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Maintenance of skeletal muscle mass and strength throughout life is crucial for heathy living and longevity. Several signaling pathways have been implicated in the regulation of skeletal muscle mass in adults. TGF-ß-activated kinase 1 (TAK1) is a key protein, which coordinates the activation of multiple signaling pathways. Recently, it was discovered that TAK1 is essential for the maintenance of skeletal muscle mass and myofiber hypertrophy following mechanical overload. Forced activation of TAK1 in skeletal muscle causes hypertrophy and attenuates denervation-induced muscle atrophy. TAK1-mediated signaling in skeletal muscle promotes protein synthesis, redox homeostasis, mitochondrial health, and integrity of neuromuscular junctions. In this article, we have reviewed the role and potential mechanisms through which TAK1 regulates skeletal muscle mass and growth. We have also proposed future areas of research that could be instrumental in exploring TAK1 as therapeutic target for improving muscle mass in various catabolic conditions and diseases.
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Quinasas Quinasa Quinasa PAM , Músculo Esquelético , Humanos , Hipertrofia , Quinasas Quinasa Quinasa PAM/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Muscle atrophy is a common complication of chronic kidney disease (CKD). Irisin, a novel muscle cytokine, protects against muscle atrophy, but its specific role in CKD-associated muscle atrophy requires further elucidation. Because the ubiquitin-proteasome system (UPS) plays an important role in CKD muscle atrophy, our study will explore whether irisin affects UPS and alleviate CKD-associated muscle atrophy. In this study, an adenine-fed mouse model of CKD and urotension II (UII)-induced C2C12 myotubes were used as in vivo and in vitro models of muscle atrophy. The results showed that renal function, mouse weight, and the cross-sectional area (CSA) of skeletal muscles were significantly improved in CKD mice treated with irisin. Moreover, irisin effectively mitigated the decreases in phosphorylated Forkhead box O 3a (p-FOXO3A) levels and increases in the levels of E3 ubiquitin ligases, such as muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx/atrogin1), in both the muscles of CKD mice and UII-induced C2C12 myotubes. In addition, irisin significantly increased the expression levels of myogenic differentiation factor D (MyoD) in the muscles of CKD mice. Our study is the first to demonstrate that irisin ameliorates skeletal muscle atrophy by inhibiting UPS upregulation and improving satellite cell differentiation in CKD.
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Doxorubicin (DOX) is a chemotherapy drug used to treat various types of cancer, but it is associated with significant side effects such as skeletal muscle atrophy. Exercise has been found to prevent skeletal muscle atrophy through the modulation of mitochondrial pathways. Mitochondrial transplantation (MT) may mitigate toxicity, neurological disorders, kidney and liver injury, and skeletal muscle atrophy. The objective of this study was to evaluate the effects of MT, exercise, and MT with exercise on DOX-induced skeletal muscle atrophy. Male Sprague Dawley rats were randomly assigned to the following groups: control, DOX, MT with DOX, exercise with DOX, and exercise with MT and DOX. A 10-day treadmill running exercise and MT (6.5 µg/100 µL) to tibialis anterior (TA) muscle were administered prior to a single injection of DOX (20 mg/kg). Our data showed that exercise and MT with exercise led to an increase in cross-sectional area of the TA muscle. Exercise, MT and MT with exercise reduced inflammation and maintained mitochondrial enzyme activity. Additionally, exercise and MT have been shown to regulate mitochondrial fusion/fission. Our findings revealed that exercise and MT with exercise prevented oxidative damage. Furthermore, MT and MT with exercise decreased apoptosis and MT with exercise triggered mitochondrial biogenesis. These findings demonstrate the importance of exercise in the prevention of skeletal muscle atrophy and emphasize the significant benefits of MT with exercise. To the best of our knowledge, this is the first study to demonstrate the therapeutic effects of MT with exercise in DOX-induced skeletal muscle atrophy.
