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1.
J Vis Exp ; (167)2021 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-33522516

RESUMO

Skeletal muscle has a remarkable ability to regenerate following injury, which is driven by obligate tissue resident muscle stem cells. Following injury, the muscle stem cell is activated and undergoes cell proliferation to generate a pool of myoblasts, which subsequently differentiate to form new muscle fibers. In many muscle wasting conditions, including muscular dystrophy and ageing, this process is impaired resulting in the inability of muscle to regenerate. The process of muscle regeneration in zebrafish is highly conserved with mammalian systems providing an excellent system to study muscle stem cell function and regeneration, in muscle wasting conditions such as muscular dystrophy. Here, we present a method to examine muscle regeneration in zebrafish models of muscle disease. The first step involves the use of a genotyping platform that allows the determination of the genotype of the larvae prior to eliciting an injury. Having determined the genotype, the muscle is injured using a needle stab, following which polarizing light microscopy is used to determine the extent of muscle regeneration. We therefore provide a high throughput pipeline which allows the examination of muscle regeneration in zebrafish models of muscle disease.


Assuntos
Músculo Esquelético/fisiopatologia , Doenças Musculares/fisiopatologia , Regeneração/fisiologia , Peixe-Zebra/fisiologia , Animais , Modelos Animais de Doenças , Embrião não Mamífero/fisiopatologia , Genótipo , Laminina/deficiência , Laminina/metabolismo , Larva/fisiologia , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Doenças Musculares/patologia , Peixe-Zebra/embriologia
2.
Molecules ; 26(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572728

RESUMO

Volumetric Muscle Loss (VML) is associated with muscle loss function and often untreated and considered part of the natural sequelae of trauma. Various types of biomaterials with different physical and properties have been developed to treat VML. However, much work remains yet to be done before the scaffolds can pass from the bench to the bedside. The present review aims to provide a comprehensive summary of the latest developments in the construction and application of natural polymers-based tissue scaffolding for volumetric muscle injury. Here, the tissue engineering approaches for treating volumetric muscle loss injury are highlighted and recent advances in cell-based therapies using various sources of stem cells are elaborated in detail. An overview of different strategies of tissue scaffolding and their efficacy on skeletal muscle cells regeneration and migration are presented. Furthermore, the present paper discusses a wide range of natural polymers with a special focus on proteins and polysaccharides that are major components of the extracellular matrices. The natural polymers are biologically active and excellently promote cell adhesion and growth. These bio-characteristics justify natural polymers as one of the most attractive options for developing scaffolds for muscle cell regeneration.


Assuntos
Músculo Esquelético/efeitos dos fármacos , Doenças Musculares/tratamento farmacológico , Regeneração/efeitos dos fármacos , Tecidos Suporte/química , Materiais Biocompatíveis/uso terapêutico , Matriz Extracelular/efeitos dos fármacos , Humanos , Músculo Esquelético/lesões , Músculo Esquelético/patologia , Doenças Musculares/patologia , Polímeros/uso terapêutico , Cicatrização/efeitos dos fármacos
3.
BMJ Case Rep ; 14(2)2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608334

RESUMO

Necrotising myopathy is an autoimmune disease that commonly affects muscles. Here we examine a case of a middle-aged women presenting with a chief report of shortness of breath, who subsequently developed muscle weakness. Her clinical course was complicated by respiratory failure and pulmonary hypertension likely due to the underlying pathology of signal recognition particle-positive necrotising myopathy. After further evaluation, her shortness of breath was thought to be secondary to muscle pathology rather than cardiopulmonary pathology. She was transferred to our institution for workup by rheumatology. At the time of admission, 6 months after initial presentation, her weakness progressed, so that she was unable to lift her arms and legs against gravity. Furthermore, neurological examination revealed mild facial and nuchal weakness, severe proximal weakness, more moderate distal weakness and global areflexia.


