RESUMO
An 8-year-old neutered male Bengal cat was referred because of a 1-year history of progressive and relapsing generalized muscle weakness and muscle atrophy. Before referral, the cat was treated with immunosuppressive doses of oral prednisolone, intermittently for 6 mo, and had responded well when the immunosuppressive dose was maintained. Generalized paresis, diffuse muscle atrophy, and diminished spinal reflexes were present in all limbs, consistent with a generalized lower motor neuron disease. Histopathologic evaluation of muscle biopsies confirmed a pattern of muscle fiber atrophy consistent with chronic and severe denervation. No specific abnormalities were identified in the nerve biopsy or within intramuscular nerve branches. A presumptive antemortem diagnosis of an adult-onset motor neuron degeneration resembling amyotrophic lateral sclerosis (ALS) or spinal muscle atrophy was suspected. However, given the response to immunosuppressive doses of corticosteroids, an autoimmune process or other degenerative process could not be definitively excluded. Key clinical message: In this case, an adult cat had a chronic, progressive history of lower motor neuron weakness and absent spinal reflexes; biopsies revealed a neurogenic pattern of muscle fiber atrophy and histologically normal peripheral nerve and intramuscular nerve branches. Although reports of motor neuron disease are rare in the veterinary literature, this case report highlights the importance of muscle and nerve biopsies that lead to a presumptive diagnosis of motor neuron degeneration.
Dégénérescence présumée des neurones moteurs chez un chat adulteUn chat Bengal mâle castré de 8 ans a été référé en raison d'un an d'antécédents de faiblesse musculaire généralisée progressive et récidivante et d'atrophie musculaire. Avant le transfert, le chat a été traité avec des doses immunosuppressives de prednisolone orale, par intermittence pendant 6 mois, et a bien répondu lorsque la dose immunosuppressive a été maintenue. Une parésie généralisée, une atrophie musculaire diffuse et des réflexes spinaux diminués étaient présents dans tous les membres, compatibles avec une maladie généralisée des neurones moteurs inférieurs. L'évaluation histopathologique des biopsies musculaires a confirmé un schéma d'atrophie des fibres musculaires compatible avec une dénervation chronique et sévère. Aucune anomalie spécifique n'a été identifiée dans la biopsie nerveuse ou dans les branches nerveuses intramusculaires. Un diagnostic antemortem présomptif d'une dégénérescence des neurones moteurs d'apparition adulte ressemblant à la sclérose latérale amyotrophique (SLA) ou à une atrophie musculaire spinale a été suspecté. Cependant, compte tenu de la réponse aux doses immunosuppressives de corticostéroïdes, un processus auto-immun ou un autre processus dégénératif ne pouvait être définitivement exclu.Message clinique clé :Dans ce cas, un chat adulte avait des antécédents chroniques et progressifs de faiblesse des neurones moteurs inférieurs et d'absence de réflexes spinaux; les biopsies ont révélé un schéma neurogène d'atrophie des fibres musculaires et des branches nerveuses périphériques et intramusculaires histologiquement normales. Bien que les rapports de maladie des neurones moteurs soient rares dans la littérature vétérinaire, ce rapport de cas souligne l'importance des biopsies musculaires et nerveuses qui conduisent à un diagnostic présomptif de dégénérescence des neurones moteurs.(Traduit par Dr Serge Messier).
Assuntos
Doenças do Gato , Doença dos Neurônios Motores , Gatos , Masculino , Animais , Doenças do Gato/patologia , Doenças do Gato/diagnóstico , Doenças do Gato/tratamento farmacológico , Doença dos Neurônios Motores/veterinária , Doença dos Neurônios Motores/patologia , Doença dos Neurônios Motores/diagnóstico , Prednisolona/uso terapêutico , Imunossupressores/uso terapêutico , Neurônios Motores/patologia , Atrofia Muscular/veterinária , Atrofia Muscular/patologia , Músculo Esquelético/patologiaRESUMO
BACKGROUND: Muscle atrophy is a typical affliction in patients affected by knee Osteoarthritis (KOA). This study aimed to examine the potential pathogenesis and biomarkers that coalesce to induce muscle atrophy, primarily through the utilization of bioinformatics analysis. METHODS: Two distinct public datasets of osteoarthritis and muscle atrophy (GSE82107 and GSE205431) were subjected to differential gene expression analysis and gene set enrichment analysis (GSEA) to probe for common differentially expressed genes (DEGs) and conduct transcription factor (TF) enrichment analysis from such genes. Venn diagrams were used to identify the target TF, followed by the construction of a protein-protein interaction (PPI) network of the common DEGs governed by the target TF. Hub genes were determined through the CytoHubba plug-in whilst their biological functions were assessed using GSEA analysis in the GTEx database. To validate the study, reverse transcriptase real-time quantitative polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and Flow Cytometry techniques were employed. RESULTS: A total of 138 common DEGs of osteoarthritis and muscle atrophy were identified, with 16 TFs exhibiting notable expression patterns in both datasets. Venn diagram analysis identified early growth response gene-1 (EGR1) as the target TF, enriched in critical pathways such as epithelial mesenchymal transition, tumor necrosis factor-alpha signaling NF-κB, and inflammatory response. PPI analysis revealed five hub genes, including EGR1, FOS, FOSB, KLF2, and JUNB. The reliability of EGR1 was confirmed by validation testing, corroborating bioinformatics analysis trends. CONCLUSIONS: EGR1, FOS, FOSB, KLF2, and JUNB are intricately involved in muscle atrophy development. High EGR1 expression directly regulated these hub genes, significantly influencing postoperative muscle atrophy progression in KOA patients.
