment (HOMA). Resultados. A idade mediana dos pacientes com SAS foi de 41,1 anos, com predominância de etnia branca e de sexo feminino. Os pacientes apresentaram prevalência maior de SM (42,9% vs. 13,1%; P < 0,001) e valor maior de resistência insulínica, quando comparados ao grupo controle. Além disso, os pacientes apresentaram maior nível sérico de resistina, em contraste com um menor nível de leptina e similar de adiponectina, quando comparado ao grupo controle. Em uma análise adicional, quando foram comparados os pacientes com SM (N=18) e sem (N=24) SM, os primeiros apresentavam maior idade (48,7 vs. 35,4 anos; P < 0,001), com duração semelhante da doença, status da doença, esquema terapêutico, resistência insulínica e nível sérico de adipocitocinas. Conclusões. Maior frequência de SM e maior valor de resistência insulínica foram observados em pacientes com SAS, com alto nível sérico de resistina e baixo nível de leptina. Além disso, os pacientes de SAS com SM apresentavam idade mais avançada, a exemplo do que ocorrem com outras miopatias inflamatórias idiopáticas com SM / Objectives. A high frequency of metabolic syndrome (MetS) has been recently described in different idiopathic inflammatory myopathies, but not for antisynthetase syndrome (ASS). Therefore, we determined the prevalence of MetS in ASS and the association of MetS with the risk factors of cardiovascular diseases and with ASS-related disease characteristics. Methods. A cross-sectional single center study of 42 consecutive patients with ASS was conducted from 2012 to 2015. For the control group, 84 healthy individuals were matched with patients for gender, age, ethnicity and body mass index-matched, in the same period. All patients had at least four of five items of Bohan and Peter\'s criteria (1975) and also the follow signal and/or symptoms at onset of disease: arthritis, pulmonary involvement, Raynaud\'s phenomenon, fever, \"mechanics\' hands\" and antisynthetase autoantibodies. The disease status was defined, basing on the International Myositis Assessment and Clinical Studies Group (IMACS) questionnaires. Clinical, laboratory and treatment data were collected using a standardized protocol. MetS was defined according to the 2009 Joint Interim Statement. The serum adipocytokine analysis (adiponectin, leptin and resistin) was performed by standardized method, whereas the insulin resistance was performed by Homeostatic Model Assessment (HOMA) method. Results. ASS patients had a median age of 41.1 years and were predominantly female and of white ethnicity. The patients had a higher frequency of MetS (42.9% vs. 13.1%; P < 0.001) and of insulin resistance than controls. Moreover, patients had higher resistin, lower leptin and similar adiponectin levels in serum than controls. Further analysis of the ASS patients with (N=18) and without (N=24) MetS revealed that individuals with the syndrome were older (48.7 vs. 35.4 years; P < 0.001) age at disease onset and had similar disease duration, disease status, treatment, insulin resistance and serum adipocytokine levels. Conclusions. The prevalence of MetS was high in patients with ASS, who also had serum resistin and low leptin levels. Moreover, ASS patients with MetS were older at disease onset, mirroring findings seen in other idiopathic inflammatory myopathies

Objetivos. Alta prevalência de síndrome metabólica (SM) tem sido descrita recentemente em diferentes miopatias inflamatórias idiopáticas, mas não em síndrome antissintetase (SAS). Portanto, avaliamos a frequência de SM em SAS e a associação de SM com os fatores de risco de doenças cardiovasculares e as características da doença relacionada à SAS. Métodos. Trata-se de um estudo transversal, único centro, no qual 42 pacientes consecutivos com SAS foram pareados por sexo, idade, etnia e índice de massa corporal com 84 indivíduos saudáveis, no período de 2012 a 2015. Todos os pacientes apresentavam pelo menos quatro dos cinco itens dos critérios de Bohan e Peter (1975) e também os seguintes sinais e/ou sintomas no início da doença: artrite, acometimento pulmonar, fenômeno de Raynaud, febre, \"mãos de mecânico\" e autoanticorpos antissintetases. O status da SAS foi avaliado, baseando-se nos questionários de International Myositis Assessment and Clinical Studies Group (IMACS). Os dados clínicos, laboratoriais e terapêuticos foram coletados por meio de um protocolo padronizado. A SM foi definida de acordo com a Joint Interim Statement de 2009. A análise de adipocitocinas séricas (adiponectina, leptina e resistina) foi feita através de método padronizado, enquanto que a análise de resistência insulínica foi realizada através do método de Homeostatic Model Assessment (HOMA). Resultados. A idade mediana dos pacientes com SAS foi de 41,1 anos, com predominância de etnia branca e de sexo feminino. Os pacientes apresentaram prevalência maior de SM (42,9% vs. 13,1%; P < 0,001) e valor maior de resistência insulínica, quando comparados ao grupo controle. Além disso, os pacientes apresentaram maior nível sérico de resistina, em contraste com um menor nível de leptina e similar de adiponectina, quando comparado ao grupo controle. Em uma análise adicional, quando foram comparados os pacientes com SM (N=18) e sem (N=24) SM, os primeiros apresentavam maior idade (48,7 vs. 35,4 anos; P < 0,001), com duração semelhante da doença, status da doença, esquema terapêutico, resistência insulínica e nível sérico de adipocitocinas. Conclusões. Maior frequência de SM e maior