RESUMO

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/métodos

RESUMO

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 DBA

RESUMO

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 , Neuropeptídeos

RESUMO

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/farmacologia

RESUMO

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/patologia

RESUMO

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/toxicidade

RESUMO

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 , Gasderminas

RESUMO

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 , Multiômica

RESUMO

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/patologia

RESUMO

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 fármacos

RESUMO

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/patologia

RESUMO

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 (∼200%, 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, ∼8% VL atrophy with 2 weeks of leg immobilization increased MyHCTotal fragmentation (∼108%, 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.

Assuntos

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/metabolismo

RESUMO

Muscle wasting is a universal hallmark of aging which is displayed by a wide range of organisms, although the causes and mechanisms of this phenomenon are not fully understood. We used Drosophila to characterize the phenomenon of spontaneous muscle fiber degeneration (SMFD) during aging. We found that SMFD occurs across diverse types of somatic muscles, progresses with chronological age, and positively correlates with functional muscle decline. Data from vital dyes and morphological markers imply that degenerative fibers most likely die by necrosis. Mechanistically, SMFD is driven by the damage resulting from muscle contractions, and the nervous system may play a significant role in this process. Our quantitative model of SMFD assessment can be useful in identifying and validating novel genetic factors that influence aging-related muscle wasting.

Assuntos

Envelhecimento , Estresse Mecânico , Animais , Envelhecimento/genética , Envelhecimento/fisiologia , Drosophila melanogaster/genética , Atrofia Muscular/genética , Atrofia Muscular/patologia , Atrofia Muscular/fisiopatologia , Atrofia Muscular/metabolismo , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/metabolismo , Contração Muscular

RESUMO

This study investigated the anti-sarcopenic effect of fermented Tenebrio molitor larvae (mealworms) extract (FME) in both dexamethasone (DEX)-treated C2C12 cells and mice. FME (100 µg/mL) increased the diameter of myotubes and inhibited the gene and protein expression of atrogin-1 compared to DEX- or non-fermented mealworms extract (ME)-treated C2C12 cells. Male C57BL/6N mice were divided into five groups: Normal Control (NC), DEX (10 mg/kg, intraperitoneal), and three groups of DEX+FME (100, 200, or 500 mg FME/kg/day, oral) for two weeks. FME at doses of 200 and 500 mg/kg effectively improved grip strength when compared to the DEX group. Histological analysis of the quadriceps muscle showed a larger muscle fiber size in the DEX+FME groups compared to DEX group. FME (200 and 500 mg/kg) significantly increased cross-sectional area of the muscle fiber compared to DEX group. FME (500 mg/kg) significantly decreased the ubiquitin, atrogin-1 and MuRF-1 protein levels, and increased levels of MHC and MyoG in DEX-treated mice. The puromycin labeling assay revealed that FME increased protein synthesis in DEX-induced muscle atrophy. The FME treatment demonstrated significant upregulation in phosphorylation levels, including mTOR, FoxO3α, Akt, and PI3K compared to DEX group. In conclusion, FME inhibited the increase in proteins associated with muscle atrophy, including, atrogin-1 and MuRF-1, by regulating the PI3K-Akt-FoxO3α pathway. FME improved the PI3K-Akt-mTOR signaling pathway, which was reduced by DEX. This study suggests that FME has the potential for use in sarcopenia therapy, possibly serving as a natural agent that counteracts the negative effects of DEX on muscle tissue.

Assuntos

Dexametasona , Proteína Forkhead Box O3 , Larva , Atrofia Muscular , Transdução de Sinais , Tenebrio , Animais , Masculino , Camundongos , Linhagem Celular , Dexametasona/farmacologia , Fermentação , Proteína Forkhead Box O3/metabolismo , Larva/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/induzido quimicamente , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tenebrio/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo

RESUMO

Oxidative stress contributes to the loss of skeletal muscle mass and function in cancer cachexia. However, this outcome may be mitigated by an improved endogenous antioxidant defence system. Here, using the well-established oxidative stress-inducing muscle atrophy model of Lewis lung carcinoma (LLC) in 13-week-old male C57BL/6J mice, we demonstrate that extracellular superoxide dismutase (EcSOD) levels increase in the cachexia-prone extensor digitorum longus muscle. LLC transplantation significantly increased interleukin-1ß (IL-1ß) expression and release from extensor digitorum longus muscle fibres. Moreover, IL-1ß treatment of C2C12 myotubes increased NBR1, p62 phosphorylation at Ser351, Nrf2 nuclear translocation and EcSOD protein expression. Additional studies in vivo indicated that intramuscular IL-1ß injection is sufficient to stimulate EcSOD expression, which is prevented by muscle-specific knockout of p62 and Nrf2 (i.e. in p62 skmKO and Nrf2 skmKO mice, respectively). Finally, since an increase in circulating IL-1ß may lead to unwanted outcomes, we demonstrate that targeting this pathway at p62 is sufficient to drive muscle EcSOD expression in an Nrf2-dependent manner. In summary, cancer cachexia increases EcSOD expression in extensor digitorum longus muscle via muscle-derived IL-1ß-induced upregulation of p62 phosphorylation and Nrf2 activation. These findings provide further mechanistic evidence for the therapeutic potential of p62 and Nrf2 to mitigate cancer cachexia-induced muscle atrophy. KEY POINTS: Oxidative stress plays an important role in muscle atrophy during cancer cachexia. EcSOD, which mitigates muscle loss during oxidative stress, is upregulated in 13-week-old male C57BL/6J mice of extensor digitorum longus muscles during cancer cachexia. Using mouse and cellular models, we demonstrate that cancer cachexia promotes muscle EcSOD protein expression via muscle-derived IL-1ß-dependent stimulation of the NBR1-p62-Nrf2 signalling pathway. These results provide further evidence for the potential therapeutic targeting of the NBR1-p62-Nrf2 signalling pathway downstream of IL-1ß to mitigate cancer cachexia-induced muscle atrophy.