Assuntos
Artroplastia do Joelho , Proteína 1 de Resposta de Crescimento Precoce , Atrofia Muscular , Osteoartrite do Joelho , Humanos , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/etiologia , Atrofia Muscular/genética , Atrofia Muscular/patologia , Artroplastia do Joelho/efeitos adversos , Osteoartrite do Joelho/genética , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/cirurgia , Osteoartrite do Joelho/patologia , Masculino , Complicações Pós-Operatórias/metabolismo , Complicações Pós-Operatórias/genética , Complicações Pós-Operatórias/etiologia , Feminino , Mapas de Interação de Proteínas/genética , Biomarcadores/metabolismo , Expressão Gênica/genética , Biologia Computacional/métodosRESUMO
Melatonin has been reported to regulate circadian rhythms and have anti-inflammatory characteristics in various inflammatory autoimmune diseases, but its effects in diseases-associated muscle atrophy remain controversial. This study is aimed to determine the evidence of melatonin in rheumatoid arthritis (RA)-related pathological muscle atrophy. We used initially bioinformatics results to show that melatonin regulated significantly the correlation between pro-inflammation and myogenesis in RA synovial fibroblasts (RASF) and myoblasts. The conditioned medium (CM) from melatonin-treated RASF was incubated in myoblasts with growth medium and differentiated medium to investigate the markers of pro-inflammation, atrophy, and myogenesis. We found that melatonin regulated RASF CM-induced pathological muscle pro-inflammation and atrophy in myoblasts and differentiated myocytes through NF-κB signaling pathways. We also showed for the first time that miR-30c-1-3p is negatively regulated by three inflammatory cytokines in human RASF, which is associated with murine-differentiated myocytes. Importantly, oral administration with melatonin in a collagen-induced arthritis (CIA) mouse model also significantly improved arthritic swelling, hind limb grip strength as well as pathological muscle atrophy. In conclusion, our study is the first to demonstrate not only the underlying mechanism whereby melatonin decreases pro-inflammation in RA-induced pathological muscle atrophy but also increases myogenesis in myoblasts and differentiated myocytes.
Assuntos
Artrite Reumatoide , Fibroblastos , Melatonina , Músculo Esquelético , Melatonina/farmacologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Artrite Reumatoide/tratamento farmacológico , Humanos , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Animais , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/patologia , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Membrana Sinovial/efeitos dos fármacos , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Experimental/tratamento farmacológico , Masculino , Mioblastos/metabolismo , Mioblastos/efeitos dos fármacos , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Atrofia Muscular/tratamento farmacológico , Camundongos Endogâmicos DBARESUMO
Sarcopenia is characterized by accelerated muscle mass and function loss, which burdens and challenges public health worldwide. Several studies indicated that selenium deficiency is associated with sarcopenia; however, the specific mechanism remains unclear. Here, we demonstrated that selenoprotein W (SELENOW) containing selenium in the form of selenocysteine functioned in sarcopenia. SELENOW expression is up-regulated in dexamethasone (DEX)-induced muscle atrophy and age-related sarcopenia mouse models. Knockout (KO) of SELENOW profoundly aggravated the process of muscle mass loss in the two mouse models. Mechanistically, SELENOW KO suppressed the RAC1-mTOR cascade by the interaction between SELENOW and RAC1 and induced the imbalance of protein synthesis and degradation. Consistently, overexpression of SELENOW in vivo and in vitro alleviated the muscle and myotube atrophy induced by DEX. SELENOW played a role in age-related sarcopenia and regulated the genes associated with aging. Together, our study uncovered the function of SELENOW in age-related sarcopenia and provides promising evidence for the prevention and treatment of sarcopenia.
Assuntos
Camundongos Knockout , Complexo de Endopeptidases do Proteassoma , Biossíntese de Proteínas , Sarcopenia , Selenoproteína W , Ubiquitina , Animais , Complexo de Endopeptidases do Proteassoma/metabolismo , Camundongos , Sarcopenia/metabolismo , Sarcopenia/genética , Sarcopenia/patologia , Ubiquitina/metabolismo , Selenoproteína W/genética , Selenoproteína W/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/efeitos dos fármacos , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Dexametasona/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Modelos Animais de Doenças , Atrofia Muscular/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/patologia , Atrofia Muscular/induzido quimicamente , Envelhecimento/metabolismo , Masculino , Transdução de Sinais , NeuropeptídeosRESUMO
BACKGROUND: Sarcopenic obesity, which is associated with a poorer prognosis than that of sarcopenia alone, may be positively affected by soy isoflavones, known inhibitors of muscle atrophy. Herein, we hypothesize that these compounds may prevent sarcopenic obesity by upregulating the gut metabolites with anti-inflammatory effects. METHODS: To explore the effects of soy isoflavones on sarcopenic obesity and its mechanisms, we employed both in vivo and in vitro experiments. Mice were fed a high-fat, high-sucrose diet with or without soy isoflavone supplementation. Additionally, the mouse C2C12 myotube cells were treated with palmitic acid and daidzein in vitro. RESULTS: The isoflavone considerably reduced muscle atrophy and the expression of the muscle atrophy genes in the treated group compared to the control group (Fbxo32, p = 0.0012; Trim63, p < 0.0001; Foxo1, p < 0.0001; Tnfa, p = 0.1343). Elevated levels of daidzein were found in the muscles and feces of the experimental group compared to the control group (feces, p = 0.0122; muscle, p = 0.0020). The real-time PCR results demonstrated that the daidzein decreased the expression of the palmitate-induced inflammation and muscle atrophy genes in the C2C12 myotube cells (Tnfa, p = 0.0201; Il6, p = 0.0008; Fbxo32, p < 0.0001; Hdac4, p = 0.0002; Trim63, p = 0.0114; Foxo1, p < 0.0001). Additionally, it reduced the palmitate-induced protein expression related to the muscle atrophy in the C2C12 myotube cells (Foxo1, p = 0.0078; MuRF1, p = 0.0119). CONCLUSIONS: The daidzein suppressed inflammatory cytokine- and muscle atrophy-related gene expression in the C2C12 myotubes, thereby inhibiting muscle atrophy.
