Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.615
Filtrar
1.
Wiad Lek ; 75(3): 634-640, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35522870

RESUMO

OBJECTIVE: The aim: To evaluate muscle changes after sciatic nerve damage with the injection of bone marrow aspirate cells. PATIENTS AND METHODS: Materials and methods: 36 rabbits underwent sciatic nerve cross-section and neuroraphy, bone marrow aspirate cells were injected directly or 7 weeks after neuroraphy. Changes in skeletal muscle morphology (photomicrographs of histological sections were analyzed for morphometric analysis of collagen region, quantitative analysis of conducted collagen density and measurement of muscle fibers diameter) and biochemical parameters (catalase activity, superoxide dismutase and glutathione peroxidase measurements and level of TBARS was determined) at 8, 12, and 16 weeks were examined. RESULTS: Results: There is atrophy of muscle fibers in denervated muscles, and it has a negative tendency between 8 and 12 weeks. Delayed bone marrow aspirate cells injection into the muscles at 7 week - delayed atrophy and formation of TBA reactive substances. But bone marrow aspirate cells injection into the muscles directly after neuroraphy increased collagen formation, and development of fibrosis in areas of atrophy. CONCLUSION: Conclusions: Sciatic nerve injury results in atrophy of muscle tissue, which is partially delayed after delayed bone marrow aspirate cells injection at week 7. Muscle atrophy was characterized by a sharp increase in TBARS levels at 12 and 16 weeks and catalase activity at 12 weeks, and changes in biochemical parameters were partially normalized after the use of cell aspirates, to a greater extent with delayed injection.


Assuntos
Medula Óssea , Traumatismos dos Nervos Periféricos , Animais , Antioxidantes , Catalase , Colágeno , Denervação , Humanos , Denervação Muscular , Músculo Esquelético/inervação , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Coelhos , Nervo Isquiático/lesões , Nervo Isquiático/patologia , Substâncias Reativas com Ácido Tiobarbitúrico
2.
Cell ; 185(9): 1618-1618.e1, 2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35487192

RESUMO

Skeletal muscle size is highly plastic and sensitive to a variety of stimuli. Muscle atrophy occurs as the result of changes in multiple signaling pathways that regulate both protein synthesis and degradation. The signaling pathways that are activated or inhibited depend on the specific stimuli that are altered. To view this SnapShot, open of download the PDF.


Assuntos
Músculo Esquelético , Atrofia Muscular , Humanos , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Transdução de Sinais/fisiologia
5.
Zhongguo Gu Shang ; 35(4): 374-8, 2022 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-35485157

RESUMO

As an important exercise and energy metabolism organ of the human body, the normal maintenance of skeletal muscle mass is essential for the body to perform normal physiological functions. The autophagy-lysosome (AL) pathway is a physiological or pathological mechanism that is ubiquitous in normal and diseased cells. It plays a key role in the maintaining of protein balance, removing damaged organelles, and the stability of internal environment. The smooth progress of the autophagy process needs to go through multiple steps, which are completed under the coordinated action of multiple factors. Autophagy maintains the muscle homeostasis of a healthy body by removing cell components such as damaged myofibrils and isolated cytoplasmic proteins. Autophagy could also provide the initial energy required for cell proliferation, promote muscle regeneration and remodeling after injury. At the same time, autophagy disorder is also an important cause of age-related skeletal muscle atrophy. Autophagy could affect the response of skeletal muscle to exercise, and increasing the level of basic autophagy is beneficial to improve the adaptive response of skeletal muscle to exercise. This article summarizes the role and pathways of autophagy in the maintenance of skeletal muscle quality, in order to provide effective rehabilitation strategies for clinical prevention and treatment of muscle atrophy.


Assuntos
Músculo Esquelético , Transdução de Sinais , Autofagia/fisiologia , Exercício Físico/fisiologia , Humanos , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia
6.
Nat Commun ; 13(1): 2201, 2022 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-35459245

RESUMO

Skeletal muscle mass is regulated through coordinated activation of multiple signaling pathways. TAK1 signalosome has been found to be activated in various conditions of muscle atrophy and hypertrophy. However, the role and mechanisms by which TAK1 regulates skeletal muscle mass remain less understood. Here, we demonstrate that supraphysiological activation of TAK1 in skeletal muscle of adult mice stimulates translational machinery, protein synthesis, and myofiber growth. TAK1 causes phosphorylation of elongation initiation factor 4E (eIF4E) independent of mTOR. Inactivation of TAK1 disrupts neuromuscular junction morphology and causes deregulation of Smad signaling. Using genetic approaches, we demonstrate that TAK1 prevents excessive loss of muscle mass during denervation. TAK1 favors the nuclear translocation of Smad4 and cytoplasmic retention of Smad6. TAK1 is also required for the phosphorylation of eIF4E in denervated skeletal muscle. Collectively, our results demonstrate that TAK1 supports skeletal muscle growth and prevents neurogenic muscle atrophy in adult mice.


