RESUMEN
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.
Asunto(s)
Estrés del Retículo Endoplásmico , Lactobacillus delbrueckii , Lipopolisacáridos , Atrofia Muscular , Animales , Lipopolisacáridos/toxicidad , Porcinos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Atrofia Muscular/inducido químicamente , Atrofia Muscular/metabolismo , Atrofia Muscular/prevención & control , Atrofia Muscular/patología , Destete , Proteolisis , Probióticos/farmacología , Inflamación/metabolismo , Miositis/inducido químicamente , Miositis/metabolismo , Miositis/patología , Citocinas/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/efectos de los fármacosRESUMEN
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.
Asunto(s)
Hiperfosfatemia , Músculo Esquelético , Atrofia Muscular , Fosfatos , Animales , Hiperfosfatemia/patología , Ratones , Atrofia Muscular/patología , Atrofia Muscular/metabolismo , Atrofia Muscular/etiología , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Fosfatos/sangre , Fosfatos/metabolismo , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/metabolismo , Modelos Animales de Enfermedad , Ratones Noqueados , Masculino , Colágeno Tipo IV/metabolismo , Colágeno Tipo IV/genética , Ratones Endogámicos C57BL , Proteínas Klotho/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologíaRESUMEN
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.
Asunto(s)
Virus Chikungunya , Músculo Esquelético , Atrofia Muscular , Estrés Oxidativo , Animales , Atrofia Muscular/virología , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Ratones , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/virología , Fiebre Chikungunya/patología , Fiebre Chikungunya/virología , Fiebre Chikungunya/metabolismo , Inflamación/patología , Inflamación/metabolismo , Inflamación/virología , Proteínas Musculares/metabolismo , Proteínas Musculares/genética , Replicación Viral , Ratones Endogámicos C57BL , Proteínas Ligasas SKP Cullina F-box/metabolismo , Proteínas Ligasas SKP Cullina F-box/genética , Infecciones por Alphavirus/virología , Infecciones por Alphavirus/patología , Infecciones por Alphavirus/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Proteínas de Motivos Tripartitos/genética , Modelos Animales de Enfermedad , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
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.
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Músculo Esquelético , Proteínas de Unión al ARN , Animales , Ratones , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Humanos , Inflamación/metabolismo , Inflamación/patología , Inflamación/genética , Ratones Noqueados , Atrofia Muscular/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/patología , MicroARNs/genética , MicroARNs/metabolismo , Ratones Endogámicos C57BL , Interferón gamma/metabolismoRESUMEN
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.
Asunto(s)
Metilación de ADN , Epigénesis Genética , Músculo Esquelético , Atrofia Muscular , Humanos , Atrofia Muscular/genética , Atrofia Muscular/patología , Atrofia Muscular/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Animales , Envejecimiento/genética , Envejecimiento/patologíaRESUMEN
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.
Asunto(s)
Caquexia , Atrofia Muscular , Miogenina , Miostatina , Caquexia/patología , Caquexia/metabolismo , Caquexia/etiología , Animales , Atrofia Muscular/patología , Atrofia Muscular/metabolismo , Ratones , Miostatina/metabolismo , Miostatina/genética , Miogenina/metabolismo , Miogenina/genética , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Neoplasias/complicaciones , Neoplasias/patología , Neoplasias/metabolismo , Ratones Endogámicos C57BL , Masculino , Transducción de Señal , Folistatina/metabolismo , HumanosRESUMEN
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.
Asunto(s)
Envejecimiento , Estrés Mecánico , Animales , Envejecimiento/genética , Envejecimiento/fisiología , Drosophila melanogaster/genética , Atrofia Muscular/genética , Atrofia Muscular/patología , Atrofia Muscular/fisiopatología , Atrofia Muscular/metabolismo , Fibras Musculares Esqueléticas/patología , Fibras Musculares Esqueléticas/metabolismo , Contracción MuscularRESUMEN
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.
Asunto(s)
Curcumina , Simulación del Acoplamiento Molecular , Farmacología en Red , Músculo Cuádriceps , Regeneración , Animales , Curcumina/farmacología , Regeneración/efectos de los fármacos , Ratas , Músculo Cuádriceps/efectos de los fármacos , Músculo Cuádriceps/patología , Masculino , Factor de Transcripción STAT3/metabolismo , Atrofia Muscular/patología , Atrofia Muscular/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Ratas Sprague-Dawley , Apoptosis/efectos de los fármacos , Mapas de Interacción de Proteínas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Modelos Animales de EnfermedadRESUMEN
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⯵g/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 (10â¯mg/kg, intraperitoneal), and three groups of DEX+FME (100, 200, or 500â¯mg FME/kg/day, oral) for two weeks. FME at doses of 200 and 500â¯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 500â¯mg/kg) significantly increased cross-sectional area of the muscle fiber compared to DEX group. FME (500â¯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.