Assuntos
Citocinas , Isoflavonas , Atrofia Muscular , Isoflavonas/farmacologia , Animais , Camundongos , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Atrofia Muscular/prevenção & controle , Masculino , Citocinas/metabolismo , Citocinas/genética , Linhagem Celular , Camundongos Endogâmicos C57BL , Proteínas Musculares/metabolismo , Proteínas Musculares/genética , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Sarcopenia/prevenção & controle , Sarcopenia/metabolismo , Sarcopenia/tratamento farmacológico , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Dieta Hiperlipídica/efeitos adversos , Obesidade/metabolismo , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Glycine max/química , Modelos Animais de Doenças , Ácido Palmítico/farmacologiaRESUMO
BACKGROUND: This study aimed to assess the effects of enteral nutrition with different protein concentrations on muscle mass in severe pneumonia patients, providing insights for enteral nutrition practice in intensive care units (ICUs). METHODS: A total of 120 severe pneumonia patients admitted to Dazhou Central Hospital's ICU between June 1, 2022, and February 1, 2023, meeting inclusion criteria, were randomly assigned to either a high-protein group (n = 60, 1.8 g/kg/d) or a standard-protein group (n = 60, 1.2 g/kg/d). Changes in relevant indicators were monitored on days 1, 5, and 10 of ICU admission, including quadriceps and diaphragm thickness, nutritional status (prealbumin and albumin), and adverse events such as diarrhea and constipation. RESULTS: Autoregressive of order 1 model (AR(1)) analysis revealed a decrease in both quadriceps and diaphragm thickness over time in both groups. A significant group × time interaction was observed in quadriceps thickness. By day 10, compared to baseline, quadriceps thickness decreased in the high-protein (-0.315 cm [95% CI, -0.340 to -0.289]) and standard-protein (-0.429 cm [95% CI, -0.455 to -0.404]) groups. The high-protein group exhibited a lower quadriceps atrophy rate (13.97 ± 2.43%) compared to the standard-protein group (18.96 ± 2.61%), showing a significant difference (P < 0.001). No significant differences were found in diaphragmatic thickness between groups and over time. By day 10, both groups exhibited decreased diaphragmatic muscle thickness compared to baseline. The high-protein group (33.76 ± 5.09%) had a slightly lower phrenic atrophy rate compared to the standard-protein group (33.41 ± 4.53%). Both groups experienced enteral nutritional intolerance manifested as diarrhea, constipation, and other adverse events. CONCLUSION: High-protein enteral nutrition significantly improved quadriceps thickness and demonstrated good safety in severe pneumonia patients, suggesting its suitability for widespread clinical application.
Assuntos
Nutrição Enteral , Unidades de Terapia Intensiva , Pneumonia , Respiração Artificial , Humanos , Nutrição Enteral/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Respiração Artificial/métodos , Pneumonia/terapia , Idoso , Proteínas Alimentares/administração & dosagem , Estado Nutricional , Diafragma , Músculo Quadríceps , Atrofia Muscular/prevenção & controle , Atrofia Muscular/etiologia , Dieta Rica em Proteínas/métodosRESUMO
Androgens exert their effects primarily by binding to the androgen receptor (AR), a ligand-dependent nuclear receptor. While androgens have anabolic effects on skeletal muscle, previous studies reported that AR functions in myofibers to regulate skeletal muscle quality, rather than skeletal muscle mass. Therefore, the anabolic effects of androgens are exerted via nonmyofiber cells. In this context, the cellular and molecular mechanisms of AR in mesenchymal progenitors, which play a crucial role in maintaining skeletal muscle homeostasis, remain largely unknown. In this study, we demonstrated expression of AR in mesenchymal progenitors and found that targeted AR ablation in mesenchymal progenitors reduced limb muscle mass in mature adult, but not young or aged, male mice, although fatty infiltration of muscle was not affected. The absence of AR in mesenchymal progenitors led to remarkable perineal muscle hypotrophy, regardless of age, due to abnormal regulation of transcripts associated with cell death and extracellular matrix organization. Additionally, we revealed that AR in mesenchymal progenitors regulates the expression of insulin-like growth factor 1 (Igf1) and that IGF1 administration prevents perineal muscle atrophy in a paracrine manner. These findings indicate that the anabolic effects of androgens regulate skeletal muscle mass via, at least in part, AR signaling in mesenchymal progenitors.