Assuntos
Doenças Autoimunes/sangue , Doenças Autoimunes/patologia , Doenças Musculares/sangue , Doenças Musculares/patologia , Partícula de Reconhecimento de Sinal/sangue , Doenças Autoimunes/tratamento farmacológico , Eletromiografia/métodos , Inibidores Enzimáticos/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Pessoa de Meia-Idade , Doenças Musculares/tratamento farmacológico , Ácido Micofenólico/uso terapêutico , Necrose , Prednisona/uso terapêutico
4.
Poult Sci ; 100(3): 100804, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33516474

RESUMO

Fibrosis has also been recorded as a prominent pathological feature within wooden breast (WB) myopathy of broiler chickens. This study was conducted to evaluate the accumulation of fibril collagen, deposition of the extracellular matrix (ECM) components, and the underlying mechanism mediating the pathogenic fibrotic process in the pectoralis major (PM) muscle of WB-affected birds. Broiler chickens were categorized into the control and WB groups based on the evaluation of myopathic lesions. Results indicated that the total content and area of collagen in cross-sections of the PM muscle, as well as the augmented expression of collagen-I and fibronectin in the ECM, were greatly increased in birds with WB. Wooden breast myopathy upregulated expressions of transforming growth factor-beta (TGF-ß) and the phosphorylation of Smad 2 and 3, thereby activating TGF-ß-mediated Smad signaling pathway, which further enhanced the transcription of profibrotic mediators. In addition, regulators involved in collagen biosynthesis and cross-linking including prolyl 4-hydroxylase, lysyl oxidase, lysyl hydroxylase, and decorin were increased in the WB muscle. Finally, the expressions of both matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) were increased in the WB muscle, which might be related with reduced ECM remodeling. Overall, WB myopathy induces severe fibrosis by enhancing ECM deposition and collagen cross-linking in the PM muscle of broiler chickens, possibly via the activation of TGF-ß signaling and the dysregulation of the MMP and TIMP system.


Assuntos
Doenças Musculares , Músculos Peitorais , Doenças das Aves Domésticas , Transdução de Sinais , Fator de Crescimento Transformador beta , Animais , Galinhas/genética , Fibrose/genética , Fibrose/fisiopatologia , Fibrose/veterinária , Doenças Musculares/genética , Doenças Musculares/patologia , Doenças Musculares/veterinária , Músculos Peitorais/fisiopatologia , Doenças das Aves Domésticas/genética , Doenças das Aves Domésticas/patologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
5.
Rinsho Shinkeigaku ; 61(1): 47-50, 2021 Jan 29.
Artigo em Japonês | MEDLINE | ID: mdl-33328421

RESUMO

A 69-year-old woman was admitted to our hospital because of limb weakness. She was diagnosed to have chronic renal failure due to diabetes mellitus and had suffered from pericardial effusion at 67 years of age. She started taking colchicine 18 months before admission and thereafter gradually developed muscle weakness in her limbs and had become bedridden at the time of admission. The withdrawal of colchicine improved her limb weakness, and therefore we diagnosed her to have colchicine myopathy. Her muscle strength did not completely recover even after six months from cessation of colchicine. It was suggested that renal failure and muscle disuse had prevented the full recovery of her muscles in addition to the long-term use of colchicine. Typical colchicine myopathy improves rapidly, but the long-term use of colchicine is considered to cause muscle weakness. Although the CK level was elevated, the elevated CK and myopathy had been overlooked because the CK baseline was low due to the patient's small amount of muscle mass. Moreover, the estimated GFR was recorded to be higher than her actual renal function due to her small amount of muscle mass, therefore the risk of colchicine myopathy in this case remained unrecognized.


Assuntos
Colchicina/efeitos adversos , Falência Renal Crônica/tratamento farmacológico , Doenças Musculares/induzido quimicamente , Idoso , Colchicina/administração & dosagem , Feminino , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/fisiopatologia , Debilidade Muscular/induzido quimicamente , Debilidade Muscular/diagnóstico , Debilidade Muscular/patologia , Músculo Esquelético/patologia , Doenças Musculares/diagnóstico , Doenças Musculares/patologia , Fatores de Tempo , Suspensão de Tratamento
7.
Sci Rep ; 10(1): 22146, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33335232