Assuntos

Caquexia , Interleucina-1beta , Camundongos Endogâmicos C57BL , Músculo Esquelético , Fator 2 Relacionado a NF-E2 , Transdução de Sinais , Superóxido Dismutase , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Caquexia/metabolismo , Caquexia/etiologia , Caquexia/genética , Masculino , Interleucina-1beta/metabolismo , Músculo Esquelético/metabolismo , Camundongos , Superóxido Dismutase/metabolismo , Superóxido Dismutase/genética , Proteína Sequestossoma-1/metabolismo , Proteína Sequestossoma-1/genética , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/complicações , Carcinoma Pulmonar de Lewis/genética , Atrofia Muscular/metabolismo , Atrofia Muscular/etiologia , Atrofia Muscular/genética , Camundongos Knockout , Estresse Oxidativo

RESUMO

Chikungunya (CHIKV) and Mayaro (MAYV) viruses are arthritogenic alphaviruses that promote an incapacitating and long-lasting inflammatory muscle-articular disease. Despite studies pointing out the importance of skeletal muscle (SkM) in viral pathogenesis, the long-term consequences on its physiology and the mechanism of persistence of symptoms are still poorly understood. Combining molecular, morphological, nuclear magnetic resonance imaging, and histological analysis, we conduct a temporal investigation of CHIKV and MAYV replication in a wild-type mice model, focusing on the impact on SkM composition, structure, and repair in the acute and late phases of infection. We found that viral replication and induced inflammation promote a rapid loss of muscle mass and reduction in fiber cross-sectional area by upregulation of muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin-1 expression, both key regulators of SkM fibers atrophy. Despite a reduction in inflammation and clearance of infectious viral particles, SkM atrophy persists until 30 days post-infection. The genomic CHIKV and MAYV RNAs were still detected in SkM in the late phase, along with the upregulation of chemokines and anti-inflammatory cytokine expression. In agreement with the involvement of inflammatory mediators on induced atrophy, the neutralization of TNF and a reduction in oxidative stress using monomethyl fumarate, an agonist of Nrf2, decreases atrogen expression and atrophic fibers while increasing weight gain in treated mice. These data indicate that arthritogenic alphavirus infection could chronically impact body SkM composition and also harm repair machinery, contributing to a better understanding of mechanisms of arthritogenic alphavirus pathogenesis and with a description of potentially new targets of therapeutic intervention.

Assuntos

Vírus Chikungunya , Músculo Esquelético , Atrofia Muscular , Estresse Oxidativo , Animais , Atrofia Muscular/virologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Camundongos , Músculo Esquelético/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/virologia , Febre de Chikungunya/patologia , Febre de Chikungunya/virologia , Febre de Chikungunya/metabolismo , Inflamação/patologia , Inflamação/metabolismo , Inflamação/virologia , Proteínas Musculares/metabolismo , Proteínas Musculares/genética , Replicação Viral , Camundongos Endogâmicos C57BL , Proteínas Ligases SKP Culina F-Box/metabolismo , Proteínas Ligases SKP Culina F-Box/genética , Infecções por Alphavirus/virologia , Infecções por Alphavirus/patologia , Infecções por Alphavirus/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Proteínas com Motivo Tripartido/genética , Modelos Animais de Doenças , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética

RESUMO

Skeletal muscle atrophy is a morbidity and mortality risk factor that happens with disuse, chronic disease, and aging. The tissue remodeling that happens during recovery from atrophy or injury involves changes in different cell types such as muscle fibers, and satellite and immune cells. Here, we show that the previously uncharacterized gene and protein Zfp697 is a damage-induced regulator of muscle remodeling. Zfp697/ZNF697 expression is transiently elevated during recovery from muscle atrophy or injury in mice and humans. Sustained Zfp697 expression in mouse muscle leads to a gene expression signature of chemokine secretion, immune cell recruitment, and extracellular matrix remodeling. Notably, although Zfp697 is expressed in several cell types in skeletal muscle, myofiber-specific Zfp697 genetic ablation in mice is sufficient to hinder the inflammatory and regenerative response to muscle injury, compromising functional recovery. We show that Zfp697 is an essential mediator of the interferon gamma response in muscle cells and that it functions primarily as an RNA-interacting protein, with a very high number of miRNA targets. This work identifies Zfp697 as an integrator of cell-cell communication necessary for tissue remodeling and regeneration.