Assuntos
Fator de Crescimento Insulin-Like I , Células-Tronco Mesenquimais , Músculo Esquelético , Receptores Androgênicos , Animais , Masculino , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genética , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/genética , Músculo Esquelético/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Camundongos , Atrofia Muscular/metabolismo , Atrofia Muscular/patologiaRESUMO
Skeletal muscle dysfunction in critical illnesses leaves survivors weak and functionally impaired. Macrophages infiltrate muscles; however, their functional role is unclear. We aim to examine muscle leukocyte composition and the effect of macrophages on muscle mass and function in the murine acute lung injury (ALI)-associated skeletal muscle wasting model. We performed flow cytometry of hindlimb muscle to identify myeloid cells pre-injury and time points up to 29 days after intratracheal lipopolysaccharide ALI. We evaluated muscle force and morphometrics after systemic and intramuscular clodronate-induced macrophage depletions between peak lung injury and recovery (day 5-6) versus vehicle control. Our results show muscle leukocytes changed over ALI course with day 3 neutrophil infiltration (130.5 ± 95.6cells/mg control to 236.3 ± 70.6cells/mg day 3) and increased day 10 monocyte abundance (5.0 ± 3.4%CD45+CD11b+ day 3 to 14.0 ± 2.6%CD45+CD11b+ day 10, p = 0.005). Although macrophage count did not significantly change, pro-inflammatory (27.0 ± 7.2% day 3 to 7.2 ± 3.8% day 10, p = 0.02) and anti-inflammatory (30.5 ± 11.1% day 3 to 52.7 ± 9.7% day 10, p = 0.09) surface marker expression changed over the course of ALI. Macrophage depletion following peak lung injury increased muscle mass and force generation. These data suggest muscle macrophages beyond peak lung injury limit or delay muscle recovery. Targeting macrophages could augment muscle recovery following lung injury.
Assuntos
Lesão Pulmonar Aguda , Macrófagos , Camundongos Endogâmicos C57BL , Músculo Esquelético , Animais , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/fisiopatologia , Lesão Pulmonar Aguda/metabolismo , Camundongos , Macrófagos/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/lesões , Masculino , Atrofia Muscular/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Lipopolissacarídeos/toxicidadeRESUMO
BACKGROUND: It is plausible that supplementation with specific amino acids or metabolites could attenuate skeletal muscle wasting during critical illness. The aim of this systematic review was to explore if amino acids or their derivatives impact skeletal muscle wastage in critically ill adults. METHODS: Four databases were systematically searched to identify randomised control trials which delivered enteral supplemental amino acids, or their metabolites compared with placebo, standard care or no intervention, to critically ill patients and reported outcomes of skeletal muscle mass, plasma amino acids, nitrogen balance, or muscle strength. Two authors independently completed screening, data extraction, and risk of bias assessment using the Cochrane Risk of Bias 2 Tool. A meta-analysis was planned but heterogeneity in the type of intervention used and outcome assessment precluded this. Therefore, data were synthesised using vote counting. RESULTS: Thirty randomised control trials, comprising 1976 patients were included. The most frequently studied interventional amino acid or metabolite was glutamine (n = 12 trials), a combination (n = 9), arginine (n = 6), ß-hydroxy ß-methylbutyrate (HMB) (n = 2) or ornithine (n = 1). Six trials (including 284 participants) measured skeletal muscle following supplementation, four of which used HMB alone or in combination as the intervention. Of these, one trial observed an attenuation of muscle wasting with a combination of amino acids, one observed an exacerbation of muscle wasting with HMB, three trials observed no impact on muscle wasting with HMB or a combination of amino acids and one trial reported no information. CONCLUSION: Six trials have investigated the effect of enteral amino acid or amino acid metabolite supplementation on muscle mass in critically ill. Heterogeneity of interventions, outcome assessments and direction of effects limits the certainty regarding the effect of supplemental amino acids, or their metabolites, on skeletal muscle wasting during critical illness. The trial protocol is registered on PROSPERO (CRD42021275989).
Assuntos
Aminoácidos , Estado Terminal , Suplementos Nutricionais , Músculo Esquelético , Atrofia Muscular , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Estado Terminal/terapia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Aminoácidos/administração & dosagem , Atrofia Muscular/tratamento farmacológico , Nutrição Enteral/métodos , ValeratosRESUMO
ABSTRACT: Background: Sepsis commonly leads to skeletal muscle atrophy, characterized by substantial muscle weakness and degeneration, ultimately contributing to an adverse prognosis. Studies have shown that programmed cell death is an important factor in the progression of muscle loss in sepsis. However, the precise role and mechanism of pyroptosis in skeletal muscle atrophy are not yet fully comprehended. Therefore, we aimed to examine the role and mechanism of action of the pyroptosis effector protein GSDMD in recognized cellular and mouse models of sepsis. Methods: The levels of GSDMD and N-GSDMD in skeletal muscle were evaluated 2, 4, and 8 days after cecal ligation and puncture. Sepsis was produced in mice that lacked the Gsdmd gene (Gsdmd knockout) and in mice with the normal Gsdmd gene (wild-type) using a procedure called cecal ligation and puncture. The degree of muscular atrophy in the gastrocnemius and tibialis anterior muscles was assessed 72 h after surgery in the septic mouse model. In addition, the architecture of skeletal muscles, protein expression, and markers associated with pathways leading to muscle atrophy were examined in mice from various groups 72 h after surgery. The in vitro investigations entailed the use of siRNA to suppress Gsdmd expression in C2C12 cells, followed by stimulation of these cells with lipopolysaccharide to evaluate the impact of Gsdmd downregulation on muscle atrophy and the related signaling cascades. Results: This study has demonstrated that the GSDMD protein, known as the "executive" protein of pyroptosis, plays a crucial role in the advancement of skeletal muscle atrophy in septic mice. The expression of N-GSDMD in the skeletal muscle of septic mice was markedly higher compared with the control group. The Gsdmd knockout mice exhibited notable enhancements in survival, muscle strength, and body weight compared with the septic mice. Deletion of the Gsdmd gene reduced muscular wasting in the gastrocnemius and tibialis anterior muscles caused by sepsis. Studies conducted in living organisms ( in vivo ) and in laboratory conditions ( in vitro ) have shown that the absence of the Gsdmd gene decreases indicators of muscle loss associated with sepsis by blocking the IL18/AMPK signaling pathway. Conclusion: The results of this study demonstrate that the lack of Gsdmd has a beneficial effect on septic skeletal muscle atrophy by reducing the activation of IL18/AMPK and inhibiting the ubiquitin-proteasome system and autophagy pathways. Therefore, our research provides vital insights into the role of pyroptosis in sepsis-related skeletal muscle wasting, which could potentially lead to the development of therapeutic and interventional approaches for preventing septic skeletal muscle atrophy.
