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1.
J Med Life ; 14(1): 121-124, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33767797

RESUMO

This case report describes a rare case of progressive muscle weakness in a patient treated for eosinophilic fasciitis (EF) for many years before being diagnosed with a second autoimmune disease: dermatomyositis. Our case is a report of a 65-year-old male diagnosed with eosinophilic fasciitis 7 years before being evaluated in our service at Mayo Clinic in Jacksonville, Florida, due to progressive muscle weakness despite the chronic treatment with methotrexate. Contrast-enhanced magnetic resonance imaging of the lower extremity showed enhancement throughout the thigh musculature, which led us to pursue biopsies of the fascia and muscle in order to confirm the diagnosis of EF associated with myopathy. This case illustrates the need to consider the possibility of myopathy in patients diagnosed with EF whenever muscle weakness is more prominent than expected.


Assuntos
Eosinofilia/patologia , Fasciite/patologia , Idoso , Biópsia , Articulação do Cotovelo/patologia , Eosinofilia/diagnóstico por imagem , Eosinofilia/tratamento farmacológico , Fáscia/patologia , Fasciite/diagnóstico por imagem , Fasciite/tratamento farmacológico , Humanos , Imagem por Ressonância Magnética , Masculino , Metotrexato/uso terapêutico , Músculos/patologia , Atrofia Muscular/patologia , Pele/patologia
2.
Life Sci ; 273: 119296, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33675897

RESUMO

AIMS: Skeletal muscle mass and strength are reduced in asthma and contribute to compromised functional capacity in asthmatic patients. However, an effective pharmacological intervention remains elusive, partly because molecular mechanisms dictating muscle decline in asthma are not known. MATERIALS: We investigated the potential contribution(s) of skeletal muscle sarcoplasmic reticulum Ca2+ ATPase (SERCA) to muscle atrophy and weakness in asthmatic patients. Quadriceps muscle biopsies were taken from 58 to 72 years old male patients with mild and advanced asthma and the SERCA activity was analyzed in association with cellular redox environment and myonuclear domain (MND) size. KEY FINDINGS: Maximal SERCA activity was reduced in skeletal muscles of mild and advanced asthmatics and was associated with reduced expression of SERCA2 protein and upregulation of sarcolipin, a SERCA inhibitory lipoprotein. We also found downregulation of Ca2+ release protein calstabin and upregulation of Ca2+ buffer, calsequestrin in skeletal muscles of asthmatic patients. The atrophic single muscle fibers had smaller cytoplasmic domains per myonucleus possibly indicating the reduced transcriptional reserves of individual myonuclei. Plasma periostin and CAF22 levels were significantly elevated in asthmatic patients and showed a strong correlation with hand-grip strength. These changes were accompanied by substantially elevated markers of global oxidative stress including lipid peroxidation and mitochondrial ROS production. CONCLUSION: Taken together, our data suggest that muscle weakness and atrophy in asthma is in part driven by SERCA dysfunction and oxidative stress. The data propose SERCA dysfunction as a therapeutic intervention to address muscle decline in asthma.


Assuntos
Asma/complicações , Biomarcadores/sangue , Cálcio/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/patologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Idoso , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/enzimologia , Atrofia Muscular/enzimologia , Atrofia Muscular/etiologia , Retículo Sarcoplasmático
3.
Nat Commun ; 12(1): 330, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436614

RESUMO

Skeletal muscle is the protein reservoir of our body and an important regulator of glucose and lipid homeostasis. Consequently, the growth or the loss of muscle mass can influence general metabolism, locomotion, eating and respiration. Therefore, it is not surprising that excessive muscle loss is a bad prognostic index of a variety of diseases ranging from cancer, organ failure, infections and unhealthy ageing. Muscle function is influenced by different quality systems that regulate the function of contractile proteins and organelles. These systems are controlled by transcriptional dependent programs that adapt muscle cells to environmental and nutritional clues. Mechanical, oxidative, nutritional and energy stresses, as well as growth factors or cytokines modulate signaling pathways that, ultimately, converge on protein and organelle turnover. Novel insights that control and orchestrate such complex network are continuously emerging and will be summarized in this review. Understanding the mechanisms that control muscle mass will provide therapeutic targets for the treatment of muscle loss in inherited and non-hereditary diseases and for the improvement of the quality of life during ageing.