Asunto(s)
Dexametasona , Proteína Forkhead Box O3 , Larva , Atrofia Muscular , Transducción de Señal , Tenebrio , Animales , Masculino , Ratones , Línea Celular , Dexametasona/farmacología , Fermentación , Proteína Forkhead Box O3/metabolismo , Larva/efectos de los fármacos , Ratones Endogámicos C57BL , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/patología , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Atrofia Muscular/tratamiento farmacológico , Atrofia Muscular/patología , Atrofia Muscular/metabolismo , Atrofia Muscular/inducido químicamente , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Tenebrio/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
CONTEXT: Sepsis leads to multiple organ dysfunction and negatively impacts patient outcomes. Skeletal muscle disuse is a significant comorbidity in septic patients during their ICU stay due to prolonged immobilization. HYPOTHESIS: Combination of sepsis and muscle disuse will promote a unique proteomic signature in skeletal muscle in comparison to disuse and sepsis separately. METHODS AND MODELS: Following cecal ligation and puncture (CLP) or Sham surgeries, mice were subjected to hindlimb suspension (HLS) or maintained normal ambulation (NA). Tibialis anterior muscles from 24 C57BL6/J male mice were harvested for proteomic analysis. Proteomic profiles were assessed using nano-liquid chromatography with tandem mass spectrometry, followed by data analysis including Partial Least Squares Discriminant Analysis (PLS-DA), to compare the differential protein expression across groups. RESULTS: A total of 2876 differentially expressed proteins were identified, with marked differences between groups. In mice subjected to CLP and HLS combined, there was a distinctive proteomic signature characterized by a significant decrease in the expression of proteins involved in mitochondrial function and muscle metabolism, alongside a marked increase in proteins related to muscle degradation pathways. The PLS-DA demonstrated a clear separation among experimental groups, highlighting the unique profile of the CLP/HLS group. This suggests an important interaction between sepsis-induced inflammation and disuse atrophy mechanisms in sepsis-induced myopathy. INTERPRETATIONS AND CONCLUSIONS: Our findings reveal a complex proteomic landscape in skeletal muscle exposed to sepsis and disuse, consistent with an exacerbation of muscle protein degradation under these combined stressors. The identified proteins and their roles in cellular stress responses and muscle pathology provide potential targets for intervention to mitigate muscle dysfunction in septic conditions, highlighting the importance of addressing both sepsis and disuse concurrently in clinical and experimental settings.
Asunto(s)
Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Músculo Esquelético , Proteómica , Sepsis , Animales , Ratones , Sepsis/metabolismo , Sepsis/fisiopatología , Músculo Esquelético/metabolismo , Masculino , Proteómica/métodos , Miembro Posterior/metabolismo , Suspensión Trasera , Atrofia Muscular/metabolismo , Atrofia Muscular/patologíaRESUMEN
This study aimed to evaluate the influence of combined intermittent fasting (IF) and high-intensity interval training (HIIT) on morphology, caspase-independent apoptosis signaling pathway, and myostatin expression in soleus and gastrocnemius (white portion) muscles from healthy rats. Sixty-day-old male Wistar rats (n = 60) were divided into four groups: control (C), IF, high-intensity-interval training (T), and high-intensity-interval training and intermittent fasting (T-IF). The C and T groups received ad libitum chow daily; IF and T-IF received the same standard chow every other day. Animals from T and T-IF underwent a HIIT protocol five times a week for 12 weeks. IF reduced gastrocnemius mass and increased pro-apoptotic proteins apoptosis-inducing factor (AIF) and endonuclease G (EndoG) in soleus and cleaved-to-non-cleaved PARP-1 ratio and myostatin expression in gastrocnemius white portion. HIIT increased AIF and apoptosis repressor with caspase recruitment domain expression in soleus and cleaved-to-total PARP-1 ratio in gastrocnemius muscle white portion. The combination of IF and HIIT reduced fiber cross-sectional area in both muscles, increased EndoG and AIF expression, and decreased cleaved-to-non-cleaved PARP-1 ratio in gastrocnemius muscle white portion. Muscle responses to IF and HIIT are directly impacted by the muscle fiber type composition and are modulated, at least in part, by myostatin and caspase-independent apoptosis signaling.