valor de resistência insulínica foram observados em pacientes com SAS, com alto nível sérico de resistina e baixo nível de leptina. Além disso, os pacientes de SAS com SM apresentavam idade mais avançada, a exemplo do que ocorrem com outras miopatias inflamatórias idiopáticas com SM / Objectives. A high frequency of metabolic syndrome (MetS) has been recently described in different idiopathic inflammatory myopathies, but not for antisynthetase syndrome (ASS). Therefore, we determined the prevalence of MetS in ASS and the association of MetS with the risk factors of cardiovascular diseases and with ASS-related disease characteristics. Methods. A cross-sectional single center study of 42 consecutive patients with ASS was conducted from 2012 to 2015. For the control group, 84 healthy individuals were matched with patients for gender, age, ethnicity and body mass index-matched, in the same period. All patients had at least four of five items of Bohan and Peter\'s criteria (1975) and also the follow signal and/or symptoms at onset of disease: arthritis, pulmonary involvement, Raynaud\'s phenomenon, fever, \"mechanics\' hands\" and antisynthetase autoantibodies. The disease status was defined, basing on the International Myositis Assessment and Clinical Studies Group (IMACS) questionnaires. Clinical, laboratory and treatment data were collected using a standardized protocol. MetS was defined according to the 2009 Joint Interim Statement. The serum adipocytokine analysis (adiponectin, leptin and resistin) was performed by standardized method, whereas the insulin resistance was performed by Homeostatic Model Assessment (HOMA) method. Results. ASS patients had a median age of 41.1 years and were predominantly female and of white ethnicity. The patients had a higher frequency of MetS (42.9% vs. 13.1%; P < 0.001) and of insulin resistance than controls. Moreover, patients had higher resistin, lower leptin and similar adiponectin levels in serum than controls. Further analysis of the ASS patients with (N=18) and without (N=24) MetS revealed that individuals with the syndrome were older (48.7 vs. 35.4 years; P < 0.001) age at disease onset and had similar disease duration, disease status, treatment, insulin resistance and serum adipocytokine levels. Conclusions. The prevalence of MetS was high in patients with ASS, who also had serum resistin and low leptin levels. Moreover, ASS patients with MetS were older at disease onset, mirroring findings seen in other idiopathic inflammatory myopathies

Myofibrillogenesis is a complex process, which involves assembly of hundreds of structural proteins in a highly ordered manner to form the contractile structural unit of muscle, the sarcomere. Several myopathic conditions reported in humans are caused due to abnormal myofibrillogenesis owing to mutations in the genes coding for many of these structural proteins. These myopathies have highly variable clinical features and time of onset. Since their aetiology is poorly understood, it becomes imperative to have a model system to study the muscle defects. Present study proposes to employ the Indirect Flight Muscle (IFM) system in Drosophila melanogaster as a model to analyse the development/onset of some of these myopathies and resulting pathophysiology. We have carried out a systematic study on mutations in two major proteins of the sarcomere, actin and myosin, to understand the pathophysiology associated with the disease conditions and in turn gain insights into the process of myofibrillogenesis. To verify whether the human muscle phenotypes are observed in flies, we analysed the IFM for functional and structural defects categorised by the presence of aberrant sarcomeric structures. An important question that we have addressed is whether mutants of the Drosophila IFM recapitulate human conditions and whether it can serve as a good genetic model to study the developmental mechanisms of the human skeletal myopathies in vivo. Mutations of the human ACTA1 skeletal actin gene produce seven congenital myopathies – actin myopathy, nemaline rod myopathy, intranuclear rod myopathy, congenital fibre type disproportion, congenital myopathy with core-like areas, cap disease and zebra body myopathy. Four known mutations in Act88F—a Drosophila homologue of ACTA1—occur at the same actin residues mutated in ten ACTA1 nemaline mutations, A138D/P, R256H/L, G268C/D/R/S and R372C/S. These Act88F mutants were examined for muscle phenotypes with nemaline structures. Mutant homozygotes show phenotypes ranging from lack of myofibrils to almost normal sarcomeres at eclosion. Whereas, heterozygotes do allow myofibrillar assembly to certain extent; however, atypical structures are seen adjacent to normal sarcomeres. Aberrant Z disc-like structures and serial Z disc arrays, ‘zebra bodies’, are observed in homozygotes and heterozygotes of all the four Act88F mutants. The electron-dense structures observed in electron micrographs show homologies to human nemaline bodies/rods, but are much smaller than those typically found in the human myopathy. A possible mechanism for the ‘zebra bodies’ is proposed based on this study. Analysis of IFM at early developmental stages shows that in three of the mutants, there is an abnormal myofibril assembly leading to malformed sarcomeres mirrored in the adult stages. In one of the Act88F mutants, normal myofibrils are seen post-eclosion but the IFM show activity dependant progression of muscle degeneration. All the Act88F mutants produce