Assuntos
Doença , Saúde , Atrofia Muscular/patologia , Animais , Humanos , Hipertrofia , Desenvolvimento Muscular , Transdução de Sinais
4.
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
5.
PLoS One ; 15(9): e0238208, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881928

RESUMO

INTRODUCTION: Peripheral nerve injury (PNI) often leads to significant functional loss in patients and poses a challenge to physicians since treatment options for improving functional outcomes are limited. Recent studies suggest that erythropoietin and glucocoticoids have beneficial effects as mediators of neuro-regenerative processes. We hypothesized that combination treatment with erythropoietin and glucocoticoids would have a synergistic effect on functional outcome after PNI. MATERIALS AND METHODS: Sciatic nerve crush injury was simulated in ten-week-old male C57BL/6 mice. The mice were divided into four groups according to the type of drugs administered (control, erythropoietin, dexamethasone, and erythropoietin with dexamethasone). Motor functional recovery was monitored by walking track analysis at serial time points up to 28 days after injury. Morphological analysis of the nerve was performed by immunofluorescent staining for neurofilament (NF) heavy chain and myelin protein zero (P0) in cross-sectional and whole-mount nerve preparations. Additionally, morphological analysis of the muscle was performed by Hematoxylin and eosin staining. RESULTS: Combination treatment with erythropoietin and dexamethasone significantly improved the sciatic functional index at 3, 7, 14, and 28 days after injury. Fluorescence microscopy of cross sectional nerve revealed that the combination treatment increased the ratio of P0/NF-expressing axons. Furthermore, confocal microscopy of the whole-mount nerve revealed that the combination treatment increased the fluorescence intensity of P0 expression. The cross-sectional area and minimum Feret's diameter of the muscle fibers were significantly larger in the mice which received combination treatment than those in the controls. CONCLUSION: Our results demonstrated that combination treatment with erythropoietin and dexamethasone accelerates functional recovery and reduces neurogenic muscle atrophy caused by PNI in mice, which may be attributed to the preservation of myelin and Schwann cell re-myelination. These findings may provide practical therapeutic options for patients with acute PNI.


Assuntos
Dexametasona/uso terapêutico , Eritropoetina/uso terapêutico , Músculos/metabolismo , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Nervo Isquiático/metabolismo , Doença Aguda , Animais , Axônios/metabolismo , Dexametasona/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Eritropoetina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Músculos/patologia , Atrofia Muscular/patologia , Atrofia Muscular/prevenção & controle , Proteína P0 da Mielina/metabolismo , Traumatismos dos Nervos Periféricos/patologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Remielinização/efeitos dos fármacos , Células de Schwann/citologia , Células de Schwann/metabolismo , Nervo Isquiático/patologia
6.
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
7.
Life Sci ; 261: 118298, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32822717

RESUMO

AIMS: 1) Characterize the progression of exercise intolerance in monocrotaline-induced pulmonary hypertension (PH) in mice and 2) evaluate the therapeutic effect of aerobic exercise training (AET) on counteracting skeletal and cardiac dysfunction in PH. MAIN METHODS: Wild type C57BL6/J mice were studied in two different time points: 2 months and 4 months. Exercise tolerance was evaluated by graded treadmill exercise test. The AET was performed in the last month of treatment of 4 months' time point. Cardiac function was evaluated by echocardiography. Skeletal muscle cross-sectional area was assessed by immunofluorescence. The diameter of cardiomyocytes and pulmonary edema were quantified by staining with hematoxylin-eosin. The variables were compared among the groups by two-way ANOVA or non-paired Student's t-test. Significance level was set at p < 0.05. KEY FINDINGS: After 2 months of MCT treatment, mice presented pulmonary edema, right cardiac dysfunction and left ventricle hypertrophy. After 4 months of MCT treatment, mice showed pulmonary edema, right and left cardiac dysfunction and remodeling associated with exercise intolerance and skeletal muscle atrophy. AET was able to reverse cardiac left ventricle dysfunction and remodeling, prevent exercise intolerance and skeletal muscle dysfunction. Thus, our data provide evidence of skeletal muscle abnormalities on advanced PH. AET was efficient in inducing an anti-cardiac remodeling effect besides preventing exercise intolerance. SIGNIFICANCE: Our study provides a robust model of PH in mice, as well as highlights the importance of AET as a preventive strategy for exercise intolerance and, skeletal and cardiac muscle abnormalities in PH.