Asunto(s)
Factor Inductor de la Apoptosis , Apoptosis , Ayuno , Entrenamiento de Intervalos de Alta Intensidad , Fibras Musculares de Contracción Lenta , Atrofia Muscular , Miostatina , Ratas Wistar , Transducción de Señal , Animales , Masculino , Apoptosis/fisiología , Ayuno/metabolismo , Ayuno/fisiología , Miostatina/metabolismo , Entrenamiento de Intervalos de Alta Intensidad/métodos , Ratas , Transducción de Señal/fisiología , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Factor Inductor de la Apoptosis/metabolismo , Fibras Musculares de Contracción Lenta/metabolismo , Fibras Musculares de Contracción Rápida/metabolismo , Fibras Musculares de Contracción Rápida/patología , Endodesoxirribonucleasas/metabolismo , Condicionamiento Físico Animal/métodos , Condicionamiento Físico Animal/fisiología , Músculo Esquelético/metabolismo , Ayuno Intermitente , Poli(ADP-Ribosa) Polimerasa-1RESUMEN
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.
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Apolipoproteínas E , Proteínas de Transferencia de Ésteres de Colesterol , HDL-Colesterol , Disferlina , Ratones Noqueados , Distrofia Muscular de Cinturas , Animales , Proteínas de Transferencia de Ésteres de Colesterol/genética , Proteínas de Transferencia de Ésteres de Colesterol/deficiencia , Disferlina/genética , Disferlina/deficiencia , HDL-Colesterol/sangre , Ratones , Apolipoproteínas E/genética , Apolipoproteínas E/deficiencia , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/patología , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Atrofia Muscular/genética , Atrofia Muscular/patología , Atrofia Muscular/metabolismo , Masculino , Apolipoproteínas B/sangre , Apolipoproteínas B/genética , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration, leading to neuromuscular junction (NMJ) dismantling and severe muscle atrophy. The nuclear receptor interaction protein (NRIP) functions as a multifunctional protein. It directly interacts with calmodulin or α-actinin 2, serving as a calcium sensor for muscle contraction and maintaining sarcomere integrity. Additionally, NRIP binds with the acetylcholine receptor (AChR) for NMJ stabilization. Loss of NRIP in muscles results in progressive motor neuron degeneration with abnormal NMJ architecture, resembling ALS phenotypes. Therefore, we hypothesize that NRIP could be a therapeutic factor for ALS. METHODS: We used SOD1 G93A mice, expressing human SOD1 with the ALS-linked G93A mutation, as an ALS model. An adeno-associated virus vector encoding the human NRIP gene (AAV-NRIP) was generated and injected into the muscles of SOD1 G93A mice at 60 days of age, before disease onset. Pathological and behavioral changes were measured to evaluate the therapeutic effects of AAV-NRIP on the disease progression of SOD1 G93A mice. RESULTS: SOD1 G93A mice exhibited lower NRIP expression than wild-type mice in both the spinal cord and skeletal muscle tissues. Forced NRIP expression through AAV-NRIP intramuscular injection was observed in skeletal muscles and retrogradely transduced into the spinal cord. AAV-NRIP gene therapy enhanced movement distance and rearing frequencies in SOD1 G93A mice. Moreover, AAV-NRIP increased myofiber size and slow myosin expression, ameliorated NMJ degeneration and axon terminal denervation at NMJ, and increased the number of α-motor neurons (α-MNs) and compound muscle action potential (CMAP) in SOD1 G93A mice. CONCLUSIONS: AAV-NRIP gene therapy ameliorates muscle atrophy, motor neuron degeneration, and axon terminal denervation at NMJ, leading to increased NMJ transmission and improved motor functions in SOD1 G93A mice. Collectively, AAV-NRIP could be a potential therapeutic drug for ALS.