Assuntos
Fator de Iniciação 4E em Eucariotos , MAP Quinase Quinase Quinases , Desenvolvimento Muscular , Músculo Esquelético , Animais , Fator de Iniciação 4E em Eucariotos/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Desenvolvimento Muscular/genética , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Fosforilação , Transdução de Sinais/fisiologia
7.
Am J Physiol Cell Physiol ; 322(5): C814-C824, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35319902

RESUMO

Cachexia is a complex metabolic syndrome that occurs in approximately 50% of patients with cancer. Skeletal muscle atrophy is the primary clinical feature. Interleukin (IL)-17A, a proinflammatory factor, plays an important role in many chronic inflammatory diseases. Here, we describe a novel signaling pathway through which IL-17A induced muscle atrophy. We conducted a retrospective clinical study to investigate the relationship between IL-17A and the skeletal muscle index in patients with lung adenocarcinoma. We also investigated the involvement of JAK2/STAT3 signaling pathway regarding the main features of cachexia by injecting Lewis lung carcinoma (LLC) cells into C57BL/6 mice as a model to replicate cancer-induced cachexia. In vitro, C2C12 myotubes were treated with recombinant IL-17A, anti-IL-17A monoclonal antibody, STAT3 inhibitor AG490, and LLC-conditioned medium. Cell viability and aging were also evaluated. We found that in cancer conditions, increased serum levels of IL-17A were related to muscle wasting. JAK2/STAT3 phosphorylation was observed in the muscle of LLC tumor-bearing mice, accompanied by decreased MHC/Myog levels and increased MuRF1/Atrogin-1 levels. Administration of anti-IL-17A monoclonal antibody and AG490 slowed muscle atrophy development. Consistent with the in vivo findings, C2C12 myotubes treated with IL-17A and LLC-conditioned medium demonstrated phosphorylated JAK2/STAT3 signaling, resulting in MHC loss and myotube atrophy. IL-17A also inhibited C2C12 cell proliferation, cell cycle breaking, and cellular senescence. Our results identify that phosphorylation of IL-17A/JAK2/STAT3 signaling pathway appears to be an important component in the pathogenesis of LLC tumor-induced cachexia. Targeted therapy of IL-17A may be a promising approach to reduce skeletal muscle loss in patients with cancer.


Assuntos
Carcinoma Pulmonar de Lewis , Neoplasias Pulmonares , Animais , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/uso terapêutico , Caquexia/metabolismo , Carcinoma Pulmonar de Lewis/metabolismo , Meios de Cultivo Condicionados/metabolismo , Meios de Cultivo Condicionados/farmacologia , Humanos , Interleucina-17/metabolismo , Janus Quinase 2/metabolismo , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/patologia , Estudos Retrospectivos , Fator de Transcrição STAT3/metabolismo
8.
J Hazard Mater ; 432: 128654, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35286933

RESUMO

Fluoride at high doses is a well-known toxic agent for the musculoskeletal system, primarily in bone and cartilage cells. Research on fluoride toxicity concerning particularly on the skeletal muscle is scanty. We hypothesized that during skeletal fluorosis, along with bone, muscle is also affected, so we have evaluated the effects of Sodium fluoride (NaF) on mouse skeletal muscles. Sodium fluoride (80 ppm) was administered to 5-week-old C57BL6 mice drinking water for 15 and 60 days, respectively. We carried out histology, primary culture, molecular and proteomic analysis of fluoride administered mouse skeletal muscles. Results indicated an increase in the muscle mass (hypertrophy) in vivo and myotubes ex vivo by activating the IGF1/PI3/Akt/mTOR signalling pathway due to short term NaF exposure. The long-term exposure of mice to NaF caused loss of muscle proteins leading to muscle atrophy due to activation of the ubiquitin-proteasome pathway. Differentially expressed proteins were characterized and mapped using a proteomic approach. Moreover, the factors responsible for protein synthesis and PI3/Akt/mTOR pathway were upregulated, leading to muscle hypertrophy during the short term NaF exposure. Long term exposure to NaF resulted in down-regulation of metabolic pathways. Elevated myostatin resulted in the up-regulation of the muscle-specific E3 ligases-MuRF1, promoting the ubiquitination and proteasome-mediated degradation of critical sarcomeric proteins.