Assuntos
Tolerância ao Exercício/fisiologia , Hipertensão Pulmonar/fisiopatologia , Miócitos Cardíacos/metabolismo , Condicionamento Físico Animal/fisiologia , Animais , Progressão da Doença , Teste de Esforço , Hipertensão Pulmonar/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Atrofia Muscular/patologia , Fatores de Tempo
8.
Life Sci ; 258: 118243, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32791154

RESUMO

AIMS: Although autophagy impairment is a well-established cause of muscle atrophy and P300 has recently been identified as an important regulator of autophagy, the effects of P300 on autophagy and muscle atrophy in type 2 diabetes (T2D) remain unexplored. We aimed at characterizing the role of P300 in diabetic muscle and its underlying mechanism. MAIN METHODS: Protein levels of phosphorylated P300, total P300, acetylated histone H3, LC3, p62 and myosin heavy chain, and mRNA levels of Atrogin-1 and MuRF1 were analyzed in palmitic acid (PA)-treated myotubes and db/db mice. Autophagic flux was assessed using transmission electron microscopy, immunofluorescence and mRFP-GFP-LC3 lentivirus transfection in cells. Muscle weight, blood glucose and grip strength were measured in mice. Hematoxylin and eosin (H&E) staining was performed to determine changes in muscle fiber size. To investigate the effects of P300 on autophagy and myofiber remodeling, a P300 specific inhibitor, c646, was utilized. 3-Methyladenine (3-MA) was utilized to inhibit autophagosomes formation, and chloroquine (CQ) was used to block autophagic flux. KEY FINDINGS: Phosphorylation of P300 in response to PA enhanced its activity and subsequently suppressed autophagic flux, leading to atrophy-related morphological and molecular changes in myotubes. Inhibition of P300 reestablished autophagic flux and ameliorated PA-induced myotubes atrophy. However, this effect was largely abolished by co-treatment with the autophagy inhibitor CQ. In vivo results demonstrated that inhibition of P300 partially rescued muscle wasting in db/db mice, accompanied with autophagy reactivation. SIGNIFICANCE: The findings revealed that T2D-induced overactivation of P300 contributes to muscle atrophy by blocking autophagic flux.


Assuntos
Autofagia/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Proteína p300 Associada a E1A/metabolismo , Atrofia Muscular/metabolismo , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Proteína p300 Associada a E1A/genética , Força da Mão/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Atrofia Muscular/genética , Atrofia Muscular/patologia , Mioblastos/metabolismo , Mioblastos/patologia
9.
PLoS One ; 15(8): e0236164, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760085

RESUMO

Hyaluronan (HA) is a nonsulfated glycosaminoglycan that has been widely used for biomedical applications. Here, we have analyzed the effect of HA on the rescue of primary cells under stress as well as its potential to recover muscle atrophy and validated the developed model in vitro using primary muscle cells derived from rats. The potentials of different HAs were elucidated through comparative analyses using pharmaceutical grade a) high (HHA) and b) low molecular weight (LHA) hyaluronans, c) hybrid cooperative complexes (HCC) of HA in three experimental set-ups. The cells were characterized based on the expression of myogenin, a muscle-specific biomarker, and the proliferation was analyzed using Time-Lapse Video Microscopy (TLVM). Cell viability in response to H2O2 challenge was evaluated by 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, and the expression of the superoxide dismutase enzyme (SOD-2) was assessed by western blotting. Additionally, in order to establish an in vitro model of atrophy, muscle cells were treated with tumor necrosis factor-alpha (TNF-α), along with hyaluronans. The expression of Atrogin, MuRF-1, nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-kB), and Forkhead-box-(Fox)-O-3 (FoxO3a) was evaluated by western blotting to elucidate the molecular mechanism of atrophy. The results showed that HCC and HHA increased cell proliferation by 1.15 and 2.3 folds in comparison to un-treated cells (control), respectively. Moreover, both pre- and post-treatments of HAs restored the cell viability, and the SOD-2 expression was found to be reduced by 1.5 fold in HA-treated cells as compared to the stressed condition. Specifically in atrophic stressed cells, HCC revealed a noteworthy beneficial effect on the myogenic biomarkers indicating that it could be used as a promising platform for tissue regeneration with specific attention to muscle cell protection against stressful agents.


Assuntos
Ácido Hialurônico/farmacologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Atrofia Muscular/terapia , Medicina Regenerativa/métodos , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultura/metabolismo , Géis , Humanos , Ácido Hialurônico/química , Peróxido de Hidrogênio/toxicidade , Microscopia Intravital , Peso Molecular , Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/patologia , Miogenina/análise , Miogenina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Cultura Primária de Células , Ratos , Superóxido Dismutase/análise , Superóxido Dismutase/metabolismo , Imagem com Lapso de Tempo , Fator de Necrose Tumoral alfa/metabolismo
10.
Arch Biochem Biophys ; 692: 108511, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32710883