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Esclerosis Amiotrófica Lateral , Dependovirus , Modelos Animales de Enfermedad , Terapia Genética , Ratones Transgénicos , Neuronas Motoras , Atrofia Muscular , Animales , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/terapia , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Terapia Genética/métodos , Atrofia Muscular/genética , Atrofia Muscular/terapia , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Dependovirus/genética , Ratones , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Unión Neuromuscular/metabolismo , Unión Neuromuscular/patología , Vectores Genéticos/administración & dosificación , Degeneración Nerviosa/genética , Degeneración Nerviosa/terapia , Masculino , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismoRESUMEN
Obesity-induced muscle atrophy leads to physical impairment and metabolic dysfunction, which are risky for older adults. The activity of pyruvate dehydrogenase (PDH), a critical regulator of glucose metabolism, is reduced in obesity. Additionally, PDH activator dichloroacetate (DCA) improves metabolic dysfunction. However, the effects of PDH activation on skeletal muscles in obesity remain unclear. Thus, this study aimed to evaluate the effects of PDH activation by DCA treatment on obesity-induced muscle atrophy in vitro and in vivo and elucidate the possible underlying mechanisms. Results showed that PDH activation by DCA treatment ameliorated muscle loss, decreased the cross-sectional area, and reduced grip strength in C57BL/6 mice fed a high-fat diet (HFD). Elevation of muscle atrophic factors atrogin-1 and muscle RING-finger protein-1 (MuRF-1) and autophagy factors LC3BII and p62 were abrogated by DCA treatment in palmitate-treated C2C12 myotubes and in the skeletal muscles of HFD-fed mice. Moreover, p-Akt, p-FoxO1, and p-FoxO3 protein levels were reduced and p-NF-κB p65 and p-p38 MAPK protein levels were elevated in palmitate-treated C2C12 myotubes, which were restored by DCA treatment. However, the protective effects of DCA treatment against myotube atrophy were reversed by treatment with Akt inhibitor MK2206. Taken together, our study demonstrated that PDH activation by DCA treatment can alleviate obesity-induced muscle atrophy. It may serve as a basis for developing novel strategies to prevent obesity-associated muscle loss.
Asunto(s)
Ácido Dicloroacético , Dieta Alta en Grasa , Ratones Endogámicos C57BL , Atrofia Muscular , Obesidad , Animales , Ácido Dicloroacético/farmacología , Ácido Dicloroacético/uso terapéutico , Atrofia Muscular/prevención & control , Atrofia Muscular/etiología , Atrofia Muscular/tratamiento farmacológico , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Ratones , Masculino , Dieta Alta en Grasa/efectos adversos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Complejo Piruvato Deshidrogenasa/metabolismo , Línea Celular , Activación Enzimática/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/patología , Fibras Musculares Esqueléticas/metabolismo , Autofagia/efectos de los fármacosRESUMEN
Despite advancements in treatment, approximately 25% of patients with breast cancer experience long-term skeletal muscle wasting (SMW), which limits mobility, reduces drug tolerance and adversely impacts survival. By understanding the underlying molecular mechanisms of SMW, we may be able to develop new strategies to alleviate this condition and improve the lives of patients with breast cancer. Chemokines are small soluble factors that regulate homing of immune cells to tissues during inflammation. In breast cancers, overexpression of C-C chemokine ligand 2 (CCL2) correlates with unfavorable prognosis. Elevated levels of CCL2 in peripheral blood indicate possible systemic effects of this chemokine in patients with breast cancer. Here, we investigated the role of CCL2 signaling on SMW in tumor and non-tumor contexts. In vitro, increasing concentrations of CCL2 inhibited myoblast and myotube function through C-C chemokine receptor 2 (CCR2)-dependent mechanisms involving JNK, SMAD3 and AMPK signaling. In healthy mice, delivery of recombinant CCL2 protein promoted SMW in a dose-dependent manner. In vivo knockdown of breast tumor-derived CCL2 partially protected against SMW. Overall, chronic, upregulated CCL2-CCR2 signaling positively regulates SMW, with implications for therapeutic targeting.
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Neoplasias de la Mama , Quimiocina CCL2 , Músculo Esquelético , Transducción de Señal , Animales , Quimiocina CCL2/metabolismo , Femenino , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Humanos , Receptores CCR2/metabolismo , Ratones , Línea Celular Tumoral , Modelos Animales de Enfermedad , Atrofia Muscular/patología , Atrofia Muscular/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Fibras Musculares Esqueléticas/efectos de los fármacos , Mioblastos/metabolismo , Ratones Endogámicos C57BLRESUMEN
Sepsis is a major cause of in-hospital deaths. Improvements in treatment result in a greater number of sepsis survivors. Approximately 75% of the survivors develop muscle weakness and atrophy, increasing the incidence of hospital readmissions and mortality. However, the available preclinical models of sepsis do not address skeletal muscle disuse, a key component for the development of sepsis-induced myopathy. Our objective in this protocol is to provide a step-by-step guideline for a mouse model that reproduces the clinical setting experienced by a bedridden septic patient. Male C57Bl/6 mice were used to develop this model. Mice underwent cecal ligation and puncture (CLP) to induce sepsis. Four days post-CLP, mice were subjected to hindlimb suspension (HLS) for seven days. Results were compared with sham-matched surgeries and/or animals with normal ambulation (NA). Muscles were dissected for in vitro muscle mechanics and morphological assessments. The model results in marked muscle atrophy and weakness, a similar phenotype observed in septic patients. The model represents a platform for testing potential therapeutic strategies for the mitigation of sepsis-induced myopathy.