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Diabetes has become a serious public health crisis, presenting significant challenges to individuals worldwide. As the largest organ in the human body, skeletal muscle is a significant target of this chronic disease, yet muscle wasting as a complication of diabetes is still not fully understood and effective treatment methods have yet to be developed. Here, we discuss the targets involved in inducing muscle wasting under diabetic conditions, both validated targets and emerging targets. Diabetes-induced skeletal muscle wasting is known to involve changes in various signaling molecules and pathways, such as protein degradation pathways, protein synthesis pathways, mitochondrial function, and oxidative stress inflammation. Recent studies have shown that some of these present potential as promising therapeutic targets, including the neuregulin 1/epidermal growth factor receptor family, advanced glycation end-products, irisin, ferroptosis, growth differentiation factor 15 and more. This study's investigation and discussion of such pathways and their potential applications provides a theoretical basis for the development of clinical treatments for diabetes-induced muscle wasting and a foundation for continued focus on this disease.
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AIM: It has long been recognized that resistance exercise can substantially increase skeletal muscle mass and strength, but whether it can protect against glucocorticoid-induced muscle atrophy and its potential mechanism is yet to be determined. This study aimed to investigate the protective effects of resistance exercise in dexamethasone-induced muscle atrophy and elucidate the possible function of exercise-induced protein Sestrin2 in this process. METHODS: Eight-week-old male C57BL/6J mice carried out the incremental mouse ladder exercise for 11 weeks. Two weeks before the end of the intervention, mice were daily intraperitoneally injected with dexamethasone. Body composition, muscle mass, and exercise performance were examined to evaluate muscle atrophy. In vitro, C2C12 cells were used for RT-qPCR, Western Blot, and immunofluorescence experiments to elucidate the potential mechanism. RESULTS: Our results showed that long-term resistance exercise is an effective intervention for dexamethasone-induced muscle atrophy. We also found that Sestrin2 plays a vital role in dexamethasone-induced muscle atrophy. In both animal (P = .0006) and cell models (P = .0266), dexamethasone intervention significantly reduced the protein expression of Sestrin2, which was increased (P = .0112) by resistance exercise. Inversely, overexpression of Sestrin2 improved (P < .0001) dexamethasone-induced myotube cell atrophy by reducing the activation of the ubiquitin-proteasome pathway via inhibiting Forkhead box O3 (FoxO3a) and myostatin (MSTN)/small mother against decapentaplegic (Smad) signaling pathways. CONCLUSION: Taken together, our results indicated that Sestrin2 may serve as an effective molecule that mimics the protective effect of resistance exercise on dexamethasone-induced muscle atrophy.
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Músculo Esquelético , Entrenamiento de Fuerza , Animales , Masculino , Ratones , Línea Celular , Dexametasona/farmacología , Ratones Endogámicos C57BL , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/inducido químicamente , Atrofia Muscular/prevención & control , Atrofia Muscular/metabolismo , Miostatina/metabolismo , Miostatina/farmacología , Sestrinas/metabolismoRESUMEN
Skeletal muscle is the largest metabolic organ of the human body. Maintaining the best quality control and functional integrity of mitochondria is essential for the health of skeletal muscle. However, mitochondrial dysfunction characterized by mitochondrial dynamic imbalance and mitophagy disruption can lead to varying degrees of muscle atrophy, but the underlying mechanism of action is still unclear. Although mitochondrial dynamics and mitophagy are two different mitochondrial quality control mechanisms, a large amount of evidence has indicated that they are interrelated and mutually regulated. The former maintains the balance of the mitochondrial network, eliminates damaged or aged mitochondria, and enables cells to survive normally. The latter degrades damaged or aged mitochondria through the lysosomal pathway, ensuring cellular functional health and metabolic homeostasis. Skeletal muscle atrophy is considered an urgent global health issue. Understanding and gaining knowledge about muscle atrophy caused by mitochondrial dysfunction, particularly focusing on mitochondrial dynamics and mitochondrial autophagy, can greatly contribute to the prevention and treatment of muscle atrophy. In this review, we critically summarize the recent research progress on mitochondrial dynamics and mitophagy in skeletal muscle atrophy, and expound on the intrinsic molecular mechanism of skeletal muscle atrophy caused by mitochondrial dynamics and mitophagy. Importantly, we emphasize the potential of targeting mitochondrial dynamics and mitophagy as therapeutic strategies for the prevention and treatment of muscle atrophy, including pharmacological treatment and exercise therapy, and summarize effective methods for the treatment of skeletal muscle atrophy.