RESUMO

(-)-Epigallocatechin-3-gallate (EGCG), the most abundant catechin component in green tea, has been reported to attenuate age-associated insulin resistance, lipogenesis and loss of muscle mass through restoring Akt activity in skeletal muscle in our previous and present studies. Accumulated data has suggested that polyphenols regulate signaling pathways involved in aging process such as inflammation and oxidative stress via modulation of miRNA expression. Here we found that miRNA-486-5p was significantly decreased in both aged senescence accelerated mouse-prone 8 (SAMP8) mice and late passage C2C12 cells. Thus, we further investigated the regulatory effect of EGCG on miRNA-486-5p expression in age-regulated muscle loss. SAMP8 mice were fed with chow diet containing without or with 0.32% EGCG from aged 32 weeks for 8 weeks. Early passage (<12 passages) and late passage (>30 passages) of C2C12 cells were treated without or with EGCG at concentrations of 50 µM for 24h. Our data showed that EGCG supplementation increased miRNA-486-5p expression in both aged SAMP8 mice and late passage C2C12 cells. EGCG stimulated AKT phosphorylation and inhibited FoxO1a-mediated MuRF1 and Atrogin-1 transcription via up-regulating the expression of miR-486 in skeletal muscle of 40-wk-old SAMP8 mice as well as late passage C2C12 cells. In addition, myostatin expression was increased in late passage C2C12 cells and anti-myostatin treatment upregulated the expression of miR-486-5p. Our results identify a unique mechanism of a dietary constituent of green tea and suggest that use of EGCG or compounds derived from it attenuates age-associated muscle loss via myostatin/miRNAs/ubiquitin-proteasome signaling.


Assuntos
Envelhecimento/metabolismo , Catequina/análogos & derivados , Regulação da Expressão Gênica/efeitos dos fármacos , MicroRNAs/metabolismo , Proteínas Musculares/biossíntese , Atrofia Muscular/metabolismo , Miostatina/biossíntese , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Envelhecimento/patologia , Animais , Catequina/química , Catequina/farmacologia , Linhagem Celular , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Proteínas Musculares/genética , Atrofia Muscular/genética , Atrofia Muscular/patologia , Miostatina/genética , Chá/química
11.
Medicine (Baltimore) ; 99(27): e21139, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629749

RESUMO

INTRODUCTION: Most symptomatic large-to-massive rotator cuff tears (RCTs) should be operated, but the surgical reparability depended on the degree of rotator cuff muscle atrophy or fatty infiltration. The orthopedic surgeons will decide whether the teared stump is reparable during the surgery, but preoperative evaluation can be done by some assessment tools. Magnetic resonance imaging (MRI) was used in recent studies to predict the reparability of large-to-massive RCTs, but the clinical availability was not as good as ultrasound. We hypothesize that the ultrasound elastography can predict the reparability of large-to-massive RCTs. METHODS: This is a prospective observational study and participants with large-to-massive RCTs who are going to have surgeries will be included. Out investigators will evaluate the shoulder passive range of motion (ROM) and strength of all participants. Participants' degree of shoulder pain and activities of daily living (ADLs) will be assessed by American Shoulder and Elbow Surgeons (ASES) score. The ultrasound elastography will be used to evaluate the tissue quality of supraspinatus muscle and infraspinatus muscle. To test the reliability of the ultrasound elastography, two physicians will perform the ultrasound elastography independently and twenty participants will be selected for the reliability test. Besides, MRI will be used to evaluate the size of tear, the degree of tendon retraction, fatty infiltration of rotator cuff muscles, and muscle atrophy. Finally, the orthopedic surgeons will perform surgeries and decide whether the teared stump can be completely repaired intraoperatively. The primary analysis is the predictive validity of ultrasound elastography for the reparability of large-to-massive RCTs. Before the predictive validity of ultrasound elastography is measured, our investigators will assess the reliability of ultrasound elastography when administered to cases with large-to-massive RCTs, and we will check the correlations between the findings of ultrasound elastography and MRI. DISCUSSION: The outcome will provide the evidence of ultrasound elastography for preoperative evaluation of large-to-massive RCTs. The relationships between the findings of ultrasound elastography and MRI will also be examined for further analysis. TRIAL REGISTRATION: Clinicaltrials.gov NCT03682679. Date of Registration: 25 September 2018, https://clinicaltrials.gov/ct2/show/NCT03682679?cond=rotator+cuff&cntry=TW&draw=2&rank=1.