Asunto(s)
Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Enfermedades Musculares , Sepsis , Animales , Sepsis/complicaciones , Ratones , Masculino , Enfermedades Musculares/etiología , Enfermedades Musculares/patología , Atrofia Muscular/etiología , Atrofia Muscular/patología , Músculo Esquelético , Suspensión TraseraRESUMEN
Diabetic muscular atrophy is becoming a fast-growing problem worldwide, including sarcopenia, which is associated with substantial mortality and morbidity risk. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been marketed and suggested to exert protective effects on not only glycemic control but also diabetic complications in diabetic patients. In this study, we investigated the therapeutic use of GLP-1RAs exendin-4, compared to antidiabetic drug metformin, for the intervention of muscular dysfunction during diabetic conditions using a streptozotocin (STZ)-induced diabetic mouse model. The results showed that both exendin-4 and metformin could effectively alleviate hyperglycemia in diabetic mice, and also counteract diabetes-induced muscle weight loss, weaker grip, and changes in muscle fiber cross-sectional area distribution. Unexpectedly, exendin-4, but not metformin, enhanced the increased kidney weight and histological change in diabetic mice. Taken together, these findings suggest that both exendin-4 and metformin could effectively improve the diabetic hyperglycemia and muscular dysfunction; but exendin-4 may aggravate the nephropathy in STZ-induced diabetic mice.
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Diabetes Mellitus Experimental , Exenatida , Receptor del Péptido 1 Similar al Glucagón , Metformina , Animales , Exenatida/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Metformina/farmacología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Ratones , Masculino , Hipoglucemiantes/farmacología , Estreptozocina , Modelos Animales de Enfermedad , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Péptidos/farmacología , Ponzoñas/farmacología , Atrofia Muscular/tratamiento farmacológico , Atrofia Muscular/patología , Atrofia Muscular/etiologíaRESUMEN
BACKGROUND: The study aimed to determine the grade of retraction and atrophy according to the time elapsed in traumatic isolated full-thickness supraspinatus (SS) tears in young patients. METHODS: One thousand twenty-six patients, who underwent arthroscopic shoulder surgery, were retrospectively reviewed. Pre-operative magnetic resonance imaging (MRI) of 69 patients aged 18 to 40 years with isolated traumatic full-thickness SS lesions remaining after exclusion criteria were evaluated for tendon retraction and atrophy grades. SS retraction was determined from a T2-weighted oblique coronal MRI slice, and the atrophy grade was determined from the T1-weighted oblique sagittal MRI slice. The patients were divided into four groups 0-1 month, 1-3 months, 3-6 months, and 6-12 months according to the time between trauma and MRI. The relationship of tendon retraction and muscle atrophy with elapsed time was evaluated, in addition, comparisons between groups were made. RESULTS: Thirty-one (45%) of the patients were female and their mean age was 30 ± 7.3 (18-40) years. The mean age of men was 30.5 ± 6.9 (18-39) years (p = 0.880). The time between rupture and MRI was moderately correlated with retraction and strongly correlated with atrophy grades (r = 0.599, 0.751, respectively). It was observed that there was a statistically significant difference between the 1st (0-1 month) and 2nd (1-3 months) groups (p = 0.003, 0.001, respectively), and between the 2nd and 3rd (3-6 months) groups (p = 0.032, 0.002, respectively), but there was no significant difference between the 3rd and 4th (6-12 months) groups (p = 0.118, 0.057, respectively). In addition, there was a moderate correlation between tendon retraction and atrophy grades (r = 0.668). Power (1- b) in post hoc analysis was calculated as 0.826. CONCLUSIONS: The current study, supported by arthroscopy, showed that there is a moderate and strong positive correlation between the time elapsed after trauma and the level of retraction and degree of atrophy in traumatic full-thickness SS tears, and demonstrated the importance of early surgical intervention in young patients.