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Dinámicas Mitocondriales , Mitofagia , Músculo Esquelético , Atrofia Muscular , Humanos , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Atrofia Muscular/terapia , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Animales , Mitocondrias/metabolismo , Mitocondrias/patologíaRESUMEN
Skeletal muscular atrophy is a complex disease involving a large number of gene expression regulatory networks and various biological processes. Despite extensive research on this topic, its underlying mechanisms remain elusive, and effective therapeutic approaches are yet to be established. Recent studies have shown that epigenetics play an important role in regulating skeletal muscle atrophy, influencing the expression of numerous genes associated with this condition through the addition or removal of certain chemical modifications at the molecular level. This review article comprehensively summarizes the different types of modifications to DNA, histones, RNA, and their known regulators. We also discuss how epigenetic modifications change during the process of skeletal muscle atrophy, the molecular mechanisms by which epigenetic regulatory proteins control skeletal muscle atrophy, and assess their translational potential. The role of epigenetics on muscle stem cells is also highlighted. In addition, we propose that alternative splicing interacts with epigenetic mechanisms to regulate skeletal muscle mass, offering a novel perspective that enhances our understanding of epigenetic inheritance's role and the regulatory network governing skeletal muscle atrophy. Collectively, advancements in the understanding of epigenetic mechanisms provide invaluable insights into the study of skeletal muscle atrophy. Moreover, this knowledge paves the way for identifying new avenues for the development of more effective therapeutic strategies and pharmaceutical interventions.
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Epigénesis Genética , Músculo Esquelético , Atrofia Muscular , Humanos , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Músculo Esquelético/patología , Músculo Esquelético/metabolismo , Animales , Histonas/metabolismo , Histonas/genética , Metilación de ADN/genética , Empalme Alternativo/genéticaRESUMEN
Arsenic is a well-known environmental toxicant and emerging evidence suggests that arsenic exposure has potential skeletal muscle toxicity; however, the underlying mechanism has not yet been clarified. The aim of this study was to investigate the correlation among adverse effects of subchronic and chronic environmental arsenic exposure on skeletal muscle as well as specific myokines secretion and angiotensin II (AngII)-melatonin (MT) axis in rats. Four-week-old rats were exposed to arsenite (iAs) in drinking water at environmental relevant concentration of 10 ppm for 3 or 9 months. Results indicated that the gastrocnemius muscle had atrophied and its mass was decreased in rats exposed to arsenite for 9 months, whereas, they had no significant changes in rats exposed to arsenite for 3 months. The levels of serum-specific myokine irisin and gastrocnemius muscle insulin-like growth factor-1 (IGF-1) were increased in 3-month exposure group and decreased in 9-month exposure group, while serum myostatin (MSTN) was increased significantly in 9-month exposure group. In addition, serum AngII level increased both in 3- and 9-month exposure groups, while serum MT level increased in 3-month exposure group and decreased in 9-month exposure group. Importantly, the ratio of AngII to MT level in serum increased gradually with the prolongation of arsenite exposure. It showed a certain correlation between AngII-MT axis and gastrocnemius muscle mass, gastrocnemius muscle level of IGF-1 or serum levels of irisin and MSTN. In conclusion, the disruption of AngII-MT axis balance may be a significant factor for skeletal muscle atrophy induced by chronic environmental arsenic exposure.