Assuntos
Lesões do Manguito Rotador/diagnóstico por imagem , Ruptura/cirurgia , Ombro/fisiopatologia , Atividades Cotidianas , Tecido Adiposo/patologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Atrofia Muscular/patologia , Valor Preditivo dos Testes , Período Pré-Operatório , Estudos Prospectivos , Amplitude de Movimento Articular/fisiologia , Reprodutibilidade dos Testes , Manguito Rotador/patologia , Lesões do Manguito Rotador/patologia
12.
Am J Physiol Cell Physiol ; 319(2): C441-C454, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32639872

RESUMO

Skeletal muscle atrophy is caused by a decrease in muscle size and strength and results from a range of physiological conditions, including denervation, immobilization, corticosteroid exposure and aging. Newly named dual-specificity phosphatase 29 (Dusp29) has been identified as a novel neurogenic atrophy-induced gene in skeletal muscle. Quantitative PCR analysis revealed that Dusp29 expression is significantly higher in differentiated myotubes compared with proliferating myoblasts. To determine how Dusp29 is transcriptionally regulated in skeletal muscle, fragments of the promoter region of Dusp29 were cloned, fused to a reporter gene, and found to be highly inducible in response to ectopic expression of the myogenic regulatory factors (MRF), MyoD and myogenin. Furthermore, site-directed mutagenesis of conserved E-box elements within the proximal promoter of Dusp29 rendered a Dusp29 reporter gene unresponsive to MRF overexpression. Dusp29, an atypical Dusp also known as Dupd1/Dusp27, was found to attenuate the ERK1/2 branch of the MAP kinase signaling pathway in muscle cells and inhibit muscle cell differentiation when ectopically expressed in proliferating myoblasts. Interestingly, Dusp29 was also found to destabilize AMPK protein while simultaneously enriching the phosphorylated pool of AMPK in muscle cells. Additionally, Dusp29 overexpression resulted in a significant increase in the glucocorticoid receptor (GR) protein and elevation in GR phosphorylation. Finally, Dusp29 was found to significantly impair the ability of the glucocorticoid receptor to function as a transcriptional activator in muscle cells treated with dexamethasone. Identifying and characterizing the function of Dusp29 in muscle provides novel insights into the molecular and cellular mechanisms for skeletal muscle atrophy.


Assuntos
Fosfatases de Especificidade Dupla/genética , Atrofia Muscular/genética , Proteína MyoD/genética , Miogenina/genética , Animais , Diferenciação Celular/genética , Linhagem Celular , Proliferação de Células/genética , Regulação da Expressão Gênica/genética , Humanos , Sistema de Sinalização das MAP Quinases/genética , Células Musculares/metabolismo , Células Musculares/patologia , Atrofia Muscular/patologia , Mioblastos/metabolismo , Fosforilação/genética , Receptores de Glucocorticoides/genética , Transdução de Sinais , Ativação Transcricional/genética
13.
Am J Physiol Cell Physiol ; 319(2): C419-C431, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32639875

RESUMO

Small noncoding microRNAs (miRNAs) are important regulators of skeletal muscle size, and circulating miRNAs within extracellular vesicles (EVs) may contribute to atrophy and its associated systemic effects. The purpose of this study was to understand how muscle atrophy and regrowth alter in vivo serum EV miRNA content. We also associated changes in serum EV miRNA with protein synthesis, protein degradation, and miRNA within muscle, kidney, and liver. We subjected adult (10 mo) F344/BN rats to three conditions: weight bearing (WB), hindlimb suspension (HS) for 7 days to induce muscle atrophy, and HS for 7 days followed by 7 days of reloading (HSR). Microarray analysis of EV miRNA content showed that the overall changes in serum EV miRNA were predicted to target major anabolic, catabolic, and mechanosensitive pathways. MiR-203a-3p was the only miRNA demonstrating substantial differences in HS EVs compared with WB. There was a limited association of EV miRNA content to the corresponding miRNA content within the muscle, kidney, or liver. Stepwise linear regression demonstrated that EV miR-203a-3p was correlated with muscle mass and muscle protein synthesis and degradation across all conditions. Finally, EV miR-203a-3p expression was significantly decreased in human subjects who underwent unilateral lower limb suspension (ULLS) to induce muscle atrophy. Altogether, we show that serum EV miR-203a-3p expression is related to skeletal muscle protein turnover and atrophy. We suggest that serum EV miR-203a-3p content may be a useful biomarker and future work should investigate whether serum EV miR-203a-3p content is mechanistically linked to protein synthesis and degradation.


