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2.
Nat Commun ; 11(1): 4653, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938923

RESUMO

Cancer cells demand excess nutrients to support their proliferation, but how tumours exploit extracellular amino acids during systemic metabolic perturbations remain incompletely understood. Here, we use a Drosophila model of high-sugar diet (HSD)-enhanced tumourigenesis to uncover a systemic host-tumour metabolic circuit that supports tumour growth. We demonstrate coordinate induction of systemic muscle wasting with tumour-autonomous Yorkie-mediated SLC36-family amino acid transporter expression as a proline-scavenging programme to drive tumourigenesis. We identify Indole-3-propionic acid as an optimal amino acid derivative to rationally target the proline-dependency of tumour growth. Insights from this whole-animal Drosophila model provide a powerful approach towards the identification and therapeutic exploitation of the amino acid vulnerabilities of tumourigenesis in the context of a perturbed systemic metabolic network.


Assuntos
Açúcares da Dieta/efeitos adversos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Neoplasias Experimentais/fisiopatologia , Prolina/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos/metabolismo , Animais , Animais Geneticamente Modificados , Carcinogênese , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Hemolinfa/efeitos dos fármacos , Hemolinfa/metabolismo , Larva , Debilidade Muscular/induzido quimicamente , Debilidade Muscular/patologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/patologia , Neoplasias Experimentais/etiologia , Proteínas Nucleares/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transativadores/genética , Proteínas ras/genética
3.
Medicine (Baltimore) ; 99(34): e21830, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846828

RESUMO

Brachial plexus birth palsy (BPBP) is a neurologic injury that can result in mild to full paralysis of the affected upper extremity. In severe cases, nerve surgery is often performed before age 1 year. Several studies report gains in elbow flexion with onabotulinum toxin type A (OBTT-A) injections to the triceps; however, its use in infants is not widely reported. The purpose of this study is to present our experience using these injections before 6 months of age to therapeutically unmask elbow flexion and diagnostically guide surgical decision making.This is a retrospective observational cohort study. The cohort included infants with BPBP who received OBTT-A injection to the triceps before age 6 months. Indications for the injections include trace elbow flexion and palpable co-contraction of the biceps and triceps. Elbow flexion was evaluated using the Toronto Test score. Therapeutic success was defined as an increase in post-injection scores. These scores were then used diagnostically as an indication for surgery if the infant did not achieve full elbow flexion by 8 months. A treatment algorithm for OBTT-A triceps injection was developed based on all treatment options offered to infants with elbow flexion deficits seen in the clinic.Of the 12 infants that received OBTT-A triceps injections, 10 (83%) had improved Toronto test elbow flexion scores post-injection. Gains in elbow flexion once attained were maintained. Of the 9 OBTT-A infants with at least 2 years follow-up, 4 achieved full elbow flexion without surgery; the remainder after surgery. No complications with OBTT-A injections were noted and patients were followed on average 6 years. The average age at time of injection was 4 months (range: 2-5 months). Compared to other treatments given, OBTT-A infants tended to present with more elbow flexion than the 4 infants requiring immediate surgical intervention and less elbow flexion than the 16 infants treated conservatively.OBTT-A injection to the triceps in infants with BPBP before 6 months of age therapeutically improved elbow flexion and diagnostically guided surgical decisions when full elbow flexion was not achieved by 8 months of age with no known complications.


Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Articulação do Cotovelo/fisiopatologia , Músculo Esquelético/fisiopatologia , Paralisia do Plexo Braquial Neonatal/tratamento farmacológico , Fármacos Neuromusculares/uso terapêutico , Amplitude de Movimento Articular/efeitos dos fármacos , Braço , Toxinas Botulínicas Tipo A/administração & dosagem , Criança , Pré-Escolar , Tomada de Decisão Clínica , Seguimentos , Humanos , Lactente , Injeções Intramusculares , Paralisia do Plexo Braquial Neonatal/fisiopatologia , Paralisia do Plexo Braquial Neonatal/cirurgia , Fármacos Neuromusculares/administração & dosagem , Estudos Retrospectivos
4.
PLoS One ; 15(8): e0237097, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810864

RESUMO

Neurofibromatosis type 1 (NF1) is a genetic disorder that affects a range of tissue systems, however the associated muscle weakness and fatigability can have a profound impact on quality of life. Prior studies using the limb-specific Nf1 knockout mouse (Nf1Prx1-/-) revealed an accumulation of intramyocellular lipid (IMCL) that could be rescued by a diet supplemented with L-carnitine and enriched for medium-chain fatty acids (MCFAs). In this study we used the Nf1Prx1-/- mouse to model a range of dietary interventions designed to reduce IMCL accumulation, and analyze using other modalities including in situ muscle physiology and lipid mass spectrometry. Histological IMCL accumulation was significantly reduced by a range of treatments including L-carnitine and high MCFAs alone. A low-fat diet did not affect IMCL, but did provide improvements to muscle strength. Supplementation yielded rapid improvements in IMCL within 4 weeks, but were lost once treatment was discontinued. In situ muscle measurements were highly variable in Nf1Prx1-/- mice, attributable to the severe phenotype present in this model, with fusion of the hips and an overall small hind limb muscle size. Lipidome analysis enabled segregation of the normal and modified chow diets, and fatty acid data suggested increased muscle lipolysis with the intervention. Acylcarnitines were also affected, suggestive of a mitochondrial fatty acid oxidation disorder. These data support the theory that NF1 is a lipid storage disease that can be treated by dietary intervention, and encourages future human trials.


Assuntos
Metabolismo dos Lipídeos , Força Muscular , Músculo Esquelético/metabolismo , Neurofibromatose 1/dietoterapia , Animais , Carnitina/administração & dosagem , Carnitina/uso terapêutico , Suplementos Nutricionais , Ácidos Graxos/administração & dosagem , Ácidos Graxos/uso terapêutico , Feminino , Camundongos , Músculo Esquelético/fisiopatologia , Neurofibromatose 1/genética , Neurofibromina 1/genética
6.
PLoS One ; 15(8): e0237651, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817684

RESUMO

Body dysmorphic disorder (BDD) is associated with severe comorbidity and impairment. Muscle dysmorphia (MD) is a subtype of BDD which has rarely been assessed outside of undergraduate student samples. Further, there are limited data comparing MD to other psychiatric disorders, including BDD. Thus, the aim of the current study is to explore differences in symptom severity and conformity to masculine norms in men diagnosed with BDD or MD. Men from the greater Boston, Massachusetts area completed a one-time assessment, which included clinician-based structured interviews and self-report questionnaires assessing MD symptom severity, BDD symptom severity, and conformity to traditional masculine norms. The sample was N = 30 men (MD: n = 15; BDD: n = 15). Statistically significant medium to large effects emerged with the MD group experiencing greater MD and BDD symptom severity, and positive attitudes towards the use of violence to solve problems. Although not reaching statistical significance, additional medium-to-large effects also emerged with the MD group reporting greater emotional restriction/suppression, heterosexual self-presentation, and desired sexual promiscuity compared to the BDD group. Findings suggest that men diagnosed with MD may experience greater MD/BDD symptom severity and endorsement of some components of 'traditional' masculine norms, compared to men diagnosed with BDD. Results may suggest that addressing some forms of rigid masculine norms (e.g., use of violence) in therapy could be useful in treating MD; however, additional research comparing clinical samples of men with MD and BDD are needed to guide the nosology, assessment, and treatment of MD.