Assuntos
Água Potável , Fluoreto de Sódio , Animais , Fluoretos/toxicidade , Hipertrofia/induzido quimicamente , Hipertrofia/metabolismo , Hipertrofia/patologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteômica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fluoreto de Sódio/metabolismo , Fluoreto de Sódio/toxicidade , Serina-Treonina Quinases TOR/metabolismo
9.
Sci Rep ; 12(1): 3344, 2022 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-35228612

RESUMO

Incomplete functional recovery after peripheral nerve injury (PNI) often results in devastating physical disabilities in human patients. Despite improved progress in surgical and non-surgical approaches, achieving complete functional recovery following PNI remains a challenge. This study demonstrates that phentolamine may hold a significant promise in treating nerve injuries and denervation induced muscle atrophy following PNI. In a sciatic nerve crush injury mouse model, we found that phentolamine treatment enhanced motor and functional recovery, protected axon myelination, and attenuated injury-induced muscle atrophy in mice at 14 days post-injury (dpi) compared to saline treatment. In the soleus of phentolamine treated animals, we observed the downregulation of phosphorylated signal transducer and activator of transcription factor 3 (p-STAT3) as well as muscle atrophy-related genes Myogenin, muscle ring finger 1 (MuRF-1), and Forkhead box O proteins (FoxO1, FoxO3). Our results show that both nerve and muscle recovery are integral components of phentolamine treatment-induced global functional recovery in mice at 14 dpi. Moreover, phentolamine treatment improved locomotor functional recovery in the mice after spinal cord crush (SCC) injury. The fact that phentolamine is an FDA approved non-selective alpha-adrenergic blocker, clinically prescribed for oral anesthesia reversal, hypertension, and erectile dysfunction makes this drug a promising candidate for repurposing in restoring behavioral recovery following PNI and SCC injuries, axonal neuropathy, and muscle wasting disorders.


Assuntos
Traumatismos dos Nervos Periféricos , Neuropatia Ciática , Animais , Axônios/metabolismo , Humanos , Masculino , Camundongos , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Regeneração Nervosa , Fentolamina/uso terapêutico , Recuperação de Função Fisiológica/fisiologia , Nervo Isquiático/lesões
10.
Mediators Inflamm ; 2022: 2567150, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35132306

RESUMO

BACKGROUND: Curcumin is a polyphenol plant-derived compound with anti-inflammatory, antioxidant stress, and anticancer properties that make it have the potential to treat cancer cachexia. However, the role of it in breast cancer cachexia remains unclear. METHODS: The 4T1 cells were subcutaneously injected into BALB/c mice to induce breast cancer cachexia. After tumor formation, the animals were divided into groups and given curcumin or saline interventions. The therapeutic effect of curcumin on breast cancer cachexia was characterized by tumor growth, changes in body mass and gastrocnemius mass, muscle function test, histopathology, and serum nutrition indexes. Mitochondrial function in muscle tissue was observed by transmission electron microscopy and ATP detection, muscle inflammatory factors were detected by ELISA, muscle differential metabolites were detected by 1HNMR metabolomics, and the muscle tissue ubiquitination levels and NF-KB expression were also analyzed by RT-qPCR and Western blot. RESULTS: Dynamic in vivo bioluminescence imaging find that curcumin inhibited the growth of tumor in triple-negative breast cancer- (TNBC-) bearing mice, slowed down the loss of body weight and gastrocnemius weight, corrected the mitochondrial dysfunction and malnutrition status, and also significantly improved skeletal muscle function. ELISA analysis found that the level of inflammatory factors in muscle tissue was reduced. 1HNMR metabolomics analysis suggested that curcumin could regulate energy metabolism pathways. RT-qPCR and Western blot analysis found that the expression of myogenic factor myogenin was increased and the expression of myodegradation factor myostatin was decreased in the gastrocnemius; the level of ubiquitination and activation of the NF-κB pathway were also declined. CONCLUSIONS: Curcumin reduces ubiquitination, inflammation in skeletal muscle by regulating the NF-KB/UPS axis and improves muscle malignant metabolic phenotype and mitochondrial dysfunction, to alleviate muscle atrophy and loss of function in mice with breast cancer cachexia.