RESUMO

This study aims to evaluate the influence of myosteatosis on survival of patients after radical cystectomy (RC) for bladder cancer. We retrospectively identified 230 patients who underwent RC for bladder cancer at our three institutions between 2009 and 2018. Digitized free-hand outlines of the left and right psoas muscles were made on axial non-contrast computed tomography images at level L3. To assess myosteatosis, average total psoas density (ATPD) in Hounsfield Units (HU) was also calculated as an average of bilateral psoas muscle density. We compared cancer-specific survival (CSS) between high ATPD and low ATPD groups and performed cox regression hazard analyses to identify the predictors of CSS. Median ATPD was 44 HU (quartile: 39-47 Hounsfield Units). Two-year CSS rate in overall patients was 76.6%. Patients with low ATPD (< 44 HU) had significantly lower CSS rate (P = 0.01) than patients with high ATPD (≥ 44 HU). According to multivariate analysis, significant independent predictors of poor CSS were: Eastern Cooperative Oncology Group performance status ≥ 1 (P = 0.03), decreasing ATPD (P = 0.03), non-urothelial carcinoma (P = 0.01), pT ≥ 3 (P < 0.01), and pN positive (P < 0.01). In conclusion, myosteatosis (low ATPD) could be a novel predictor of prognosis after RC for bladder cancer.


Assuntos
Doenças Musculares/etiologia , Doenças Musculares/patologia , Neoplasias da Bexiga Urinária/complicações , Neoplasias da Bexiga Urinária/mortalidade , Idoso , Biomarcadores , Cistectomia , Ácidos Graxos/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Doenças Musculares/metabolismo , Gradação de Tumores , Estadiamento de Neoplasias , Período Pós-Operatório , Prognóstico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/cirurgia
8.
Nat Commun ; 11(1): 4479, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32900999

RESUMO

The giant protein titin is thought to be required for sarcomeric integrity in mature myocytes, but direct evidence for this hypothesis is limited. Here, we describe a mouse model in which Z-disc-anchored TTN is depleted in adult skeletal muscles. Inactivation of TTN causes sarcomere disassembly and Z-disc deformations, force impairment, myocyte de-stiffening, upregulation of TTN-binding mechanosensitive proteins and activation of protein quality-control pathways, concomitant with preferential loss of thick-filament proteins. Interestingly, expression of the myosin-bound Cronos-isoform of TTN, generated from an alternative promoter not affected by the targeting strategy, does not prevent deterioration of sarcomere formation and maintenance. Finally, we demonstrate that loss of Z-disc-anchored TTN recapitulates muscle remodeling in critical illness 'myosinopathy' patients, characterized by TTN-depletion and loss of thick filaments. We conclude that full-length TTN is required to integrate Z-disc and A-band proteins into the mature sarcomere, a function that is lost when TTN expression is pathologically lowered.


Assuntos
Fibras Musculares Esqueléticas/fisiologia , Proteínas Quinases/fisiologia , Sarcômeros/fisiologia , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Força Muscular/fisiologia , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Atrofia Muscular/fisiopatologia , Doenças Musculares/patologia , Doenças Musculares/fisiopatologia , Miosinas/metabolismo , Proteínas Quinases/deficiência , Proteínas Quinases/genética , Sarcômeros/patologia , Ubiquitinação
10.
Neurology ; 95(11): e1512-e1527, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32796131

RESUMO

OBJECTIVE: To clarify the prevalence, long-term natural history, and severity determinants of SEPN1-related myopathy (SEPN1-RM), we analyzed a large international case series. METHODS: Retrospective clinical, histologic, and genetic analysis of 132 pediatric and adult patients (2-58 years) followed up for several decades. RESULTS: The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years), with relatively preserved limb strength and previously unreported ophthalmoparesis in severe cases. All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant. Histopathologically, 79 muscle biopsies showed large variability, partly determined by site of biopsy and age. Multi-minicores were the most common lesion (59.5%), often associated with mild dystrophic features and occasionally with eosinophilic inclusions. Identification of 65 SEPN1 mutations, including 32 novel ones and the first pathogenic copy number variation, unveiled exon 1 as the main mutational hotspot and revealed the first genotype-phenotype correlations, bi-allelic null mutations being significantly associated with disease severity (p = 0.017). SEPN1-RM was more severe and progressive than previously thought, leading to loss of ambulation in 10% of cases, systematic functional decline from the end of the third decade, and reduced lifespan even in mild cases. The main prognosis determinants were scoliosis/respiratory management, SEPN1 mutations, and body mass abnormalities, which correlated with disease severity. We propose a set of severity criteria, provide quantitative data for outcome identification, and establish a need for age stratification. CONCLUSION: Our results inform clinical practice, improving diagnosis and management, and represent a major breakthrough for clinical trial readiness in this not so rare disease.