Assuntos
Transtornos Dismórficos Corporais/psicologia , Transtornos da Alimentação e da Ingestão de Alimentos/psicologia , Músculo Esquelético/fisiopatologia , Adulto , Transtornos Dismórficos Corporais/epidemiologia , Transtornos Dismórficos Corporais/fisiopatologia , Boston , Comorbidade , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Transtornos da Alimentação e da Ingestão de Alimentos/fisiopatologia , Humanos , Masculino , Massachusetts , Autorrelato , Índice de Gravidade de Doença , Inquéritos e Questionários , Adulto Jovem
7.
Nat Commun ; 11(1): 4167, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820177

RESUMO

Muscle regeneration depends on a robust albeit transient inflammatory response. Persistent inflammation is a feature of age-related regenerative deficits, yet the underlying mechanisms are poorly understood. Here, we find inflammatory-related CC-chemokine-receptor 2 (Ccr2) expression in non-hematopoietic myogenic progenitors (MPs) during regeneration. After injury, the expression of Ccr2 in MPs corresponds to the levels of its ligands, the chemokines Ccl2, 7, and 8. We find stimulation of Ccr2-activity inhibits MP fusion and contribution to myofibers. This occurs in association with increases in MAPKp38δ/γ signaling, MyoD phosphorylation, and repression of the terminal myogenic commitment factor Myogenin. High levels of Ccr2-chemokines are a feature of regenerating aged muscle. Correspondingly, deletion of Ccr2 in MPs is necessary for proper fusion into regenerating aged muscle. Finally, opportune Ccr2 inhibition after injury enhances aged regeneration and functional recovery. These results demonstrate that inflammatory-induced activation of Ccr2 signaling in myogenic cells contributes to aged muscle regenerative decline.


Assuntos
Mediadores da Inflamação/metabolismo , Músculo Esquelético/fisiopatologia , Receptores CCR2/metabolismo , Regeneração/fisiologia , Transdução de Sinais/fisiologia , Fatores Etários , Animais , Transplante de Células/métodos , Quimiocina CCL2/metabolismo , Quimiocina CCL7/metabolismo , Quimiocina CCL8/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Desenvolvimento Muscular/genética , Músculo Esquelético/lesões , Músculo Esquelético/metabolismo , Miogenina/genética , Miogenina/metabolismo , Receptores CCR2/genética , Regeneração/genética , Células Satélites de Músculo Esquelético/citologia , Células Satélites de Músculo Esquelético/metabolismo , Células Satélites de Músculo Esquelético/transplante , Transdução de Sinais/genética , Ferimentos e Lesões/genética , Ferimentos e Lesões/fisiopatologia , Ferimentos e Lesões/terapia
8.
PLoS One ; 15(7): e0236140, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32667936

RESUMO

BACKGROUND: Urinary Incontinence (UI) is when a person is unable to hold his/her urine effectively. This is a common problem which can develop and worsen during pregnancy. An effective way to manage UI is to educate patients on the Pelvic Floor Muscle Exercise (PFME) regularly. The present study aimed to ascertain the pregnant women's knowledge, attitudes, and practices (KAP) related to PFME. METHODS: This was a cross-sectional study done in a one primary care clinic located in a semi-urban area in Selangor, Malaysia. Simple random sampling was conducted among pregnant women aged 18 years old and above at any gestation. The validated study instruments used consisted of questions on socio-demography, KAP on UI, and also the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form to determine UI among the respondents. RESULTS: The response rate for this study was 72.1%, where 440 pregnant women consented to take part in the study. The median age of study respondents was 30 years old and majority of the study respondents was from the Malay ethnicity (80.9%). The prevalence of UI was 40.9%. The proportion of pregnant women with good knowledge, attitude and practice scores were 58.0%, 46.6% and 45.2% respectively. There was a significant association between UI and age (p = .03), body mass index (p = .03), ethnicity (p = .04), gravida. (p = .001), knowledge on PFME (p = .007) and attitude towards PFME (p = .006). CONCLUSIONS: Findings from this study fill a gap in the prevalence and KAP concerning PFME at the primary care level. The foundation areas for future education and health promotion on UI should address the importance of correct PFME. This education can be delivered through a pragmatic way to ensure its effectiveness and sustainability of the health promotion program.