Assuntos
MicroRNAs/genética , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Transtornos Musculares Atróficos/genética , Animais , Biomarcadores/metabolismo , Vesículas Extracelulares/genética , Elevação dos Membros Posteriores , Humanos , Rim/metabolismo , Fígado/metabolismo , Análise em Microsséries , Proteínas Musculares/genética , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Transtornos Musculares Atróficos/metabolismo , Transtornos Musculares Atróficos/patologia , Ratos
14.
Rinsho Shinkeigaku ; 60(8): 554-559, 2020 Aug 07.
Artigo em Japonês | MEDLINE | ID: mdl-32641626

RESUMO

A 42-year-old man with a history of two previous coronary embolisms was referred to our hospital. He had been experiencing muscle weakness since he was around 40 years old. He had muscle atrophy of the scapula, upper arm, and lower extremities, and electromyography revealed myogenic changes in the limb muscles. Histopathological analysis of the muscle biopsy specimen revealed a complete deficiency of emerin protein, and genetic examination revealed a mutation in the emerin (EMD) gene, resulting in a diagnosis of Emery-Dreifuss muscular dystrophy (EDMD). EDMD is a muscular disorder with three symptoms: joint contracture at early onset, muscle weakness and atrophy, and cardiac dysfunction. Although this patient showed no obvious joint contracture, the course and clinical symptoms vary among patients. Therefore, in patients in whom clinical diagnosis is difficult, muscle biopsy and genetic testing should be performed for EDMD in order to prevent sudden death due to this disease.


Assuntos
Contratura , Articulações , Distrofia Muscular de Emery-Dreifuss/diagnóstico , Adulto , Contratura/patologia , Humanos , Articulações/patologia , Masculino , Proteínas de Membrana/genética , Debilidade Muscular/patologia , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Distrofia Muscular de Emery-Dreifuss/genética , Distrofia Muscular de Emery-Dreifuss/patologia , Mutação , Proteínas Nucleares/genética
15.
PLoS One ; 15(6): e0230695, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559188

RESUMO

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is notorious for its associated skeletal muscle wasting (SMW) and mortality. Currently, the relationships between PDAC, SMW, and survival are poorly understood. Thus, there is great need for a faithful small animal model with quantitative longitudinal outcome measures that recapitulate clinical PDAC, to define SMW onset and assess progression. Therefore, we aimed to validate dual energy X-ray absorptiometry (DEXA) as a longitudinal measure of lean mass, and demonstrate its utility to quantify SMW in the KCKO murine model of PDAC. METHODS: In vivo body composition of: 1) untreated mice at 5, 8, 12, 18, and 22 weeks of age (n = 4) and 2) a cohort of mice with (n = 5) and without PDAC (n = 5), was determined via DEXA and lean mass of the lower hind limbs was predicted via a region of interest analysis by two-independent observers. Total body weight was determined. Tibialis anterior (TA) muscles were weighed and processed for histomorphometry immediately post-mortem. Statistical differences between groups were assessed using ANOVA and Student's t-tests. Linear regression models and correlation analysis were used to measure the association between TA and DEXA mass, and reproducibility of DEXA was quantified via the intraclass correlation coefficient (ICC). RESULTS: Lean mass in growing untreated mice determined by DEXA correlated with TA mass (r2 = 0.94; p <0.0001) and body weight (r2 = 0.89; p <0.0001). DEXA measurements were highly reproducible between observers (ICC = 0.95; 95% CI: 0.89-0.98). DEXA and TA mass also correlated in the PDAC cohort (r2 = 0.76; p <0.0001). Significant SMW in tumor-bearing mice was detected within 38 days of implantation, by DEXA, TA mass, and histomorphometry. CONCLUSIONS: DEXA is a longitudinal outcome measure of lean mass in mice. The KCKO syngeneic model is a bona fide model of PDAC associated SMW that can be quantified with longitudinal DEXA.


Assuntos
Absorciometria de Fóton , Adenocarcinoma/complicações , Atrofia Muscular/complicações , Neoplasias Pancreáticas/complicações , Animais , Composição Corporal , Estudos de Coortes , Feminino , Estudos Longitudinais , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/patologia , Atrofia Muscular/diagnóstico , Atrofia Muscular/patologia , Atrofia Muscular/fisiopatologia , Tamanho do Órgão , Prognóstico , Reprodução
16.
Medicine (Baltimore) ; 99(21): e20233, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481297