Assuntos
Curcumina , Neoplasias de Mama Triplo Negativas , Animais , Caquexia/tratamento farmacológico , Curcumina/farmacologia , Curcumina/uso terapêutico , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Músculo Esquelético/metabolismo , Atrofia Muscular/patologia , NF-kappa B/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo
11.
Am J Physiol Cell Physiol ; 322(3): C567-C580, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35171699

RESUMO

Skeletal muscle atrophy is a well-known consequence of spaceflight. Because of the potential significant impact of muscle atrophy and muscle dysfunction on astronauts and their mission, a thorough understanding of the mechanisms of this atrophy and the development of effective countermeasures is critical. Spaceflight-induced muscle atrophy is similar to atrophy seen in many terrestrial conditions, and therefore our understanding of this form of atrophy may also contribute to the treatment of atrophy in humans on Earth. The unique environmental features humans encounter in space include the weightlessness of microgravity, space radiation, and the distinctive aspects of living in a spacecraft. The disuse and unloading of muscles in microgravity are likely the most significant factors that mediate spaceflight-induced muscle atrophy and have been extensively studied and reviewed. However, there are numerous other direct and indirect effects on skeletal muscle that may be contributing factors to the muscle atrophy and dysfunction seen as a result of spaceflight. This review offers a novel perspective on the issue of muscle atrophy in space by providing a comprehensive overview of the unique aspects of the spaceflight environment and the various ways in which they can lead to muscle atrophy. We systematically review the potential contributions of these different mechanisms of spaceflight-induced atrophy and include findings from both actual spaceflight and ground-based models of spaceflight in humans, animals, and in vitro studies.


Assuntos
Voo Espacial , Ausência de Peso , Animais , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Ausência de Peso/efeitos adversos
12.
Sci Rep ; 12(1): 1966, 2022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-35121777

RESUMO

Trk-fused gene (TFG) mutations have been identified in patients with several neurodegenerative diseases. In this study, we attempted to clarify the effects of TFG deletions in motor neurons and in muscle fibers, using tissue-specific TFG knockout (vMNTFG KO and MUSTFG KO) mice. vMNTFG KO, generated by crossing TFG floxed with VAChT-Cre, showed deterioration of motor function and muscle atrophy especially in slow-twitch soleus muscle, in line with the predominant Cre expression in slow-twitch fatigue-resistant (S) and fast-twitch fatigue-resistant (FR) motor neurons. Consistently, denervation of the neuromuscular junction (NMJ) was apparent in the soleus, but not in the extensor digitorum longus, muscle. Muscle TFG expressions were significantly downregulated in vMNTFG KO, presumably due to decreased muscle IGF-1 concentrations. However, interestingly, MUSTFG KO mice showed no apparent impairment of muscle movements, though a denervation marker, AChRγ, was elevated and Agrin-induced AChR clustering in C2C12 myotubes was inhibited. Our results clarify that loss of motor neuron TFG is sufficient for the occurrence of NMJ degeneration and muscle atrophy, though lack of muscle TFG may exert an additional effect. Reduced muscle TFG, also observed in aged mice, might be involved in age-related NMJ degeneration, and this issue merits further study.


Assuntos
Fator de Crescimento Insulin-Like I/genética , Doenças Neurodegenerativas/genética , Junção Neuromuscular/genética , Receptor trkA/genética , Animais , Humanos , Camundongos , Camundongos Knockout , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/genética , Atrofia Muscular/patologia , Doenças Neurodegenerativas/patologia , Junção Neuromuscular/patologia
13.
Nat Commun ; 13(1): 894, 2022 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-35173176