Assuntos
Terapia por Exercício/métodos , Força Muscular , Músculo Esquelético/fisiopatologia , Diafragma da Pelve/fisiopatologia , Complicações na Gravidez/prevenção & controle , Atenção Primária à Saúde/estatística & dados numéricos , Incontinência Urinária/terapia , Adulto , Estudos Transversais , Feminino , Número de Gestações , Humanos , Malásia/epidemiologia , Gravidez
10.
Proc Natl Acad Sci U S A ; 117(32): 19254-19265, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719146

RESUMO

The appropriate arrangement of myonuclei within skeletal muscle myofibers is of critical importance for normal muscle function, and improper myonuclear localization has been linked to a variety of skeletal muscle diseases, such as centronuclear myopathy and muscular dystrophies. However, the molecules that govern myonuclear positioning remain elusive. Here, we report that skeletal muscle-specific CIP (sk-CIP) is a regulator of nuclear positioning. Genetic deletion of sk-CIP in mice results in misalignment of myonuclei along the myofibers and at specialized structures such as neuromuscular junctions (NMJs) and myotendinous junctions (MTJs) in vivo, impairing myonuclear positioning after muscle regeneration, leading to severe muscle dystrophy in mdx mice, a mouse model of Duchenne muscular dystrophy. sk-CIP is localized to the centrosome in myoblasts and relocates to the outer nuclear envelope in myotubes upon differentiation. Mechanistically, we found that sk-CIP interacts with the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex and the centriole Microtubule Organizing Center (MTOC) proteins to coordinately modulate myonuclear positioning and alignment. These findings indicate that sk-CIP may function as a muscle-specific anchoring protein to regulate nuclear position in multinucleated muscle cells.


Assuntos
Proteínas de Transporte/metabolismo , Núcleo Celular/metabolismo , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Miopatias Congênitas Estruturais/fisiopatologia , Proteínas Nucleares/metabolismo , Animais , Proteínas de Transporte/genética , Núcleo Celular/genética , Humanos , Camundongos , Camundongos Endogâmicos mdx , Camundongos Knockout , Músculo Esquelético/fisiopatologia , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/metabolismo , Proteínas Nucleares/genética , Especificidade de Órgãos
11.
J Bone Joint Surg Am ; 102(14): 1197-1204, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32675661

RESUMO

Coronavirus disease 2019 (COVID-19) is an emerging pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the majority of patients who become infected with SARS-CoV-2 are asymptomatic or have mild symptoms, some patients develop severe symptoms that can permanently detract from their quality of life. SARS-CoV-2 is closely related to SARS-CoV-1, which causes severe acute respiratory syndrome (SARS). Both viruses infect the respiratory system, and there are direct and indirect effects of this infection on multiple organ systems, including the musculoskeletal system. Epidemiological data from the SARS pandemic of 2002 to 2004 identified myalgias, muscle dysfunction, osteoporosis, and osteonecrosis as common sequelae in patients with moderate and severe forms of this disease. Early studies have indicated that there is also considerable musculoskeletal dysfunction in some patients with COVID-19, although long-term follow-up studies have not yet been conducted. The purpose of this article was to summarize the known musculoskeletal pathologies in patients with SARS or COVID-19 and to combine this with computational modeling and biochemical signaling studies to predict musculoskeletal cellular targets and long-term consequences of the SARS-CoV-2 infection.