RESUMO

BACKGROUND: Sepsis-induced myopathy (SIM) is a disease that causes motor dysfunction in patients with sepsis. There is currently no targeted treatment for this disease. Acupuncture has shown considerable efficacy in the treatment of sepsis and muscle weakness. Therefore, our research aims to explore the effects of acupuncture on the improvement of muscle structure and function in SIM patients and on activities of daily living. METHODS: The ACU-SIM pilot study is a single-center, propensity-score stratified, assessor-blinded, prospective pragmatic controlled trial (pCT) with a 1-year follow-up period. This study will be deployed in a multi-professional critical care department at a tertiary teaching hospital in Guangzhou, China. Ninety-eight intensive care unit subjects will be recruited and assigned to either the control group or the acupuncture group. Both groups will receive basic treatment for sepsis, and the acupuncture group will additionally receive acupuncture treatment. The primary outcomes will be the rectus femoris cross-sectional area, the Medical Research Council sum-score and time-to-event (defined as all-cause mortality or unplanned readmission to the intensive care unit due to invasive ventilation). The activities of daily living will be accessed by the motor item of the Functional Independence Measure. Recruitment will last for 2 years, and each patient will have a 1-year follow-up after the intervention. DISCUSSION: There is currently no research on the therapeutic effects of acupuncture on SIM. The results of this study may contribute to new knowledge regarding early muscle atrophy and the treatment effect of acupuncture in SIM patients, and the results may also direct new approaches and interventions in these patients. This trial will serve as a pilot study for an upcoming multicenter real-world study. TRIAL REGISTRATION: Chinese Clinical Trials Registry: ChiCTR-1900026308, registered on September 29th, 2019.


Assuntos
Terapia por Acupuntura/métodos , Debilidade Muscular/terapia , Atrofia Muscular/terapia , Doenças Musculares/terapia , Sepse/terapia , Atividades Cotidianas , Terapia por Acupuntura/efeitos adversos , China/epidemiologia , Cuidados Críticos/organização & administração , Seguimentos , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Mortalidade/tendências , Debilidade Muscular/etiologia , Debilidade Muscular/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Doenças Musculares/etiologia , Readmissão do Paciente/tendências , Projetos Piloto , Pontuação de Propensão , Estudos Prospectivos , Respiração Artificial/métodos , Respiração Artificial/estatística & dados numéricos , Sepse/complicações , Centros de Atenção Terciária/organização & administração , Resultado do Tratamento
17.
Sci Rep ; 10(1): 8593, 2020 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-32451429

RESUMO

Muscular atrophy or muscle loss is a multifactorial clinical condition during many critical illnesses like cancer, cardiovascular diseases, diabetes, pulmonary diseases etc. leading to fatigue and weakness and contributes towards a decreased quality of life. The proportion of older adults (>65 y) in the overall population is also growing and aging is another important factor causing muscle loss. Some muscle miRNAs (myomiRs) and their target genes have even been proposed as potential diagnostic, therapeutic and predictive markers for muscular atrophy. MyomirDB (http://www.myomirdb.in/) is a unique resource that provides a comprehensive, curated, user- friendly and detailed compilation of various miRNA bio-molecular interactions; miRNA-Transcription Factor-Target Gene co-regulatory networks and ~8000 tripartite regulons associated with 247 myomiRs which have been experimentally validated to be associated with various muscular atrophy conditions. For each database entry, MyomirDB compiles source organism, muscle atrophic condition, experiment duration, its level of expression, fold change, tissue of expression, experimental validation, disease and drug association, tissue-specific expression level, Gene Ontology and KEGG pathway associations. The web resource is a unique server platform which uses in-house scripts to construct miRNA-Transcription Factor-Target Gene co-regulatory networks and extract tri-partite regulons also called Feed Forward Loops. These unique features helps to offer mechanistic insights in disease pathology. Hence, MyomirDB is a unique platform for researchers working in this area to explore, fetch, compare and analyse atrophy associated miRNAs, their co-regulatory networks and FFL regulons.


Assuntos
Redes Reguladoras de Genes/genética , MicroRNAs/metabolismo , Regulon/genética , Interface Usuário-Computador , Bases de Dados Genéticas , Humanos , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Fatores de Transcrição/metabolismo
18.
PLoS One ; 15(5): e0227720, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407314

RESUMO

Numerous mutational studies have demonstrated that circadian clock proteins regulate behavior and metabolism. Nr1d1(Rev-erbα) is a key regulator of circadian gene expression and a pleiotropic regulator of skeletal muscle homeostasis and lipid metabolism. Loss of Rev-erbα expression induces muscular atrophy, high adiposity, and metabolic syndrome in mice. Here we show that, unlike knockout mice, Nr1d1 heterozygous mice are not susceptible to muscular atrophy and in fact paradoxically possess larger myofiber diameters and improved neuromuscular function, compared to wildtype mice. Heterozygous mice lacked dyslipidemia, a characteristic of Nr1d1 knockout mice and displayed increased whole-body fatty-acid oxidation during periods of inactivity (light cycle). Heterozygous mice also exhibited higher rates of glucose uptake when fasted, and had elevated basal rates of gluconeogenesis compared to wildtype and knockout littermates. Rev-erbα ablation suppressed glycolysis and fatty acid-oxidation in white-adipose tissue (WAT), whereas partial Rev-erbα loss, curiously stimulated these processes. Our investigations revealed that Rev-erbα dose-dependently regulates glucose metabolism and fatty acid oxidation in WAT and muscle.