Assuntos
Camundongos Knockout , Músculo Esquelético , Atrofia Muscular , Proteínas de Ligação a Fosfato , Sepse , Transdução de Sinais , Animais , Sepse/metabolismo , Camundongos , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Proteínas de Ligação a Fosfato/metabolismo , Masculino , Proteínas Quinases Ativadas por AMP/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Animais de Doenças , Piroptose , Camundongos Endogâmicos C57BL , GasderminasRESUMO
Eugenol (EU), the major constituent of clove oil, possesses a range of bioactivities. Here, the therapeutic potential of oral EU for mitigating skeletal muscle wasting was investigated in a long-term high-fat diet (HFD)-induced obese mice model. Male C57BL/6J mice, aged six weeks, were assigned to either a chow or a HFD for 10 weeks. Subsequently, the weight-matched HFD-fed mice were allocated into two groups, receiving either 0.2% (w/w) EU supplementation or no supplementation for 14 weeks. Our findings revealed that EU supplementation enhanced grip strength, increased hanging duration, and augmented skeletal muscle mass. RNA sequencing analysis demonstrated that EU modified the gastrocnemius muscle transcriptomic profile, and the differentially expressed genes between HFD and EU groups were mainly involved in the HIF-1 signaling pathway, TCR signaling pathway, and cGMP-PKG signaling pathway, which is well-known to be related to skeletal muscle health. Untargeted metabolomics analysis further showed that EU supplementation significantly altered the nucleotide metabolism in the GAS muscle. Analysis of 16S rRNA sequencing demonstrated that EU supplementation ameliorated the gut dysbiosis caused by HFD. The alterations in gut microbiota induced by EU were significantly correlated with indexes related to skeletal muscle atrophy. The multi-omics analysis presented the robust interaction among the skeletal muscle transcriptome, metabolome, and gut microbiome altered by EU supplementation. Our results highlight the potential of EU in skeletal muscle atrophy intervention as a functional dietary supplement.
Assuntos
Dieta Hiperlipídica , Eugenol , Camundongos Endogâmicos C57BL , Músculo Esquelético , Atrofia Muscular , Animais , Masculino , Camundongos , Dieta Hiperlipídica/efeitos adversos , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Eugenol/farmacologia , Suplementos Nutricionais , Microbioma Gastrointestinal/efeitos dos fármacos , Transcriptoma , Metabolômica , MultiômicaRESUMO
BACKGROUND: Bed rest during pregnancy can lead to reduced physical activity, impairing lower limb venous blood flow and increasing the risk of deep vein thrombosis (DVT) and muscle atrophy. We investigated the clinical efficacy of foam rolling intervention (FRI) in enhancing lower limb venous blood flow, mitigating the risk of DVT and muscle atrophy in pregnant women on bed rest. METHODS: This single-blind, randomised controlled trial enrolled 86 pregnant women with long-term bed rest for foetal protection (≥ 7 days), gestational age ≥ 20 weeks, and maternal age < 40 years. Participants were randomly assigned to a control or experimental group using a random number table. The control group received standard care, whereas the experimental group underwent FRI. Researchers and statisticians were aware of the treatment groups, however, the participants were blinded. Lower limb blood flow velocity, D-dimer levels, incidence of DVT, and the extent of lower limb muscle atrophy were assessed in both groups at baseline and post-intervention (day 7). To account for a 5% attrition rate and potential sampling error, the estimated sample size for each experimental and control group was 40. RESULTS: Before the intervention, no significant differences were observed between the experimental and control groups in peak blood flow, mean flow velocity, D-dimer values, or leg circumference (P > 0.05), however, the peak blood velocities of the popliteal veins were significantly higher in the control group (P = 0.031). On the seventh day post-intervention, the experimental group had significantly higher mean and peak blood velocities in femoral and popliteal veins, significantly (P < 0.05), lower mean D-dimer levels (P = 0.035), and a significantly smaller reduction in thigh and calf circumference (P < 0.001). Consequently, the rate of thigh muscle atrophy was significantly slower in the experimental group (P = 0.011). CONCLUSIONS: FRI is an effective intervention for improving lower limb venous blood flow, mitigating the risk of DVT and muscle atrophy in pregnant women on bed rest. TRIAL REGISTRATION: This trial was retrospectively registered with the Chinese Clinical Trial Registry on June 18, 2024 (registration number: ChiCTR2400085770).
Assuntos
Repouso em Cama , Estudos de Viabilidade , Extremidade Inferior , Atrofia Muscular , Trombose Venosa , Humanos , Feminino , Gravidez , Adulto , Método Simples-Cego , Trombose Venosa/prevenção & controle , Extremidade Inferior/irrigação sanguínea , Atrofia Muscular/prevenção & controle , Velocidade do Fluxo Sanguíneo , Produtos de Degradação da Fibrina e do Fibrinogênio/análiseRESUMO
Chronic kidney disease (CKD) is associated with various pathologic changes, including elevations in serum phosphate levels (hyperphosphatemia), vascular calcification, and skeletal muscle atrophy. Elevated phosphate can damage vascular smooth muscle cells and cause vascular calcification. Here, we determined whether high phosphate can also affect skeletal muscle cells and whether hyperphosphatemia, in the context of CKD or by itself, is associated with skeletal muscle atrophy. As models of hyperphosphatemia with CKD, we studied mice receiving an adenine-rich diet for 14 weeks and mice with deletion of Collagen 4a3 (Col4a3-/-). As models of hyperphosphatemia without CKD, we analyzed mice receiving a high-phosphate diet for three and six months as well as a genetic model for klotho deficiency (kl/kl). We found that adenine, Col4a3-/-, and kl/kl mice have reduced skeletal muscle mass and function and develop atrophy. Mice on a high-phosphate diet for six months also had lower skeletal muscle mass and function but no significant signs of atrophy, indicating less severe damage compared with the other three models. To determine the potential direct actions of phosphate on skeletal muscle, we cultured primary mouse myotubes in high phosphate concentrations, and we detected the induction of atrophy. We conclude that in experimental mouse models, hyperphosphatemia is sufficient to induce skeletal muscle atrophy and that, among various other factors, elevated phosphate levels might contribute to skeletal muscle injury in CKD.