RESUMO

Mitochondrial proteolysis is an evolutionarily conserved quality-control mechanism to maintain proper mitochondrial integrity and function. However, the physiological relevance of stress-induced impaired mitochondrial protein quality remains unclear. Here, we demonstrate that LONP1, a major mitochondrial protease resides in the matrix, plays a role in controlling mitochondrial function as well as skeletal muscle mass and strength in response to muscle disuse. In humans and mice, disuse-related muscle loss is associated with decreased mitochondrial LONP1 protein. Skeletal muscle-specific ablation of LONP1 in mice resulted in impaired mitochondrial protein turnover, leading to mitochondrial dysfunction. This caused reduced muscle fiber size and strength. Mechanistically, aberrant accumulation of mitochondrial-retained protein in muscle upon loss of LONP1 induces the activation of autophagy-lysosome degradation program of muscle loss. Overexpressing a mitochondrial-retained mutant ornithine transcarbamylase (ΔOTC), a known protein degraded by LONP1, in skeletal muscle induces mitochondrial dysfunction, autophagy activation, and cause muscle loss and weakness. Thus, these findings reveal a role of LONP1-dependent mitochondrial protein quality-control in safeguarding mitochondrial function and preserving skeletal muscle mass and strength, and unravel a link between mitochondrial protein quality and muscle mass maintenance during muscle disuse.


Assuntos
Proteases Dependentes de ATP/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Proteases Dependentes de ATP/genética , Animais , Autofagia/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/genética , Força Muscular/fisiologia , Ornitina Carbamoiltransferase/metabolismo , Proteólise , Proteostase/fisiologia
14.
Int J Mol Sci ; 23(3)2022 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-35163088

RESUMO

Transforming growth factor-beta (TGF-ß) is part of a family of molecules that is present in many body tissues and performs many different functions. Evidence has been obtained from mice and human cancer patients with bony metastases and non-metastatic disease, as well as pediatric burn patients, that inflammation leads to bone resorption and release of TGF-ß from the bone matrix with paracrine effects on muscle protein balance, possibly mediated by the generation of reactive oxygen species. Whether immobilization, which confounds the etiology of bone resorption in burn injury, also leads to the release of TGF-ß from bone contributing to muscle wasting in other conditions is unclear. The use of anti-resorptive therapy in both metastatic cancer patients and pediatric burn patients has been successful in the prevention of muscle wasting, thereby creating an additional therapeutic niche for this class of drugs. The liberation of TGF-ß may be one way in which bone helps to control muscle mass, but further investigation will be necessary to assess whether the rate of bone resorption is the determining factor for the release of TGF-ß. Moreover, whether different resorptive conditions, such as immobilization and hyperparathyroidism, also involve TGF-ß release in the pathogenesis of muscle wasting needs to be investigated.


Assuntos
Reabsorção Óssea/patologia , Proteínas Musculares/metabolismo , Atrofia Muscular/patologia , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Reabsorção Óssea/metabolismo , Humanos , Atrofia Muscular/metabolismo
15.
J Cachexia Sarcopenia Muscle ; 13(2): 1314-1328, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35170238

RESUMO

BACKGROUND: Interferon-induced protein with tetratricopeptide repeat 2 (IFIT2) is a reported metastasis suppressor in oral squamous cell carcinoma (OSCC). Metastases and cachexia may coexist. The effect of cancer metastasis on cancer cachexia is largely unknown. We aimed to address this gap in knowledge by characterizing the cachectic phenotype of an IFIT2-depleted metastatic OSCC mouse model. METHODS: Genetically engineered and xenograft tumour models were used to explore the effect of IFIT2-depleted metastatic OSCC on cancer cachexia. Muscle and organ weight changes, tumour burden, inflammatory cytokine profiles, body composition, food intake, serum albumin and C-reactive protein (CRP) levels, and survival were assessed. The activation of the IL6/p38 pathway in atrophied muscle was measured. RESULTS: IFIT2-depleted metastatic tumours caused marked body weight loss (-18.2% vs. initial body weight, P < 0.001) and a poor survival rate (P < 0.01). Skeletal muscles were markedly smaller in IFIT2-depleted metastatic tumour-bearing mice (quadriceps: -28.7%, gastrocnemius: -29.4%, and tibialis: -24.3%, all P < 0.001). Tumour-derived circulating granulocyte-macrophage colony-stimulating factor (+772.2-fold, P < 0.05), GROα (+1283.7-fold, P < 0.05), IL6 (+245.8-fold, P < 0.001), IL8 (+616.9-fold, P < 0.001), IL18 (+24-fold, P < 0.05), IP10 (+18.8-fold, P < 0.001), CCL2 (+439.2-fold, P < 0.001), CCL22 (+9.1-fold, P < 0.01) and tumour necrosis factor α (+196.8-fold, P < 0.05) were elevated in IFIT2-depleted metastatic tumour-bearing mice. Murine granulocyte colony-stimulating factor (+61.4-fold, P < 0.001) and IL6 (+110.9-fold, P < 0.01) levels were significantly increased in IFIT2-depleted metastatic tumour-bearing mice. Serum CRP level (+82.1%, P < 0.05) was significantly increased in cachectic shIFIT2 mice. Serum albumin level (-26.7%, P < 0.01) was significantly decreased in cachectic shIFIT2 mice. An assessment of body composition revealed decreased fat (-81%, P < 0.001) and lean tissue (-21.7%, P < 0.01), which was consistent with the reduced food intake (-19.3%, P < 0.05). Muscle loss was accompanied by a smaller muscle cross-sectional area (-23.3%, P < 0.05). Muscle atrophy of cachectic IFIT2-depleted metastatic tumour-bearing mice (i.v.-shIFIT2 group) was associated with elevated IL6 (+2.7-fold, P < 0.05), phospho-p38 (+2.8-fold, P < 0.05), and atrogin-1 levels (+2.3-fold, P < 0.05) in the skeletal muscle. Neutralization of IL6 rescued shIFIT2 conditioned medium-induced myotube atrophy (+24.6%, P < 0.01). CONCLUSIONS: Our results suggest that the development of shIFIT2 metastatic OSCC lesions promotes IL6 production and is accompanied by the loss of fat and lean tissue, anorexia, and muscle atrophy. This model is appropriate for the study of OSCC cachexia, especially in linking metastasis with cachexia.