Assuntos

Músculo Esquelético , Proteínas de Ligação a RNA , Animais , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/genética , Camundongos Knockout , Atrofia Muscular/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Camundongos Endogâmicos C57BL , Interferon gama/metabolismo

RESUMO

Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single-nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-dependent gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. Short hairpin RNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of muscle atrophy associated with cancer cachexia and highlight potential therapeutic targets for this disorder.

Assuntos

Caquexia , Atrofia Muscular , Miogenina , Miostatina , Caquexia/patologia , Caquexia/metabolismo , Caquexia/etiologia , Animais , Atrofia Muscular/patologia , Atrofia Muscular/metabolismo , Camundongos , Miostatina/metabolismo , Miostatina/genética , Miogenina/metabolismo , Miogenina/genética , Músculo Esquelético/patologia , Músculo Esquelético/metabolismo , Neoplasias/complicações , Neoplasias/patologia , Neoplasias/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Transdução de Sinais , Folistatina/metabolismo , Humanos

RESUMO

Sarcopenia, a condition caused by an imbalance between muscle growth and loss, can severely affect the quality of life of elderly patients with metabolic, inflammatory, and cancer diseases. Vigeo, a nuruk-fermented extract of three plants (Eleutherococcus senticosus Maxim (ESM), Achyranthes japonica (Miq.) Nakai (AJN), and Atractylodes japonica Koidzumi (AJK)) has been reported to have anti-osteoporotic effects. However, evidence of the effects of Vigeo on muscle atrophy is not available. Here, in the in vivo model of dexamethasone (Dex)-induced muscle atrophy, Vigeo treatment significantly reversed Dex-induced decreases in calf muscle volume, gastrocnemius (GA) muscle weight, and histological cross-section area. In addition, in mRNA and protein analyses isolated from GA muscle, we observed that Vigeo significantly protected against Dex-induced mouse muscle atrophy by inhibiting protein degradation regulated by atrogin and MuRF-1. Moreover, we demonstrated that Vigeo significantly promoted C2C12 cell line differentiation, as evidenced by the increased width and length of myotubes, and the increased number of fused myotubes with three or more nuclei. Vigeo alleviated the formation of myotubes compared to the control group. Vigeo also significantly increased the mRNA and protein expression of myosin heavy chain (MyHC), MyoD, and myogenin compared to that in the control. Vigeo treatment significantly reduced the mRNA and protein expression of muscle degradation markers atrogin-1 and muscle RING Finger 1 (MuRF-1) in the C2C12 cell line in vitro. Vigeo also activated the AMP-activated protein kinase (AMPK)/silent information regulator 1 (Sirt-1)/peroxisome proliferator-activated receptor-γ co-activator-1α (PGC1α) mitochondrial biogenesis pathway and the Akt/mTOR protein synthesis signaling pathway in Dex-induced myotube atrophy. These findings suggest that Vigeo may have protective effects against Dex-induced muscle atrophy. Therefore, we propose Vigeo as a supplement or potential therapeutic agent to prevent or treat sarcopenia accompanied by muscle atrophy and degeneration.

Assuntos

Proteínas Quinases Ativadas por AMP , Diferenciação Celular , Dexametasona , Fibras Musculares Esqueléticas , Atrofia Muscular , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Sirtuína 1 , Serina-Treonina Quinases TOR , Animais , Dexametasona/farmacologia , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/prevenção & controle , Atrofia Muscular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Serina-Treonina Quinases TOR/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Diferenciação Celular/efeitos dos fármacos , Sirtuína 1/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Extratos Vegetais/farmacologia , Masculino , Proteólise/efeitos dos fármacos , Proteínas Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Linhagem Celular , Proteínas Ligases SKP Culina F-Box/metabolismo , Proteínas Ligases SKP Culina F-Box/genética , Camundongos Endogâmicos C57BL , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Proteínas com Motivo Tripartido

RESUMO

Skeletal muscle atrophy, characterized by diminished muscle strength and mass, arises from various causes, including malnutrition, aging, nerve damage, and disease-related secondary atrophy. Aging markedly escalates the prevalence of sarcopenia. Concurrently, the incidence of muscle atrophy significantly rises among patients with chronic ailments such as heart failure, diabetes, and chronic obstructive pulmonary disease (COPD). Epigenetics plays a pivotal role in skeletal muscle atrophy. Aging elevates methylation levels in the promoter regions of specific genes within muscle tissues. This aberrant methylation is similarly observed in conditions like diabetes, neurological disorders, and cardiovascular diseases. This study aims to explore the relationship between epigenetics and skeletal muscle atrophy, thereby enhancing the understanding of its pathogenesis and uncovering novel therapeutic strategies.

Assuntos

Metilação de DNA , Epigênese Genética , Músculo Esquelético , Atrofia Muscular , Humanos , Atrofia Muscular/genética , Atrofia Muscular/patologia , Atrofia Muscular/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/metabolismo , Animais , Envelhecimento/genética , Envelhecimento/patologia