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Arsénico , Arsenitos , Melatonina , Ratas , Animales , Angiotensina II , Factor I del Crecimiento Similar a la Insulina , Melatonina/farmacología , Arsenitos/toxicidad , Fibronectinas , Músculo Esquelético , AtrofiaRESUMEN
Metabolic dysfunction contributes to the clinical deterioration observed in advanced cancer patients and is characterized by weight loss, skeletal muscle wasting, and atrophy of the adipose tissue. This systemic syndrome, termed cancer-associated cachexia (CAC), is a major cause of morbidity and mortality. While once attributed solely to decreased food intake, the present description of cancer cachexia is a disorder of multiorgan energy imbalance. Here we review the molecules and pathways responsible for metabolic dysfunction in CAC and the ideas that led to the current understanding.
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Caquexia/etiología , Caquexia/fisiopatología , Neoplasias/complicaciones , Tejido Adiposo Blanco/fisiopatología , Metabolismo de los Hidratos de Carbono/fisiología , Sistema Endocrino/fisiopatología , Humanos , Inflamación/complicaciones , Metabolismo de los Lípidos , Hígado/fisiopatología , Atrofia Muscular/etiologíaRESUMEN
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.
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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
The skeletal muscles account for approximately 40% of the body weight and are crucial in movement, nutrient absorption, and energy metabolism. Muscle loss and decline in function cause a decrease in the quality of life of patients and the elderly, leading to complications that require early diagnosis. Positron emission tomography/computed tomography (PET/CT) offers non-invasive, high-resolution visualization of tissues. It has emerged as a promising alternative to invasive diagnostic methods and is attracting attention as a tool for assessing muscle function and imaging muscle diseases. Effective imaging of muscle function and pathology relies on appropriate radiopharmaceuticals that target key aspects of muscle metabolism, such as glucose uptake, adenosine triphosphate (ATP) production, and the oxidation of fat and carbohydrates. In this review, we describe how [18F]fluoro-2-deoxy-D-glucose ([18F]FDG), [18F]fluorocholine ([18F]FCH), [11C]acetate, and [15O]water ([15O]H2O) are suitable radiopharmaceuticals for diagnostic imaging of skeletal muscles.
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Músculo Esquelético , Radiofármacos , Humanos , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/metabolismo , Tomografía de Emisión de Positrones/métodos , Fluorodesoxiglucosa F18 , Animales , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodosRESUMEN
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.
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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
Spinal muscular atrophy (SMA) is one of the most frequent causes of death in childhood. The disease's molecular basis is deletion or mutations in the SMN1 gene, which produces reduced survival motor neuron protein (SMN) levels. As a result, there is spinal motor neuron degeneration and a large increase in muscle atrophy, in which the ubiquitin-proteasome system (UPS) plays a significant role. In humans, a paralogue of SMN1, SMN2 encodes the truncated protein SMNΔ7. Structural differences between SMN and SMNΔ7 affect the interaction of the proteins with UPS and decrease the stability of the truncated protein. SMN loss affects the general ubiquitination process by lowering the levels of UBA1, one of the main enzymes in the ubiquitination process. We discuss how SMN loss affects both SMN stability and the general ubiquitination process, and how the proteins involved in ubiquitination could be used as future targets for SMA treatment.
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Atrofia Muscular Espinal , Proteína 1 para la Supervivencia de la Neurona Motora , Ubiquitinación , Humanos , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/terapia , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patología , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Proteína 1 para la Supervivencia de la Neurona Motora/metabolismo , Animales , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismo , Proteína 2 para la Supervivencia de la Neurona Motora/genética , Proteína 2 para la Supervivencia de la Neurona Motora/metabolismo , Enzimas Activadoras de UbiquitinaRESUMEN
Chronic kidney disease (CKD) is associated with significant reductions in lean body mass and in the mass of various tissues, including skeletal muscle, which causes fatigue and contributes to high mortality rates. In CKD, the cellular protein turnover is imbalanced, with protein degradation outweighing protein synthesis, leading to a loss of protein and cell mass, which impairs tissue function. As CKD itself, skeletal muscle wasting, or sarcopenia, can have various origins and causes, and both CKD and sarcopenia share common risk factors, such as diabetes, obesity, and age. While these pathologies together with reduced physical performance and malnutrition contribute to muscle loss, they cannot explain all features of CKD-associated sarcopenia. Metabolic acidosis, systemic inflammation, insulin resistance and the accumulation of uremic toxins have been identified as additional factors that occur in CKD and that can contribute to sarcopenia. Here, we discuss the elevation of systemic phosphate levels, also called hyperphosphatemia, and the imbalance in the endocrine regulators of phosphate metabolism as another CKD-associated pathology that can directly and indirectly harm skeletal muscle tissue. To identify causes, affected cell types, and the mechanisms of sarcopenia and thereby novel targets for therapeutic interventions, it is important to first characterize the precise pathologic changes on molecular, cellular, and histologic levels, and to do so in CKD patients as well as in animal models of CKD, which we describe here in detail. We also discuss the currently known pathomechanisms and therapeutic approaches of CKD-associated sarcopenia, as well as the effects of hyperphosphatemia and the novel drug targets it could provide to protect skeletal muscle in CKD.