Assuntos
Proteínas Reguladoras de Apoptose , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Proteínas de Ligação a RNA , Animais , Proteínas Reguladoras de Apoptose/genética , Caquexia/patologia , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/complicações , Humanos , Camundongos , Neoplasias Bucais/complicações , Neoplasias Bucais/patologia , Atrofia Muscular/patologia , Proteínas de Ligação a RNA/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/complicações
16.
J Cachexia Sarcopenia Muscle ; 13(2): 1289-1301, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35044098

RESUMO

BACKGROUND: Cancer-associated cachexia (CAC) is a complex syndrome of progressive muscle wasting and adipose loss with metabolic dysfunction, severely increasing the morbidity and mortality risk in cancer patients. However, there are limited studies focused on the underlying mechanisms of the progression of CAC due to the complexity of this syndrome and the lack of preclinical models that mimics its stagewise progression. METHODS: We characterized the initiation and progression of CAC in transgenic female mice with ovarian tumours. We measured proposed CAC biomarkers (activin A, GDF15, IL-6, IL-1ß, and TNF-α) in sera (n = 6) of this mouse model. The changes of activin A and GDF15 (n = 6) were correlated with the decline of bodyweight over time. Morphometry and signalling markers of muscle atrophy (n ≥ 6) and adipose tissue wasting (n ≥ 7) were assessed during CAC progression. RESULTS: Cancer-associated cachexia symptoms of the transgenic mice model used in this study mimic the progression of CAC seen in humans, including drastic body weight loss, skeletal muscle atrophy, and adipose tissue wasting. Serum levels of two cachexia biomarkers, activin A and GDF15, increased significantly during cachexia progression (76-folds and 10-folds, respectively). Overactivation of proteolytic activity was detected in skeletal muscle through up-regulating muscle-specific E3 ligases Atrogin-1 and Murf-1 (16-folds and 14-folds, respectively) with decreasing cross-sectional area of muscle fibres (P < 0.001). Muscle wasting mechanisms related with p-p38 MAPK, FOXO3, and p-AMPKα were highly activated in concurrence with an elevation in serum activin A. Dramatic fat loss was also observed in this mouse model with decreased fat mass (n ≥ 6) and white adipocytes sizes (n = 6) (P < 0.0001). The adipose tissue wasting was based on thermogenesis, supported by the up-regulation of uncoupling protein 1 (UCP1). Fibrosis in adipose tissue was also observed in concurrence with adipose tissue loss (n ≥ 13) (p < 0.0001). CONCLUSIONS: Our novel preclinical CAC mouse model mimics human CAC phenotypes and serum biomarkers. The mouse model in this study showed proteolysis in muscle atrophy, browning in adipose tissue wasting, elevation of serum activin A and GDF15, and atrophy of pancreas and liver. This mouse line would be the best preclinical model to aid in clarifying molecular mediators of CAC and dissecting metabolic dysfunction and tissue atrophy during the progression of CAC.