Assuntos
Hiperfosfatemia , Músculo Esquelético , Atrofia Muscular , Fosfatos , Animais , Hiperfosfatemia/patologia , Camundongos , Atrofia Muscular/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/etiologia , Músculo Esquelético/patologia , Músculo Esquelético/metabolismo , Fosfatos/sangue , Fosfatos/metabolismo , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/metabolismo , Modelos Animais de Doenças , Camundongos Knockout , Masculino , Colágeno Tipo IV/metabolismo , Colágeno Tipo IV/genética , Camundongos Endogâmicos C57BL , Proteínas Klotho/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologiaRESUMO
Pro-inflammatory cytokines in muscle play a pivotal role in physiological responses and in the pathophysiology of inflammatory disease and muscle atrophy. Lactobacillus delbrueckii (LD), as a kind of probiotics, has inhibitory effects on pro-inflammatory cytokines associated with various inflammatory diseases. This study was conducted to explore the effect of dietary LD on the lipopolysaccharide (LPS)-induced muscle inflammation and atrophy in piglets and to elucidate the underlying mechanism. A total of 36 weaned piglets (Duroc × Landrace × Large Yorkshire) were allotted into three groups with six replicates (pens) of two piglets: (1) Nonchallenged control; (2) LPS-challenged (LPS); (3) 0.2% LD diet and LPS-challenged (LD+LPS). On d 29, the piglets were injected intraperitoneally with LPS or sterilized saline, respectively. All piglets were slaughtered at 4 h after LPS or saline injection, the blood and muscle samples were collected for further analysis. Our results showed that dietary supplementation of LD significantly attenuated LPS-induced production of pro-inflammatory cytokines IL-6 and TNF-α in both serum and muscle of the piglets. Concomitantly, pretreating the piglets with LD also clearly inhibited LPS-induced nuclear translocation of NF-κB p65 subunits in the muscle, which correlated with the anti-inflammatory effects of LD on the muscle of piglets. Meanwhile, LPS-induced muscle atrophy, indicated by a higher expression of muscle atrophy F-box, muscle RING finger protein (MuRF1), forkhead box O 1, and autophagy-related protein 5 (ATG5) at the transcriptional level, whereas pretreatment with LD led to inhibition of these upregulations, particularly genes for MuRF1 and ATG5. Moreover, LPS-induced mRNA expression of endoplasmic reticulum stress markers, such as eukaryotic translational initiation factor 2α (eIF-2α) was suppressed by pretreatment with LD, which was accompanied by a decrease in the protein expression levels of IRE1α and GRP78. Additionally, LD significantly prevented muscle cell apoptotic death induced by LPS. Taken together, our data indicate that the anti-inflammatory effect of LD supply on muscle atrophy of piglets could be likely regulated by inhibiting the secretion of pro-inflammatory cytokines through the inactivation of the ER stress/NF-κB singling pathway, along with the reduction in protein degradation.
Assuntos
Estresse do Retículo Endoplasmático , Lactobacillus delbrueckii , Lipopolissacarídeos , Atrofia Muscular , Animais , Lipopolissacarídeos/toxicidade , Suínos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/metabolismo , Atrofia Muscular/prevenção & controle , Atrofia Muscular/patologia , Desmame , Proteólise , Probióticos/farmacologia , Inflamação/metabolismo , Miosite/induzido quimicamente , Miosite/metabolismo , Miosite/patologia , Citocinas/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/efeitos dos fármacosRESUMO
We report a case of 32-year-old man with progressive, asymmetric, proximal weakness of both upper limbs for 14 months. On examination, he had gynecomastia and wasting and weakness of his deltoid, supraspinatus, infraspinatus, pectoralis, biceps, and triceps muscles, along with sensory loss of his left C5-C8 dermatomes. Deep tendon reflexes were depressed in the upper limbs and normal in the lower limbs. There was a history of a road traffic accident 2 years ago without any neurologic deficits. We discuss the clinical approach, differential diagnosis, investigations, and treatment options for bibrachial weakness.