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Imagen por Resonancia Magnética , Atrofia Muscular , Lesiones del Manguito de los Rotadores , Humanos , Femenino , Masculino , Adulto , Adolescente , Adulto Joven , Estudios Retrospectivos , Lesiones del Manguito de los Rotadores/cirugía , Lesiones del Manguito de los Rotadores/diagnóstico por imagen , Lesiones del Manguito de los Rotadores/patología , Atrofia Muscular/patología , Atrofia Muscular/diagnóstico por imagen , Atrofia Muscular/etiología , Factores de Tiempo , Manguito de los Rotadores/patología , Manguito de los Rotadores/diagnóstico por imagen , Manguito de los Rotadores/cirugía , Artroscopía/métodos , Traumatismos de los Tendones/diagnóstico por imagen , Traumatismos de los Tendones/patología , Traumatismos de los Tendones/cirugíaRESUMEN
The deltoid muscle and rotator cuff tissue are structural components that maintain the dynamic stability of the shoulder joint. However, atrophy of the deltoid muscle may affect the stability of the shoulder joint, which in turn alters the mechanical distribution of rotator cuff tissue. Currently, the effect of muscle volume changes in the deltoid muscle on reducing the load on the rotator cuff tissue is still unknown. Therefore, this paper intends to analyze the mechanical changes of rotator cuff tissue by deltoid muscle atrophy through finite elements. Based on previously published finite element shoulder models, the deltoid muscle was modeled by constructing deltoid muscle models with different degrees of atrophy as, 100% deltoid muscle (Group 1), 80% deltoid muscle (Group 2), and 50% deltoid muscle (Group 3), respectively. The three models were given the same external load to simulate glenohumeral joint abduction, and the stress changes in the rotator cuff tissue were analyzed and recorded. In all three models, the stress in the rotator cuff tissue showed different degrees of increase with the increase of abduction angle, especially in the supraspinatus muscle. At 90° of glenohumeral abduction, supraspinatus stress increased by 58% and 118% in Group 2 and Group 3, respectively, compared with Group 1; In the subscapularis, the stress in Group 3 increased by 59% and 25% compared with Group 1 and Group 2, respectively. In addition, the stress of the infraspinatus muscle and teres minor muscle in Group 2 and Group 3 were higher than that in Group 1 during the abduction angle from 30° to 90°. Deltoid atrophy alters the abduction movement pattern of the glenohumeral joint. During glenohumeral abduction activity, deltoid atrophy significantly increases the stress on the rotator cuff tissue, whereas normal deltoid volume helps maintain the mechanical balance of the rotator cuff tissue.
Asunto(s)
Músculo Deltoides , Análisis de Elementos Finitos , Atrofia Muscular , Manguito de los Rotadores , Manguito de los Rotadores/fisiopatología , Manguito de los Rotadores/patología , Músculo Deltoides/fisiopatología , Músculo Deltoides/patología , Humanos , Atrofia Muscular/fisiopatología , Atrofia Muscular/patología , Fenómenos Biomecánicos , Articulación del Hombro/fisiopatología , Articulación del Hombro/patología , Rango del Movimiento Articular , Estrés Mecánico , MasculinoRESUMEN
Cisplatin is a widely used chemotherapy drug for the treatment of various cancers. However, although cisplatin is effective in targeting cancer cells, it has severe side effects including skeletal muscle atrophy. In this study, we aimed to characterize the role of Dihydromyricetin in cisplatin-induced muscle atrophy in mice. 5-week-old male C57BL/6 mice were treated with Dihydromyricetin for 14 days orally followed by in intraperitoneally cisplatin administration for 6 days. Gastrocnemius muscles were isolated for the following experiments. Antioxidative stress were determined by peroxidative product malondialdehyde (MDA) and antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Quadriceps muscle mass and grip strength were significantly restored by Dihydromyricetin in a dose-dependent manner. Moreover, muscle fibers were improved in Dihydromyricetin treated group. Excessive skeletal muscle E3 ubiquitin-protein ligases in cisplatin group were significantly repressed by Dihydromyricetin treatment. Dihydromyricetin significantly reduced oxidative stress induced by cisplatin by decreasing MDA level and restored SOD and GPx activities. In addition, ferroptosis was significantly reduced by Dihydromyricetin characterized by reduced iron level and ferritin heavy chain 1 and improved Gpx4 level. The present study demonstrated that Dihydromyricetin attenuated cisplatin-induced muscle atrophy by reducing skeletal muscle E3 ubiquitin-protein ligases, oxidative stress, and ferroptosis.