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Músculo Esquelético , Insuficiencia Renal Crónica , Sarcopenia , Humanos , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/etiología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Animales , Sarcopenia/metabolismo , Sarcopenia/patología , Sarcopenia/etiologíaRESUMEN
Aging is accompanied by a progressive loss of skeletal muscle mass and strength. The mechanisms underlying this phenomenon are certainly multifactorial and still remain to be fully elucidated. Changes in the cell nucleus structure and function have been considered among the possible contributing causes. This review offers an overview of the current knowledge on skeletal muscle nuclei in aging, focusing on the impairment of nuclear pathways potentially involved in age-related muscle decline. In skeletal muscle two types of cells are present: fiber cells, constituting the contractile muscle mass and containing hundreds of myonuclei, and the satellite cells, i.e., the myogenic mononuclear stem cells occurring at the periphery of the fibers and responsible for muscle growth and repair. Research conducted on different experimental models and with different methodological approaches demonstrated that both the myonuclei and satellite cell nuclei of aged skeletal muscles undergo several structural and molecular alterations, affecting chromatin organization, gene expression, and transcriptional and post-transcriptional activities. These alterations play a key role in the impairment of muscle fiber homeostasis and regeneration, thus contributing to the age-related decrease in skeletal muscle mass and function.
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Núcleo Celular , Músculo Esquelético , Músculo Esquelético/metabolismo , Núcleo Celular/metabolismo , Fibras Musculares Esqueléticas/metabolismoRESUMEN
Chronic lung disease is often accompanied by disabling extrapulmonary symptoms, notably skeletal muscle dysfunction and atrophy. Moreover, the severity of respiratory symptoms correlates with decreased muscle mass and in turn lowered physical activity and survival rates. Previous models of muscle atrophy in chronic lung disease often modeled chronic obstructive pulmonary disease (COPD) and relied on cigarette smoke exposure and LPS stimulation, but these conditions independently affect skeletal muscle even without accompanying lung disease. Moreover, there is an emerging and pressing need to understand the extrapulmonary manifestations of long-term post-viral lung disease (PVLD) as found in COVID-19. Here, we examine the development of skeletal muscle dysfunction in the setting of chronic pulmonary disease caused by infection due to the natural pathogen Sendai virus using a mouse model of PVLD. We identify a significant decrease in myofiber size when PVLD is maximal at 49 days after infection. We find no change in the relative types of myofibers, but the greatest decrease in fiber size is localized to fast-twitch-type IIB myofibers based on myosin heavy chain immunostaining. Remarkably, all biomarkers of myocyte protein synthesis and degradation (total RNA, ribosomal abundance, and ubiquitin-proteasome expression) were stable throughout the acute infectious illness and chronic post-viral disease process. Together, the results demonstrate a distinct pattern of skeletal muscle dysfunction in a mouse model of long-term PVLD. The findings thereby provide new insights into prolonged limitations in exercise capacity in patients with chronic lung disease after viral infections and perhaps other types of lung injury.NEW & NOTEWORTHY Our study used a mouse model of post-viral lung disease to study the impact of chronic lung disease on skeletal muscle. The model reveals a decrease in myofiber size that is selective for specific types of myofibers and an alternative mechanism for muscle atrophy that might be independent of the usual markers of protein synthesis and degradation. The findings provide a basis for new therapeutic strategies to correct skeletal muscle dysfunction in chronic respiratory disease.