Assuntos
Infecções por Coronavirus/complicações , Sistema Musculoesquelético/fisiopatologia , Pneumonia Viral/complicações , Betacoronavirus , Osso e Ossos/fisiopatologia , Simulação por Computador , Humanos , Articulações/fisiopatologia , Debilidade Muscular/virologia , Músculo Esquelético/fisiopatologia , Mialgia/virologia , Pandemias , Peptidil Dipeptidase A/genética , Serina Endopeptidases/genética
12.
PLoS One ; 15(7): e0236266, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726351

RESUMO

The aim of this study was an evaluation of the musculoskeletal system in women and men with Generalized Joint Hypermobility (GJH). The study included 87 participants- 40 with Generalized Joint Hypermobility (aged 21.2 ±1.8 years) and 47 (aged 21.0 ±1.3 years) in the control group (CG). The study included the Beighton score, the measurements of body composition, muscle flexibility (Straight Leg Raise test, Popliteal Angle test, Modified Thomas Test), and the measurements of muscle strength and muscle power. T-test and Mann-Whitney U Test were applied to assess the differences between independent groups. The study showed that there were no significant differences (p>.05) in the assessed body composition and the muscle flexibility between both women and men with GJH and the participants in the CG. Under isokinetic conditions for the non-dominant lower extremity, men from the CG received significantly higher (p = .02) flexion peak torque at 180°/s angular velocity. Women from the CG received a statistically significantly lower (p = .04) F/E ratio at 180°/s velocity. Under isometric conditions for both women and men with GJH, there were no statistically significant differences (p>.05) in the maximum torques in knee extension and flexion compared to the CG. For women and men with GJH, the maximum power in the lower extremities and jumping ability were not significantly different (p>.05) compared to the CG participants. The body composition, muscle flexibility, muscle strength, and muscle power of adults with Generalized Joint Hypermobility did not differ compared to healthy participants. The fact that there are no differences does not exclude the efficacy of strength training in increasing levels of muscle strength and its impact on body posture and proprioception or coordination.


Assuntos
Instabilidade Articular/fisiopatologia , Articulação do Joelho/fisiopatologia , Força Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Adulto , Composição Corporal/fisiologia , Feminino , Humanos , Instabilidade Articular/epidemiologia , Extremidade Inferior/fisiopatologia , Masculino , Amplitude de Movimento Articular/fisiologia , Adulto Jovem
14.
PLoS One ; 15(6): e0234606, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32569331

RESUMO

Skeletal muscle dysfunction is a common complication and an important prognostic factor in patients with chronic obstructive pulmonary disease (COPD). It is associated with intrinsic muscular abnormalities of the lower extremities, but it is not known whether there is an easy way to predict its presence. Using a mouse model of chronic cigarette smoke exposure, we tested the hypothesis that magnetic resonance spectroscopy allows us to detect muscle bioenergetic deficit in early stages of lung disease. We employed this technique to evaluate the synthesis rate of adenosine triphosphate (ATP) and characterize concomitant mitochondrial dynamics patterns in the gastrocnemius muscle of emphysematous mice. The fibers type composition and citrate synthase (CtS) and cytochrome c oxidase subunit IV (COX4) enzymatic activities were evaluated. We found that the rate of ATP synthesis was reduced in the distal skeletal muscle of mice exposed to cigarette smoke. Emphysematous mice showed a significant reduction in body weight gain, in the cross-sectional area of the total fiber and in the COX4 to CtS activity ratio, due to a significant increase in CtS activity of the gastrocnemius muscle. Taken together, these data support the hypothesis that in the early stage of lung disease, we can detect a decrease in ATP synthesis in skeletal muscle, partly caused by high oxidative mitochondrial enzyme activity. These findings may be relevant to predict the presence of skeletal bioenergetic deficit in the early stage of lung disease besides placing the mitochondria as a potential therapeutic target for the treatment of COPD comorbidities.