Assuntos
Genótipo , Proteínas Musculares/genética , Doenças Musculares/diagnóstico por imagem , Doenças Musculares/genética , Selenoproteínas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/patologia , Estudos Retrospectivos , Adulto Jovem
12.
Leg Med (Tokyo) ; 47: 101748, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32682296

RESUMO

The identification of muscle hemorrhage in a cadaver that is in an advanced stage of decomposition is an important but challenging task. Our study investigated whether Fourier transform infrared (FT-IR) microspectroscopy in conjunction with chemometrics could identify muscle hemorrhage using rat cadavers with advanced decomposition. In this study, an intramuscular blood injection method, instead of a mechanical injury method, was used to construct a muscle hemorrhage model, and the modeling idea of muscle hemorrhage identification was to discriminate and classify hemoglobin-leaking myofibrils from negative myofibrils. First, the optical images of hematoxylin/eosin (H&E) stained hemorrhagic muscle at different postmortem intervals (PMIs) were observed and showed that the morphological features of whole erythrocytes disappeared since the PMI of 4 d. Subsequently, principle component analysis (PCA) was performed and indicated that the biochemical differences in protein structures between fresh erythrocytes and myofibrils can be detected by the IR spectroscopic method. Ultimately, several classification models based on the partial least square discriminant analysis (PLS-DA) algorithm were successfully constructed for different PMIs and PMI ranges and achieved great prediction performances in external validations. This preliminary study demonstrates the feasibility of using FT-IR microspectroscopy combined with chemometrics as a potential approach for identifying muscle hemorrhage in cadavers with advanced decomposition for offering vital evidences in judicial process.


Assuntos
Autopsia/métodos , Patologia Legal/métodos , Hemorragia/patologia , Músculos/patologia , Doenças Musculares/patologia , Mudanças Depois da Morte , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Animais , Modelos Animais de Doenças , Eritrócitos/patologia , Masculino , Miofibrilas/patologia , Análise de Componente Principal , Ratos Sprague-Dawley
13.
Lancet Diabetes Endocrinol ; 8(7): 594-605, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32559475

RESUMO

BACKGROUND: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. FINDINGS: Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3-61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76-8·34; log-rank test p=0·0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26-17·58, p=0·021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients. INTERPRETATION: Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies. FUNDING: Netherlands Organisation for Health Research and Development, and the Sherman Foundation.


Assuntos
Biomarcadores/análise , Transtornos Mentais/patologia , Transportadores de Ácidos Monocarboxílicos/deficiência , Doenças Musculares/patologia , Transtornos do Neurodesenvolvimento/patologia , Simportadores/deficiência , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Agências Internacionais , Masculino , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Transportadores de Ácidos Monocarboxílicos/genética , Doenças Musculares/etiologia , Mutação , Transtornos do Neurodesenvolvimento/etiologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Simportadores/genética , Adulto Jovem
14.
Muscle Nerve ; 62(4): 445-454, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32478919

RESUMO

Muscle disorders are characterized by differential involvement of various muscle groups. Among these, weakness predominantly affecting finger flexors is an uncommon pattern, most frequently found in sporadic inclusion-body myositis. This finding is particularly significant when the full range of histopathological findings of inclusion-body myositis is not found on muscle biopsy. Prominent finger flexor weakness, however, is also observed in other myopathies. It occurs commonly in myotonic dystrophy types 1 and 2. In addition, individual reports and small case series have documented finger flexor weakness in sarcoid and amyloid myopathy, and in inherited myopathies caused by ACTA1, CRYAB, DMD, DYSF, FLNC, GAA, GNE, HNRNPDL, LAMA2, MYH7, and VCP mutations. Therefore, the finding of finger flexor weakness requires consideration of clinical, myopathological, genetic, electrodiagnostic, and sometimes muscle imaging findings to establish a diagnosis.