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COVID-19 , Enfermedad Pulmonar Obstructiva Crónica , Humanos , COVID-19/patología , Músculo Esquelético/metabolismo , Pulmón/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Atrofia Muscular/etiología , Atrofia Muscular/metabolismoRESUMEN
Skeletal muscle wasting and atrophy is highly prevalent in chronic renal failure (CRF) and increases the risk of mortality. According to our previous study, we speculate that urotensin II (UII) can induce skeletal muscle atrophy by upregulating ubiquitin-proteasome system(UPS) in CRF. C2C12 mouse myoblast cells were differentiated into myotubes, and myotubes were exposed to different concentrations of UII. Myotube diameters, myosin heavy chain(MHC), p-Fxo03A, skeletal muscle-specific E3 ubiquitin ligases such as muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx/atrogin1) were detected. Three animal models (the sham operation mice as normal control (NC) group, wild-type C57BL/6 mice with 5/6 nephrectomy (WT CRF) group, UII receptor gene knock out (UT KO) mice with 5/6 nephrectomy (UT KO CRF) group) were designed. Cross-sectional area (CSA) of skeletal muscle tissues in three animal models were measured, and western blot detected protein of UII, p-Fxo03A, MAFbx and MuRF1, and immunofluorescence assays explored the satellite cell marker of Myod1 and Pax7, and PCR arrays detected the muscle protein degradation genes, protein synthesis genes and the genes which were involved in muscle components. UII could decrease mouse myotube diameters, and upregulate dephosphorylated Fxo03A protein. MAFbx and MuRF1 were higher in WT CRF group than that in NC group, but after UII receptor gene was knocked out (UT KO CRF), their expressions were downregulated. UII could inhibit the expression of Myod1 but not Pax7 in animal study. We first demonstrate that skeletal muscle atrophy induced by UII associated with upregulating ubiquitin-proteasome system and inhibiting the differentiation of satellite cells in CRF mice.
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Fallo Renal Crónico , Complejo de la Endopetidasa Proteasomal , Ratones , Animales , Ubiquitina , Proteínas Ligasas SKP Cullina F-box/genética , Proteínas Ligasas SKP Cullina F-box/metabolismo , Ratones Endogámicos C57BL , Atrofia Muscular , Músculo Esquelético/metabolismo , Fibras Musculares Esqueléticas , Fallo Renal Crónico/metabolismo , Fallo Renal Crónico/patología , Diferenciación CelularRESUMEN
Skeletal muscle atrophy is a prevalent complication in multiple chronic diseases and disuse conditions. Fibroblast growth factor-inducible 14 (Fn14) is a member of the TNF receptor superfamily and a bona fide receptor of the TWEAK cytokine. Accumulating evidence suggests that Fn14 levels are increased in catabolic conditions as well as during exercise. However, the role of Fn14 in the regulation of skeletal muscle mass and function remains poorly understood. In this study, through the generation of novel skeletal muscle-specific Fn14-knockout mice, we have investigated the muscle role of Fn14 in the regulation of exercise capacity and denervation-induced muscle atrophy. Our results demonstrate that there was no difference in skeletal muscle mass between control and muscle-specific Fn14-knockout mice. Nevertheless, the deletion of Fn14 in skeletal muscle significantly improved exercise capacity and resistance to fatigue. This effect of Fn14 deletion is associated with an increased proportion of oxidative myofibers and higher capillaries number per myofiber in skeletal muscle. Furthermore, our results demonstrate that targeted deletion of Fn14 inhibits denervation-induced muscle atrophy in adult mice. Deletion of Fn14 reduced the expression of components of the ubiquitin-proteasome system and non-canonical NF-kappa B signaling in denervated skeletal muscle, as well as increased the phosphorylation of Akt kinase and FoxO3a transcription factor. Collectively, our results demonstrate that targeted inhibition of Fn14 improves exercise tolerance and inhibits denervation-induced muscle atrophy in adult mice.