dominant disruption of muscle structure and function which cannot be rescued even by three copies of the wild type Act88F gene implying that the mutants are strong antimorphs. Myosin myopathies are a group of human muscle diseases with heterogeneous clinical features and are caused by mutations in the skeletal muscle myosin heavy chain. We identified two chemical mutagen generated flightless mutants, Ifm(2)RU1 and ifm(2)RU2 that map closely to myosin heavy chain gene (Mhc) region. Since there are no structural proteins predicted in the mapped region, it was likely that these two are Mhc mutations. We show that Ifm(2)RU1 and ifm(2)RU2 are indeed Mhc mutations and the molecular aberrations affect amino acid residues present in the myosin rod region. Human muscle myosin heavy chain (MyHC) mutations that cause Laing early onset distal myopathy and myosin storage myopathy occur in this domain of the protein. Even though mutations lie in the same region of myosin rod, Ifm(2)RU1 is semidominant, whereas ifm(2)RU2 is recessive. Both the mutants show IFM defects and the presence of abnormal myofibrils. Mutant myofibrillar structures can be rescued with an additional wild type Mhc gene copy. However, the restored myofibrillar structure is incapable of rescuing the flight ability of mutants. The muscle phenotypes are due to defects in thick filament assembly which manifest from the early stages of sarcomere development. The MHC protein rod region is an α-helix that forms coiled-coils which further self assemble to form thick filaments or aggregates as observed in in vitro conditions. Biophysical and biochemical analyses reveal that the coiled-coil structure of mutant rods is not affected, however the thermodynamic stability is altered in ifm(2)RU2 mutation. Interestingly, rod aggregate size and stability are not affected in mutant rods. The Drosophila MHC mutant rods were studied along with four MHC mutant rods that harbour human rod mutations to compare the molecular consequences. The Drosophila mutations do not hamper the rod structure and assembly. Therefore, the defects may arise due to altered interactions with myosin rod binding proteins. Flightin is an extensively studied myosin rod binding protein. The amount and phosphorylation status of flightin are an extremely sensitive measure of thick filament assembly. Flightin phosphorylation is affected in the mutants suggesting a functional dependence on MHC and it also indicates MHC instability. In the light of the work done, we have assessed the mutations with respect to their structure-functional implications. The acto-myosin interactions responsible for the defects are also discussed. Formation of unusual myofibrillar structures are analysed with regards to the process of myofibrillogenesis. An understanding of this entire process with the information available from IFM is reviewed in detail. The work so far has helped in understanding the manifestation of myopathies at tissue/cellular levels with insights into the plausible mechanisms of origin of the disease phenotypes. Myopathic condition may arise due to developmental or functional defects. For therapeutic considerations, the fly provides a simple test to inspect the effects of adding extra copies of the wild type gene. We conclude that the Drosophila IFM provide a good model system for the study of human ACTA1 and MyHC myopathies.

A proteína miostatina, é um regulador negativo do crescimento muscular e a modulação de sua expressão pode consistir em tratamento para distrofias musculares. Nós estudamos expressão endógena da miostatina no músculos gastrocnêmio e diafragma de 4 modelos murinos de degeneração muscular: os camundongos Dmdmdx, SJL/J, Largemyd e Lama2dy-2J/J. Observamos que a miostatina é menos expressa no músculo gastrocnêmio do que diafragma normal, refletindo um músculo mais sujeito a lesão. Nas quatro linhagens distróficas a miostatina é menos expressa do que em camundongos normais, tanto no músculo gastrocnêmio como diafragma, sem diferença entre os dois. A analise comparativa da degeneração e regeneração muscular mostrou maior correlação da inibição da miostatina com o padrão de degeneração. Nossos resultados sugerem que o processo de degeneração, quando iniciado, e independentemente de seu grau, causa molecular primária, ou músculo afetado, parece atuar de forma similar na inibição da expressão da miostatina, possivelmente como estimulo a regeneração do dano. / Myostatin is a negative regulator of muscle growth, and its inhibition has been considered a therapeutic strategy for muscular dystrophies. We evaluated the endogenous expression of myostatin in the gastrocnemius and diaphragm muscles from 4 mouse dystrophic models including Dmdmdx, SJL/J>, Largemyd and Lama2dy2J/J. In normal mice, we observed that myostatin is less expressed in the gastrocnemius than in the diaphragm, reflecting a muscle most prone to lesions. In the 4 dystrophic models, myostatin expression was reduced, in both gastrocnemius and diaphragm muscles. The comparative analysis of the histopathology of the muscles with the expression of myostatin showed a stronger correlation with the pattern of degeneration then regeneration. Our results suggest that, when started, the process of degeneration of the muscle, independently of the primary molecular defect, or degree, seems to act in a similar pathway leading to the inhibition of the expression of myostatin in the affected muscles, possibly as a stimulus to regeneration of damage.