Assuntos
Dislipidemias/genética , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Tecido Adiposo Branco/metabolismo , Adiposidade/genética , Animais , Comportamento Animal/fisiologia , Relógios Circadianos/genética , Dislipidemias/metabolismo , Dislipidemias/patologia , Ácidos Graxos/metabolismo , Gluconeogênese/genética , Glucose/metabolismo , Heterozigoto , Humanos , Metabolismo dos Lipídeos/genética , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Camundongos , Camundongos Knockout , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Miofibrilas/genética , Miofibrilas/metabolismo , Miofibrilas/patologia , Fotoperíodo
19.
Cardiovasc Intervent Radiol ; 43(7): 981-986, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32415332

RESUMO

PURPOSE: We evaluated possible association of decreased psoas muscle area (PMA) after endovascular aneurysm repair (EVAR) by measuring the area of muscle in computed tomographic (CT) images. MATERIALS AND METHODS: We retrospectively reviewed CT images of 201 consecutive patients who underwent EVAR at our institution between April 1, 2015, and November 9, 2018, and compared them with images of 75 consecutive patients with no history of EVAR, who served as controls and underwent thoracic endovascular aortic repair (TEVAR) during the same period. We investigated EVAR and possible associated factors that might be potential predictors of decrease in PMA. RESULTS: Those patients with a history of EVAR demonstrated significantly greater mean decrease in PMA than those with a history of TEVAR after the repair procedure (mean 6.25% (8.5); P < 0.001; odds ratio [OR], 3.63; 95% confidence interval [CI] 1.90-6.90). CONCLUSION: Although EVAR is a less stressful procedure than other major abdominal surgeries, we identified it as an independent predictor of decreased area of the psoas muscle. Thus, our results might encourage post-procedural evaluation of frailty associated with psoas muscle function and prescription of appropriate rehabilitation interventions after EVAR to help prevent deterioration of patients' abilities.


Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Procedimentos Endovasculares/métodos , Atrofia Muscular/diagnóstico por imagem , Complicações Pós-Operatórias/diagnóstico por imagem , Músculos Psoas/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Procedimentos Endovasculares/efeitos adversos , Estudos de Avaliação como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/patologia , Músculos Psoas/patologia , Estudos Retrospectivos , Medição de Risco/métodos , Resultado do Tratamento
20.
Am J Pathol ; 190(8): 1713-1722, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32371051

RESUMO

Amyotrophic lateral sclerosis is a rapidly progressing and fatal disease characterized by muscular atrophy due to loss of upper and lower motor neurons. Pathogenic mutations in the TARDBP gene encoding TAR DNA binding protein-43 (TDP-43) have been identified in familial amyotrophic lateral sclerosis. We have previously reported transgenic mice with neuronal expression of human TDP-43 carrying the pathogenic A315T mutation (iTDP-43A315T mice) using a tetracycline-controlled inducible promotor system. Constitutive expression of transgenic TDP-43A315T in the absence of doxycycline resulted in pronounced early-onset and progressive neurodegeneration, and motor and memory deficits. Here, delayed transgene expression of TDP-43A315T by oral doxycycline treatment of iTDP-43A315T mice from birth till weaning was analyzed. After doxycycline withdrawal, transgenic TDP-43A315T expression gradually increased and resulted in cytoplasmic TDP-43, widespread ubiquitination, and cortical and hippocampal atrophy. In addition, these mice developed motor and gait deficits with underlying muscle atrophy, similar to that observed in the constitutive iTDP-43A315T mice. Surprisingly, in contrast to the constitutive iTDP-43A315T mice, these mice did not develop astrogliosis. In summary, delayed activation coupled with gradual increase in TDP-43A315T expression in the central nervous system of mature mice resulted in progressive functional deficits with neuron and muscle loss, but in the absence of a glial response. This suggests that astrocytosis does not contribute to functional deficits and neuronal loss upon TDP-43A315T expression in mature mice.


Assuntos
Encéfalo/metabolismo , Proteínas de Ligação a DNA/genética , Gliose/patologia , Transtornos Motores/genética , Atrofia Muscular/genética , Degeneração Neural/genética , Animais , Encéfalo/patologia , Proteínas de Ligação a DNA/metabolismo , Camundongos , Camundongos Transgênicos , Transtornos Motores/metabolismo , Transtornos Motores/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Degeneração Neural/metabolismo , Degeneração Neural/patologia
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