Assuntos
Metabolismo Energético , Músculo Esquelético/fisiopatologia , Fumaça/efeitos adversos , Trifosfato de Adenosina/biossíntese , Trifosfato de Adenosina/deficiência , Animais , Pneumopatias/diagnóstico , Espectroscopia de Ressonância Magnética/métodos , Camundongos , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Tabaco/efeitos adversos
15.
Am J Physiol Heart Circ Physiol ; 319(1): H171-H182, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32502377

RESUMO

The role of the ASIC1a in evoking the exercise pressor reflex in rats with simulated peripheral artery disease is unknown. This prompted us to determine whether ASIC1a plays a role in evoking the exaggerated exercise pressor reflex in decerebrated rats with simulated peripheral artery disease. To simulate peripheral artery disease, we ligated the left femoral artery 72 h before the experiment. The right femoral artery was freely perfused and used as a control. To test our hypothesis, we measured the effect of injecting two ASIC1a blockers into the arterial supply of the triceps surae muscles with and without the femoral artery ligated on the reflex pressor responses to 1) static contraction of the triceps surae muscles, 2) calcaneal tendon stretch, and 3) intra-arterial injection of diprotonated phosphate (pH 6.0). We found that the ASIC1a blockers psalmotoxin-1 (200 ng/kg) and mambalgin-1 (6.5 µg/kg) decreased the pressor responses to static contraction as well as the peak pressor responses to injection of diprotonated phosphate when these responses were evoked from the freely perfused hindlimb. In contrast, ASIC1a blockers only decreased the peak pressor responses evoked by injection of diprotonated phosphate in the hindlimb circulation with simulated peripheral artery disease. This inhibitory effect was less than the one measured from the healthy hindlimb. Independently of the hindlimb of interest, ASIC1a blockers had no effect on the pressor responses to tendon stretch. Our results do not support the hypothesis that ASIC1a play a role in evoking the exercise pressor reflex arising from a hindlimb with simulated peripheral artery disease.NEW & NOTEWORTHY The role of ASIC1a in evoking the metabolic component of the exercise pressor reflex in peripheral artery disease is unknown. Using a within-rat experimental design, we found that the contribution of ASIC1a decreased in a rat model of peripheral artery disease. These results have key implications to help finding better treatments and improve morbidity, quality of life, and mortality in patients with peripheral artery disease.


Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Contração Muscular , Doença Arterial Periférica/metabolismo , Esforço Físico , Reflexo , Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia , Animais , Venenos Elapídicos/farmacologia , Artéria Femoral/fisiopatologia , Masculino , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Peptídeos/farmacologia , Doença Arterial Periférica/fisiopatologia , Ratos , Ratos Sprague-Dawley , Venenos de Aranha/farmacologia , Tendões/fisiopatologia
16.
Hum Genet ; 139(11): 1443-1454, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32514796

RESUMO

Dilated cardiomyopathy (DCM) belongs to the most frequent forms of cardiomyopathy mainly characterized by cardiac dilatation and reduced systolic function. Although most cases of DCM are classified as sporadic, 20-30% of cases show a heritable pattern. Familial forms of DCM are genetically heterogeneous, and mutations in several genes have been identified that most commonly play a role in cytoskeleton and sarcomere-associated processes. Still, a large number of familial cases remain unsolved. Here, we report five individuals from three independent families who presented with severe dilated cardiomyopathy during the neonatal period. Using whole-exome sequencing (WES), we identified causative, compound heterozygous missense variants in RPL3L (ribosomal protein L3-like) in all the affected individuals. The identified variants co-segregated with the disease in each of the three families and were absent or very rare in the human population, in line with an autosomal recessive inheritance pattern. They are located within the conserved RPL3 domain of the protein and were classified as deleterious by several in silico prediction software applications. RPL3L is one of the four non-canonical riboprotein genes and it encodes the 60S ribosomal protein L3-like protein that is highly expressed only in cardiac and skeletal muscle. Three-dimensional homology modeling and in silico analysis of the affected residues in RPL3L indicate that the identified changes specifically alter the interaction of RPL3L with the RNA components of the 60S ribosomal subunit and thus destabilize its binding to the 60S subunit. In conclusion, we report that bi-allelic pathogenic variants in RPL3L are causative of an early-onset, severe neonatal form of dilated cardiomyopathy, and we show for the first time that cytoplasmic ribosomal proteins are involved in the pathogenesis of non-syndromic cardiomyopathies.