Assuntos
Caquexia , Neoplasias Ovarianas , Tecido Adiposo/patologia , Animais , Caquexia/patologia , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/patologia
17.
Am J Sports Med ; 50(4): 1078-1087, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35099310

RESUMO

BACKGROUND: Monitoring the fatty infiltration (FI) process in rotator cuff muscles is of value in establishing a treatment plan and predicting the postoperative prognosis. Quantitative T1 mapping shows promise for evaluating muscle degeneration, while its validity in monitoring rotator cuff muscle FI progression needs further investigation. PURPOSE: To determine the validity of T1 mapping in monitoring FI progression of rotator cuff muscles. STUDY DESIGN: Controlled laboratory study. METHODS: Sprague-Dawley rats (N = 108) underwent left supraspinatus (SS) and infraspinatus (IS) tenotomy only (TT), suprascapular nerve transection only (NT), or SS and IS tenotomy plus suprascapular nerve transection (TT+NT). Sham surgery on the right shoulder served as the control. The magnetic resonance imaging examination included T1 mapping performed at 12, 16, and 20 weeks postoperation. SS and IS muscles were harvested to quantitatively evaluate FI via direct evaluation (triglyceride quantification assay and histological analysis) at the same predetermined intervals. The correlation of the imaging data with direct evaluation of rotator cuff muscles was analyzed. RESULTS: T1 values were significantly lower in left SS and IS muscles at 12, 16, and 20 weeks postoperation as compared with those on the right side. T1 values of the left SS and IS muscles were continuously decreased in all groups. The TT+NT group had a greater decrease in T1 value than did the TT and NT groups. Triglyceride quantification assay and histological analysis demonstrated significant and progressive FI of the left SS and IS muscles in the 3 groups. The most serious FI changes were observed in the TT+NT group. T1 values were also well correlated with triglyceride contents and area fractions of fat. CONCLUSION: T1 mapping can be an effective imaging modality for sensitive and quantitative monitoring of FI progression in rotator cuff muscles. CLINICAL RELEVANCE: The findings of this study provide a tool for researchers to noninvasively and quantitatively monitor the process of muscle degeneration, contributing to the evaluation of surgical indication and postoperative prognosis.


Assuntos
Lesões do Manguito Rotador , Manguito Rotador , Tecido Adiposo/diagnóstico por imagem , Tecido Adiposo/patologia , Animais , Humanos , Imageamento por Ressonância Magnética/métodos , Atrofia Muscular/patologia , Ratos , Ratos Sprague-Dawley , Manguito Rotador/diagnóstico por imagem , Manguito Rotador/patologia , Manguito Rotador/cirurgia , Lesões do Manguito Rotador/diagnóstico por imagem , Lesões do Manguito Rotador/patologia , Lesões do Manguito Rotador/cirurgia
18.
Int J Mol Sci ; 23(2)2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35055073

RESUMO

Exposure to high altitude environment leads to skeletal muscle atrophy. As a hormone secreted by skeletal muscles after exercise, irisin contributes to promoting muscle regeneration and ameliorating skeletal muscle atrophy, but its role in hypoxia-induced skeletal muscle atrophy is still unclear. Our results showed that 4 w of hypoxia exposure significantly reduced body weight and gastrocnemius muscle mass of mice, as well as grip strength and the duration time of treadmill exercise. Hypoxic treatment increased HIF-1α expression and decreased both the circulation level of irisin and its precursor protein FNDC5 expression in skeletal muscle. In in vitro, CoCl2-induced chemical hypoxia and 1% O2 ambient hypoxia both reduced FNDC5, along with the increase in HIF-1α. Moreover, the decline in the area and diameter of myotubes caused by hypoxia were rescued by inhibiting HIF-1α via YC-1. Collectively, our research indicated that FNDC5/irisin was negatively regulated by HIF-1α and could participate in the regulation of muscle atrophy caused by hypoxia.


Assuntos
Fibronectinas/genética , Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/complicações , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Animais , Biomarcadores , Linhagem Celular , Fibronectinas/metabolismo , Imunofluorescência , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Imuno-Histoquímica , Masculino , Camundongos , Atrofia Muscular/patologia
19.
J Cachexia Sarcopenia Muscle ; 13(1): 743-757, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35014202