Assuntos
Dedos/fisiopatologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/fisiopatologia , Doenças Musculares/fisiopatologia , Amiloidose/patologia , Amiloidose/fisiopatologia , Miopatias Distais/patologia , Miopatias Distais/fisiopatologia , Doença de Depósito de Glicogênio Tipo II/patologia , Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Humanos , Músculo Esquelético/patologia , Doenças Musculares/patologia , Distrofias Musculares/patologia , Distrofias Musculares/fisiopatologia , Distrofia Muscular do Cíngulo dos Membros/patologia , Distrofia Muscular do Cíngulo dos Membros/fisiopatologia , Distrofia Muscular de Duchenne/patologia , Distrofia Muscular de Duchenne/fisiopatologia , Miosite de Corpos de Inclusão/patologia , Miosite de Corpos de Inclusão/fisiopatologia , Distrofia Miotônica/patologia , Distrofia Miotônica/fisiopatologia , Sarcoidose/patologia , Sarcoidose/fisiopatologia
15.
Muscle Nerve ; 62(2): 266-271, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32363625

RESUMO

BACKGROUND: Biallelic mutations in TBC1-domain containing kinase (TBCK) lead to hypotonia, global developmental delay with severe cognitive and motor deficits, and variable presentation of dysmorphic facial features and brain malformations. It remains unclear whether hypotonia in these individuals is purely neurogenic, or also caused by progressive muscle disease. METHODS: Whole exome sequencing was performed on a family diagnosed with nonspecific myopathic changes by means of histological analysis and immunohistochemistry of muscle biopsy samples. RESULTS: A novel homozygous truncation in TBCK was found in two sisters diagnosed with muscle disease and severe psychomotor delay. TBCK was completely absent in these patients. CONCLUSIONS: Our findings identify a novel early truncating variant in TBCK associated with a severe presentation and add muscle disease to the variability of phenotypes associated with TBCK mutations. Inconsistent genotype/phenotype correlation could be ascribed to the multiple roles of TBCK in intracellular signaling and endolysosomal function in different tissues.


Assuntos
Encefalopatias/genética , Mutação com Perda de Função , Hipotonia Muscular/genética , Músculo Esquelético/patologia , Doenças Musculares/genética , Proteínas Serina-Treonina Quinases/genética , Transtornos Psicomotores/genética , Convulsões/genética , Adolescente , Encéfalo/diagnóstico por imagem , Encefalopatias/diagnóstico por imagem , Criança , Deficiências do Desenvolvimento/genética , Feminino , Homozigoto , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imagem por Ressonância Magnética , Debilidade Muscular/genética , Debilidade Muscular/patologia , Doenças Musculares/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Reflexo Anormal/genética , Índice de Gravidade de Doença , Irmãos , Síndrome , Sequenciamento Completo do Exoma
16.
Nat Commun ; 11(1): 2417, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415060

RESUMO

Striated muscle contraction is regulated by the translocation of troponin-tropomyosin strands over the thin filament surface. Relaxation relies partly on highly-favorable, conformation-dependent electrostatic contacts between actin and tropomyosin, which position tropomyosin such that it impedes actomyosin associations. Impaired relaxation and hypercontractile properties are hallmarks of various muscle disorders. The α-cardiac actin M305L hypertrophic cardiomyopathy-causing mutation lies near residues that help confine tropomyosin to an inhibitory position along thin filaments. Here, we investigate M305L actin in vivo, in vitro, and in silico to resolve emergent pathological properties and disease mechanisms. Our data suggest the mutation reduces actin flexibility and distorts the actin-tropomyosin electrostatic energy landscape that, in muscle, result in aberrant contractile inhibition and excessive force. Thus, actin flexibility may be required to establish and maintain interfacial contacts with tropomyosin as well as facilitate its movement over distinct actin surface features and is, therefore, likely necessary for proper regulation of contraction.