Assuntos
Cardiomiopatia Dilatada/genética , Mutação de Sentido Incorreto/genética , Proteínas Ribossômicas/genética , Ribossomos/genética , Alelos , Exoma/genética , Feminino , Coração/fisiopatologia , Humanos , Lactente , Recém-Nascido , Masculino , Músculo Esquelético/fisiopatologia , Linhagem , Fenótipo , RNA/genética
17.
PLoS One ; 15(5): e0233531, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32453807

RESUMO

Several studies have investigated the use of invasive and non-invasive stimulation methods to enhance nerve regeneration, and varying degrees of effectiveness have been reported. However, due to the use of different parameters in these studies, a fair comparison between the effectiveness of invasive and non-invasive stimulation methods is not possible. The present study compared the effectiveness of invasive and non-invasive stimulation using similar parameters. Eighteen Sprague Dawley rats were classified into three groups: the iES group stimulated with fully implantable device, the tES group stimulated with transcutaneous electrical nerve stimulation (TENS), and the injury group (no stimulation). The iES and tES groups received stimulation for 6 weeks starting immediately after the injury. Motor function was evaluated using the sciatic functional index (SFI) every week. The SFI values increased over time in all groups; faster and superior functional recovery was observed in the iES group than in the tES group. Histological evaluation of the nerve sections and gastrocnemius muscle sections were performed every other week. The axon diameter and muscle fiber area in the iES group were larger, and the g-ratio in the iES group was closer to 0.6 than those in the tES group. To assess the cause of the difference in efficiency, a 3D rat anatomical model was used to simulate the induced electric fields in each group. A significantly higher concentration and intensity around the sciatic nerve was observed in the iES group than in the tES group. Vector field distribution showed that the field was orthogonal to the sciatic nerve spread in the tES group, whereas it was parallel in the iES group; this suggested that the tES group was less effective in nerve stimulation. The results indicated that even though rats in the TENS group showed better recovery than those in the injury group, it cannot replace direct stimulation yet because rats stimulated with the invasive method showed faster recovery and superior outcomes. This was likely attributable to the greater concentration and parallel distribution of electric field with respect to target nerve.


Assuntos
Lesões por Esmagamento/terapia , Regeneração Nervosa/fisiologia , Neuropatia Ciática/terapia , Estimulação Elétrica Nervosa Transcutânea , Animais , Axônios/efeitos da radiação , Lesões por Esmagamento/fisiopatologia , Lesões por Esmagamento/cirurgia , Modelos Animais de Doenças , Humanos , Fibras Musculares Esqueléticas/fisiologia , Fibras Musculares Esqueléticas/efeitos da radiação , Músculo Esquelético/fisiopatologia , Músculo Esquelético/efeitos da radiação , Compressão Nervosa/métodos , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/fisiologia , Nervo Isquiático/crescimento & desenvolvimento , Nervo Isquiático/fisiopatologia , Nervo Isquiático/cirurgia , Neuropatia Ciática/fisiopatologia , Neuropatia Ciática/cirurgia
18.
Adv Exp Med Biol ; 1279: 37-51, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32350822