RESUMO

BACKGROUND: CCAAT/enhancer-binding protein ß (C/EBPß) is a transcription factor whose high expression in human cancers is associated with tumour aggressiveness and poor outcomes. Most advanced cancer patients will develop cachexia, characterized by loss of skeletal muscle mass. In response to secreted factors from cachexia-inducing tumours, C/EBPß is stimulated in muscle, leading to both myofibre atrophy and the inhibition of muscle regeneration. Involved in the regulation of immune responses, C/EBPß induces the expression of many secreted factors, including cytokines. Because tumour-secreted factors drive cachexia and aggressive tumours have higher expression of C/EBPß, we examined a potential role for C/EBPß in the expression of tumour-derived cachexia-inducing factors. METHODS: We used gain-of-function and loss-of-function approaches in vitro and in vivo to evaluate the role of tumour C/EBPß expression on the secretion of cachexia-inducing factors. RESULTS: We report that C/EBPß overexpression up-regulates the expression of 260 secreted protein genes, resulting in a secretome that inhibits myogenic differentiation (-31%, P < 0.05) and myotube maturation [-38% (fusion index) and -25% (myotube diameter), P < 0.05]. We find that knockdown of C/EBPß in cachexia-inducing Lewis lung carcinoma cells restores myogenic differentiation (+25%, P < 0.0001) and myotube diameter (+90%, P < 0.0001) in conditioned medium experiments and, in vivo, prevents muscle wasting (-51% for small myofibres vs. controls, P < 0.01; +140% for large myofibres, P < 0.01). Conversely, overexpression of C/EBPß in non-cachectic tumours converts their secretome into a cachexia-inducing one, resulting in reduced myotube diameter (-41%, P < 0.0001, EL4 model) and inhibition of differentiation in culture (-26%, P < 0.01, EL4 model) and muscle wasting in vivo (+98% small fibres, P < 0.001; -76% large fibres, P < 0.001). Comparison of the differently expressed transcripts coding for secreted proteins in C/EBPß-overexpressing myoblasts with the secretome from 27 different types of human cancers revealed ~18% similarity between C/EBPß-regulated secreted proteins and those secreted by highly cachectic tumours (brain, pancreatic, and stomach cancers). At the protein level, we identified 16 novel secreted factors that are present in human cancer secretomes and are up-regulated by C/EBPß. Of these, we tested the effect of three factors (SERPINF1, TNFRSF11B, and CD93) on myotubes and found that all had atrophic potential (-33 to -36% for myotube diameter, P < 0.01). CONCLUSIONS: We find that C/EBPß is necessary and sufficient to induce the secretion of cachexia-inducing factors by cancer cells and loss of C/EBPß in tumours attenuates muscle atrophy in an animal model of cancer cachexia. Our findings establish C/EBPß as a central regulator of cancer cachexia and an important therapeutic target.


Assuntos
Caquexia , Carcinoma Pulmonar de Lewis , Animais , Caquexia/patologia , Carcinoma Pulmonar de Lewis/complicações , Carcinoma Pulmonar de Lewis/patologia , Humanos , Desenvolvimento Muscular , Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/patologia
20.
Cell Prolif ; 55(3): e13181, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35088922

RESUMO

OBJECTIVES: Insulin resistance in chronic kidney disease (CKD) stimulates muscle wasting, but the molecular processes behind the resistance are undetermined. However, inflammation in skeletal muscle is implicated in the pathogenesis of insulin resistance and cachexia. Toll-like receptors (TLRs) are known to regulate local innate immune responses, and microarray data have shown that Tlr13 is upregulated in the muscles of mice with CKD, but the relevance is unknown. MATERIALS AND METHODS: We performed in vitro experiments in C2C12 myotubes and constructed a CKD murine model using subtotal nephrectomy to conduct experiments in vivo. RESULTS: Tlr13 expression was stimulated in C2C12 myotubes treated with uremic serum. The expression of Tlr13 was also upregulated in the tibialis anterior muscles of mice with CKD. Tlr13 knockdown with siRNAs in skeletal muscle cells decreased insulin resistance despite the inclusion of uremic serum. This led to increased levels of p-AKT and suppression of protein degradation. Using immunofluorescence staining and coimmunoprecipitation assay, we found that TLR13 recruits IRF3, which activates Irf3 expression, resulting in decreased AKT activity. Moreover, insulin resistance and proteolysis are re-induced by Irf3 overexpression under Tlr13 deletion. CONCLUSIONS: Our results indicate that TLR13 is involved in CKD-mediated insulin resistance in muscle. In catabolic conditions where insulin signaling is impaired, targeting TLR13 may improve insulin sensitivity and prevent muscle atrophy.


Assuntos
Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Insuficiência Renal Crônica/metabolismo , Receptores Toll-Like/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...