Assuntos
Citoesqueleto de Actina/metabolismo , Actinas/química , Doenças Musculares/patologia , Animais , Animais Geneticamente Modificados , Cardiomiopatia Hipertrófica , Biologia Computacional , Drosophila melanogaster/metabolismo , Feminino , Voo Animal , Humanos , Ligação de Hidrogênio , Masculino , Microscopia de Fluorescência , Simulação de Dinâmica Molecular , Contração Muscular , Mutação , Análise de Componente Principal , Multimerização Proteica , Eletricidade Estática , Transgenes , Tropomiosina/química
17.
Rinsho Shinkeigaku ; 60(5): 334-339, 2020 May 26.
Artigo em Japonês | MEDLINE | ID: mdl-32307395

RESUMO

Hereditary myopathy with early respiratory failure (HMERF) with heterozygous mutations in the titin gene (TTN) is characterized by respiratory failure developing from the early phase of limb weakness or gait disturbance. Here, we describe a characteristic distribution of muscle involvement in three members of a HMERF family with a TTN mutation. Despite the differences in severity exhibited among the father, daughter and son, the systemic imaging studies showed a similar pattern among these individuals. The semitendinosus and fibularis longus muscles were selectively affected, as described previously. In addition, we found marked atrophy in the sternocleidomastoid and psoas major muscles, regardless of the disease severity. The atrophy in selective trunk muscles observed in routine CT scans can be useful for the differential diagnosis of hereditary myopathies with heart and respiratory failure.


Assuntos
Conectina/genética , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Músculo Esquelético/patologia , Doenças Musculares/genética , Doenças Musculares/patologia , Mutação , Insuficiência Respiratória/genética , Insuficiência Respiratória/patologia , Adulto , Idoso , Atrofia , Diagnóstico Diferencial , Feminino , Doenças Genéticas Inatas/diagnóstico por imagem , Humanos , Masculino , Músculo Esquelético/diagnóstico por imagem , Doenças Musculares/diagnóstico por imagem , Insuficiência Respiratória/diagnóstico por imagem , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
18.
Rev Med Interne ; 41(5): 335-338, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32334861

RESUMO

INTRODUCTION: This case report signifies the need to systemically assess antimalarial toxicity in those undergoing long-term treatment. CASE REPORT: A 59-year-old man with a history of ischemic-labeled heart disease revealed by conduction disorders and cutaneous lupus treated initially with hydroxychloroquine followed by chloroquine consulted for asthenia and weight loss. Clinically, he had a muscular atrophy, a motor deficit, and an abolition of the osteo-tendinous reflexes in the lower limbs. Adverse drug effects of the antimalarial therapy were suspected-specifically, muscular and cardiac toxicity. The diagnosis was confirmed with a muscle biopsy, which showed typical and florid vacuolar myopathy. Cessation of the drug resulted in a slow regression of symptoms. CONCLUSION: Cardiac and muscular toxicity related to antimalarials are rare and sometimes fatal; thus, they must be systematically assessed in a patient with several years of exposure. A muscle biopsy could be sufficient to allow for the diagnosis.


Assuntos
Antimaláricos/efeitos adversos , Astenia , Cardiotoxicidade/diagnóstico , Doenças Musculares/induzido quimicamente , Doenças Musculares/diagnóstico , Perda de Peso , Astenia/induzido quimicamente , Astenia/diagnóstico , Biópsia , Cardiotoxicidade/etiologia , Cardiotoxicidade/patologia , Diagnóstico Diferencial , Humanos , Hidroxicloroquina/efeitos adversos , Assistência de Longa Duração , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/diagnóstico , Doenças por Armazenamento dos Lisossomos/induzido quimicamente , Doenças por Armazenamento dos Lisossomos/diagnóstico , Masculino , Pessoa de Meia-Idade , Músculos/patologia , Doenças Musculares/patologia , Perda de Peso/efeitos dos fármacos
19.
ScientificWorldJournal ; 2020: 4704825, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32292293