Assuntos
Debilidade Muscular , Humanos , Masculino , Adulto , Debilidade Muscular/etiologia , Debilidade Muscular/diagnóstico , Raciocínio Clínico , Atrofia Muscular/diagnóstico , Diagnóstico Diferencial , Ombro/fisiopatologia , Ombro/diagnóstico por imagemRESUMO
Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked disorder that causes severe neurological damage, for which there is no effective treatment. AHDS is due to inactivating mutations in the thyroid hormone transporter MCT8 that impair the entry of thyroid hormones into the brain, resulting in cerebral hypothyroidism. However, the pathophysiology of AHDS is still not fully understood and this is essential to develop therapeutic strategies. Based on evidence suggesting that thyroid hormone deficit leads to alterations in astroglial cells, including gliosis, in this work, we have evaluated astroglial impairments in MCT8 deficiency by means of magnetic resonance imaging, histological, ultrastructural, and immunohistochemical techniques, and by mining available RNA sequencing outputs. Apparent diffusion coefficient (ADC) imaging values obtained from magnetic resonance imaging showed changes indicative of alterations in brain cytoarchitecture in MCT8-deficient patients (n = 11) compared to control subjects (n = 11). Astroglial alterations were confirmed by immunohistochemistry against astroglial markers in autopsy brain samples of an 11-year-old and a 30th gestational week MCT8-deficient subjects in comparison to brain samples from control subjects at similar ages. These findings were validated and further explored in a mouse model of AHDS. Our findings confirm changes in all the astroglial populations of the cerebral cortex in MCT8 deficiency that impact astrocytic metabolic and mitochondrial cellular respiration functions. These impairments arise early in brain development and persist at adult stages, revealing an abnormal distribution, density, morphology of cortical astrocytes, along with altered transcriptome, compatible with an astrogliosis-like phenotype at adult stages. We conclude that astrocytes are potential novel therapeutic targets in AHDS, and we propose ADC imaging as a tool to monitor the progression of neurological impairments and potential effects of treatments in MCT8 deficiency.
Assuntos
Astrócitos , Encéfalo , Transportadores de Ácidos Monocarboxílicos , Hipotonia Muscular , Simportadores , Hormônios Tireóideos , Astrócitos/metabolismo , Astrócitos/patologia , Animais , Camundongos , Humanos , Transportadores de Ácidos Monocarboxílicos/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Masculino , Encéfalo/metabolismo , Encéfalo/patologia , Hormônios Tireóideos/metabolismo , Criança , Simportadores/metabolismo , Simportadores/genética , Hipotonia Muscular/metabolismo , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/metabolismo , Deficiência Intelectual Ligada ao Cromossomo X/patologia , Feminino , Adulto , Imageamento por Ressonância Magnética/métodos , Atrofia MuscularRESUMO
BACKGROUND: Dysferlin-deficient limb-girdle muscular dystrophy type 2B (Dysf) mice are notorious for their mild phenotype. Raising plasma total cholesterol (CHOL) via apolipoprotein E (ApoE) knockout (KO) drastically exacerbates muscle wasting in Dysf mice. However, dysferlinopathic patients have abnormally reduced plasma high-density lipoprotein cholesterol (HDL-C) levels. The current study aimed to determine whether HDL-C lowering can exacerbate the mild phenotype of dysferlin-null mice. METHODS: Human cholesteryl ester transfer protein (CETP), a plasma lipid transfer protein not found in mice that reduces HDL-C, and/or its optimal adapter protein human apolipoprotein B (ApoB), were overexpressed in Dysf mice. Mice received a 2% cholesterol diet from 2 months of age and characterized through ambulatory and hanging functional tests, plasma analyses, and muscle histology. RESULTS: CETP/ApoB expression in Dysf mice caused reduced HDL-C (54.5%) and elevated ratio of CHOL/HDL-C (181.3%) compared to control Dysf mice in plasma, but without raising CHOL. Compared to the severe muscle pathology found in high CHOL Dysf/ApoE double knockout mice, Dysf/CETP/ApoB mice did not show significant changes in ambulation, hanging capacity, increases in damaged area, collagen deposition, or decreases in cross-sectional area and healthy myofibre coverage. CONCLUSIONS: CETP/ApoB over-expression in Dysf mice decreases HDL-C without increasing CHOL or exacerbating muscle pathology. High CHOL or nonHDL-C caused by ApoE KO, rather than low HDL-C, likely lead to rodent muscular dystrophy phenotype humanization.
Assuntos
Apolipoproteínas E , Proteínas de Transferência de Ésteres de Colesterol , HDL-Colesterol , Disferlina , Camundongos Knockout , Distrofia Muscular do Cíngulo dos Membros , Animais , Humanos , Masculino , Camundongos , Apolipoproteínas B/sangue , Apolipoproteínas B/genética , Apolipoproteínas E/genética , Apolipoproteínas E/deficiência , Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/deficiência , HDL-Colesterol/sangue , Modelos Animais de Doenças , Disferlina/genética , Disferlina/deficiência , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/genética , Atrofia Muscular/patologia , Atrofia Muscular/metabolismo , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/patologiaRESUMO
We examined how resistance exercise (RE), cycling exercise and disuse atrophy affect myosin heavy chain (MyHC) protein fragmentation. The 1boutRE study involved younger men (n = 8; 5 ± 2 years of RE experience) performing a lower body RE bout with vastus lateralis (VL) biopsies being obtained prior to and acutely following exercise. With the 10weekRT study, VL biopsies were obtained in 36 younger adults before and 24 h after their first/naïve RE bout. Participants also engaged in 10 weeks of resistance training and donated VL biopsies before and 24 h after their last RE bout. VL biopsies were also examined in an acute cycling study (n = 7) and a study involving 2 weeks of leg immobilization (n = 20). In the 1boutRE study, fragmentation of all MyHC isoforms (MyHCTotal) increased 3 h post-RE (â¼200%, P = 0.018) and returned to pre-exercise levels by 6 h post-RE. Interestingly, a greater magnitude increase in MyHC type IIa versus I isoform fragmentation occurred 3 h post-RE (8.6 ± 6.3-fold vs. 2.1 ± 0.7-fold, P = 0.018). In 10weekRT participants, the first/naïve and last RE bouts increased MyHCTotal fragmentation 24 h post-RE (+65% and +36%, P < 0.001); however, the last RE bout response was attenuated compared to the first bout (P = 0.045). Although cycling exercise did not alter MyHCTotal fragmentation, â¼8% VL atrophy with 2 weeks of leg immobilization increased MyHCTotal fragmentation (â¼108%, P < 0.001). Mechanistic C2C12 myotube experiments indicated that MyHCTotal fragmentation is likely due to calpain proteases. In summary, RE and disuse atrophy increase MyHC protein fragmentation. Research into how ageing and disease-associated muscle atrophy affect these outcomes is needed. HIGHLIGHTS: What is the central question of this study? How different exercise stressors and disuse affect skeletal muscle myosin heavy chain fragmentation. What is the main finding and its importance? This investigation is the first to demonstrate that resistance exercise and disuse atrophy lead to skeletal muscle myosin heavy chain protein fragmentation in humans. Mechanistic in vitro experiments provide additional evidence that MyHC fragmentation occurs through calpain proteases.