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Tolerancia al Ejercicio , Factores de Necrosis Tumoral , Ratones , Animales , Receptor de TWEAK/genética , Factores de Necrosis Tumoral/metabolismo , Atrofia Muscular/metabolismo , Ratones NoqueadosRESUMEN
Catabolic conditions, such as starvation, inactivity, and cancer cachexia, induce Forkhead box O (FOXO) transcription factor(s) expression and severe muscle atrophy via the induction of ubiquitin-proteasome system-mediated muscle proteolysis, resulting in frailty and poor quality of life. Although FOXOs are clearly essential for the induction of muscle atrophy, it is unclear whether there are other factors involved in the FOXO-mediated transcriptional regulation. As such, we identified FOXO-CCAAT/enhancer-binding protein δ (C/EBPδ) signaling pathway as a novel proteolytic pathway. By comparing the gene expression profiles of FOXO1-transgenic (gain-of-function model) and FOXO1,3a,4-/- (loss-of-function model) mice, we identified several novel FOXO1-target genes in skeletal muscle including Redd1, Sestrin1, Castor2, Chac1, Depp1, Lat3, as well as C/EBPδ. During starvation, C/EBPδ abundance was increased in a FOXOs-dependent manner. Notably, knockdown of C/EBPδ prevented the induction of the ubiquitin-proteasome system and decrease of myofibers in FOXO1-activated myotubes. Conversely, C/EBPδ overexpression in primary myotubes induced myotube atrophy. Furthermore, we demonstrated that FOXO1 enhances the promoter activity of target genes in cooperation with C/EBPδ and ATF4. This research comprehensively identifies novel FOXO1 target genes in skeletal muscle and clarifies the pathophysiological role of FOXO1, a master regulator of skeletal muscle atrophy.
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Factor de Transcripción Activador 4/metabolismo , Proteína delta de Unión al Potenciador CCAAT/metabolismo , Ayuno/metabolismo , Proteína Forkhead Box O1/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Transcripción Genética/fisiología , Animales , Línea Celular , Regulación de la Expresión Génica/fisiología , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Regiones Promotoras Genéticas/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Transducción de Señal/fisiología , Ubiquitina/metabolismoRESUMEN
Skeletal muscle atrophy is known to be a marker for nutritional deficiency. The diaphragm is both a skeletal muscle and a respiratory muscle. There is not enough data in the literature about the change in diaphragm thickness (DT) in children with malnutrition. We think that malnutrition may have negative effects on diaphragm thickness. Therefore, in this study, we aimed to compare the diaphragm thicknesses of pediatric patients with primary malnutrition and a healthy control group. The DT of pediatric patients diagnosed with primary malnutrition by a pediatric gastroenterologist was prospectively evaluated by a radiology specialist by ultrasonography (USG). The obtained data were statistically compared with the data of the healthy control group. There was no statistically significant difference between the groups in terms of age and gender (p = 0.244, p = 0.494). We found that right and left diaphragm thicknesses were significantly thinner in the malnourished group than in the healthy control group (p = 0.001, p = 0.009, respectively). We found that right and left diaphragm thicknesses were thinner in those with moderate and severe malnutrition compared to the normal group (p < 0.001, p = 0.003, respectively). We found a significant weak positive correlation between weight and height Z score and right and left diaphragm thickness (respectively, r: 0.297, p < 0.001; r: 0.301, p < 0.001). Conclusion: Malnutrition is a disease that affects all systems. Our study shows that the DT is thinner in patients with malnutrition. What is Known: â¢Malnutrition causes skeletal muscle atrophy. What is New: â¢Diaphragm muscle thickness decreases in malnutrition. â¢There is a significant positive correlation between diaphragm muscle thickness and height, weight and BMI z scores.