RESUMO

Objectives: Statin-induced myopathy is one of the major causes of poor adherence and discontinuation of this medication. There are contrary results regarding association of vitamin D insufficiency with statin-induced myopathy. This study was done to determine the effect of the vitamin D3 analogue alfacalcidol on Rosuvastatin-induced myopathy in rats. Methodology. Animals were divided into six groups with 6 rats in each group. Groups I and II acted as controls, Group III and Group IV were administered Rosuvastatin 120 mg/kg/day and 160 mg/kg/day, Groups V and VI were administered alfacalcidol 0.1 µg/kg/day in addition to Rosuvastatin 120 mg/kg/day and 160 mg/kg/day, respectively. All drugs were administered orally for 15 days. Plasma creatine kinase (CK) levels were estimated on day 10 and day 15. Animals were sacrificed and muscles were sent for histopathological examination. Results: On day 10, Groups V and VI showed a statistically significant increase in plasma CK levels as compared to the control (p < 0.001) and were significantly lower (p < 0.001) as compared to Groups III and IV, respectively. However, on day 15, plasma CK levels in Groups V and VI were comparable to those of control groups with a nonsignificant difference (p > 0.05). On comparing the histology, Groups V and VI showed a significant difference as compared to statin-only groups (Groups III and IV) as there were signs of regeneration, less splitting, and fragmentation of muscle fibres. Conclusion: The present study shows that the vitamin D analogue alfacalcidol prevents statin-induced myopathy. The serum CK levels are comparable to the control group on day 15 of vitamin D administration.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/etiologia , Doenças Musculares/metabolismo , Rosuvastatina Cálcica/efeitos adversos , Vitamina D/metabolismo , Animais , Biomarcadores , Biópsia , Creatina Quinase/sangue , Modelos Animais de Doenças , Doenças Musculares/sangue , Doenças Musculares/patologia , Ratos , Ratos Wistar , Vitamina D/análogos & derivados , Deficiência de Vitamina D/complicações
20.
BMC Med Genet ; 21(1): 77, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32293312

RESUMO

BACKGROUND: Myopathy with extrapyramidal signs (MPXPS) is an autosomal recessive mitochondrial disorder which is caused by mutation in mitochondrial calcium uptake 1 (MICU1) gene located on chromosome 10q22.1. Next Generation Sequencing (NGS) technology is the most effective method for identification of pathogenic variants with the ability to overcome some limitations which Sanger sequencing may encountered. There are few reports on this rare disease around the world and here in this study we first revealed genetic identification of two affected individuals in an Iranian family with a novel mutation. CASE PRESENTATION: The proband was a 5-year-old girl from consanguenous parents. She was first clinically suspicious of affected with limb-girdle muscular dystrophy (LGMD). Muscle biopsy studies and autozygosity mapping, using four short tandem repeat (STR) markers linked to 6 genes of the most prevalent forms of LGMD, ruled out calpainopathy, dysferlinopathy, and sarcoglycanopathis. DNA sample of the proband was sent for NGS. Whole exome sequencing (WES) revealed a novel mutation c.1295delA in exon 13 of MICU1 gene. This homozygous deletion creates a frameshift and a premature stop codon downstream of canonical EF4 calcium binding motif of MICU1. According to the American College of Medical Genetics and Genomics (ACMG) guidline for sequence interpretation, this variant was a pathogenic one. Sanger sequencing in all family members confirmed the results of the WES. CONCLUSIONS: This study was the first report of MPXPS in Iranian population which also revealed a novel mutation in the MICU1 gene.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Proteínas de Transporte de Cátions/genética , Repetições de Microssatélites/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Doenças Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Pré-Escolar , Exoma/genética , Éxons/genética , Tratos Extrapiramidais/metabolismo , Tratos Extrapiramidais/patologia , Feminino , Mutação da Fase de Leitura/genética , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Irã (Geográfico)/epidemiologia , Doenças Musculares/patologia , Distrofia Muscular do Cíngulo dos Membros/patologia , Linhagem , Deleção de Sequência/genética , Sequenciamento Completo do Exoma
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