RESUMO

Movement synergies, muscle co-contraction, and decreased motor drive to muscle agonists were suggested to be major factors in motor impairments after stroke. The purpose of this study was to investigate the major muscle mechanisms contributing to motor impairment after stroke. Twelve healthy and 13 post-stroke patients participated in this observational study. Both groups participated in a single experimental session, performing hand pointing movements in multiple directions, during which EMG was assessed. Additionally, the patients underwent the Fugl-Meyer assessment. A set of features from the electromyography (EMG) signal and co-contraction ratios were used to compare the capacity to modulate the muscle activity between the two groups of participants. A correlation analysis was applied between the Euclidian distances of each target and the Fugl-Meyer scoring assessment in the post-stroke patients. We found that impaired modulation of muscle activity in post-stroke patients was characterized by significantly increased Euclidian distances between the EMG features of different target directions and by a higher variability between muscle activation compared to healthy subjects. Impaired capacity to modulate muscle activity significantly correlated with the impairment status. In conclusion, impaired motor performance post-stroke systematic disturbance in the control signal to limb muscles, which manifests as decreased capacity to modulate muscle activity, rather than co-contraction of muscle antagonists or stereotyped movement patterns.


Assuntos
Transtornos Motores/complicações , Transtornos Motores/fisiopatologia , Contração Muscular , Músculo Esquelético/fisiopatologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologia , Eletromiografia , Humanos
19.
Am J Pathol ; 190(8): 1609-1621, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32407731

RESUMO

Alzheimer disease (AD) is characterized by deterioration of cognitive capabilities with an estimated 44 million individuals worldwide living with it. Beyond memory deficits, the most common AD co-morbidities include swallowing defects (muscle), fractures (bone, muscle), and heart failure. The underlying causes of these co-morbidities and their role in AD pathophysiology are currently unknown. This review is the first to summarize the emerging picture of the cardiac and musculoskeletal deficits in human AD. We present the involvement of the heart, characterized by diastolic heart failure, the presence of amyloid deposits, and electrophysiological changes, compared with age-matched control subjects. The characteristic musculoskeletal defects in AD come from recent clinical studies and include potential underlying mechanisms (bone) in animal models. These studies detail a primary muscle weakness (without a loss of muscle mass) in patients with mild cognitive impairment, with progression of cognitive impairment to AD associating with ongoing muscle weakness and the onset of muscle atrophy. We conclude by reviewing the loss of bone density in patients with AD, paralleling the increase in fracture and fall risk in specific populations. These studies paint AD as a systemic disease in broad strokes, which may help elucidate AD pathophysiology and to allow for new ways of thinking about therapeutic interventions, diagnostic biomarkers, and the pathogenesis of this multidisciplinary disease.


Assuntos
Doença de Alzheimer/fisiopatologia , Coração/fisiopatologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Progressão da Doença , Humanos
20.
J Electromyogr Kinesiol ; 52: 102422, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32413827

RESUMO

High-density surface electromyography (HDEMG) is an electrophysiological technique that can be used to quantify the spatial distribution of activity within muscles. When pain-free individuals perform sustained or repetitive tasks, different regions within a muscle become progressively more active; this is thought to reflect a strategy to redistribute the load to different regions, thus limiting localised muscle fatigue. The use of HDEMG has revealed that when people with musculoskeletal pain perform the same tasks, the distribution of activity within the same muscle is usually different, and the same muscle region tends to be active throughout the whole task without progressive activation of different muscle regions. This potentially results in a focal overload of a muscle region, and may contribute to fatigue, localised muscle pain and potentially pain persistence and/or recurrence over time. Interestingly, not all patients with musculoskeletal pain present with this regional alteration in muscle activation, reflecting the heterogeneity of patient presentations. This article will briefly review the technique of HDEMG followed by a review of studies demonstrating spatial redistribution of muscle activity in asymptomatic people during both isometric and dynamic conditions, including functional tasks. Lastly, the article will provide a review of HDEMG studies with a focus on changes in the behaviour of the lumbar erector spine and upper trapezius in people with spinal pain. These studies have revealed subtle changes in the distribution of muscle activity in people with spinal pain, which may have relevance for onset, persistence or recurrence of symptoms and could become a target of novel therapeutic approaches.


Assuntos
Músculo Esquelético/fisiopatologia , Mialgia/fisiopatologia , Eletromiografia/métodos , Humanos , Contração Muscular , Fadiga Muscular , Mialgia/etiologia
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