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Músculo Esquelético , Transtornos Musculares Atróficos , Cadeias Pesadas de Miosina , Proteólise , Treinamento Resistido , Humanos , Treinamento Resistido/métodos , Cadeias Pesadas de Miosina/metabolismo , Masculino , Transtornos Musculares Atróficos/metabolismo , Adulto , Músculo Esquelético/metabolismo , Adulto Jovem , Biomarcadores/metabolismo , Exercício Físico/fisiologia , Músculo Quadríceps/metabolismo , Músculo Quadríceps/patologia , Isoformas de Proteínas/metabolismo , Atrofia Muscular/metabolismoRESUMO
BACKGROUND: Physical inactivity and subsequent muscle atrophy are highly prevalent in neurocritical care and are recognized as key mechanisms underlying intensive care unit acquired weakness (ICUAW). The lack of quantifiable biomarkers for inactivity complicates the assessment of its relative importance compared to other conditions under the syndromic diagnosis of ICUAW. We hypothesize that active movement, as opposed to passive movement without active patient participation, can serve as a valid proxy for activity and may help predict muscle atrophy. To test this hypothesis, we utilized non-invasive, body-fixed accelerometers to compute measures of active movement and subsequently developed a machine learning model to predict muscle atrophy. METHODS: This study was conducted as a single-center, prospective, observational cohort study as part of the MINCE registry (metabolism and nutrition in neurointensive care, DRKS-ID: DRKS00031472). Atrophy of rectus femoris muscle (RFM) relative to baseline (day 0) was evaluated at days 3, 7 and 10 after intensive care unit (ICU) admission and served as the dependent variable in a generalized linear mixed model with Least Absolute Shrinkage and Selection Operator regularization and nested-cross validation. RESULTS: Out of 407 patients screened, 53 patients (age: 59.2 years (SD 15.9), 31 (58.5%) male) with a total of 91 available accelerometer datasets were enrolled. RFM thickness changed - 19.5% (SD 12.0) by day 10. Out of 12 demographic, clinical, nutritional and accelerometer-derived variables, baseline RFM muscle mass (beta - 5.1, 95% CI - 7.9 to - 3.8) and proportion of active movement (% activity) (beta 1.6, 95% CI 0.1 to 4.9) were selected as significant predictors of muscle atrophy. Including movement features into the prediction model substantially improved performance on an unseen test data set (including movement features: R2 = 79%; excluding movement features: R2 = 55%). CONCLUSION: Active movement, as measured with thigh-fixed accelerometers, is a key risk factor for muscle atrophy in neurocritical care patients. Quantifiable biomarkers reflecting the level of activity can support more precise phenotyping of ICUAW and may direct tailored interventions to support activity in the ICU. Studies addressing the external validity of these findings beyond the neurointensive care unit are warranted. TRIAL REGISTRATION: DRKS00031472, retrospectively registered on 13.03.2023.
Assuntos
Acelerometria , Atrofia Muscular , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Acelerometria/métodos , Estudos de Coortes , Cuidados Críticos/métodos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Movimento/fisiologia , Atrofia Muscular/diagnóstico , Atrofia Muscular/epidemiologia , Atrofia Muscular/etiologia , Atrofia Muscular/fisiopatologia , Estudos ProspectivosRESUMO
BACKGROUND: Knee osteoarthritis (KOA) is a very common musculoskeletal disorder, and patients with KOA often exhibit significant quadriceps femoris muscle atrophy. It is well established that curcumin (CUR) exerts protective effects on skeletal muscle. However, the efficacy of CUR in treating KOA-induced quadriceps femoris muscle atrophy and its underlying mechanisms remain uncertain. In this study, we employed network pharmacology to investigate the mechanism by which CUR promotes regenerative repair of the quadriceps femoris muscle in rats with KOA. METHODS: The potential targets of CUR were obtained from Swiss Target Prediction. The targets of skeletal muscle regeneration were identified from GeneCard and OMIM. A Venn diagram was generated to visualize the intersection of CUR targets and skeletal muscle regeneration targets, and the core targets were identified using STRING. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were conducted using DAVID. Finally, the network pharmacology results were further validated by establishing a KOA rat model using the Hulth method. RESULTS: Network pharmacology analysis and molecular docking results revealed that CUR affects skeletal muscle regeneration through multiple targets and pathways. In vivo experimental results were validated by demonstrating that KOA causes atrophy and induces apoptosis in the quadriceps femoris muscle. Furthermore, CUR was shown to inhibit apoptosis in the quadriceps femoris muscle by regulating STAT3 and FOS, as well as the PI3K/AKT signaling pathway. CONCLUSIONS: Our study revealed the apoptosis-inhibiting effects of CUR and its underlying mechanisms. Consequently, CUR has the potential to improve quadriceps femoris muscle atrophy caused by KOA.