scholarly journals The TWEAK–Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice

2010 ◽  
Vol 188 (6) ◽  
pp. 833-849 ◽  
Author(s):  
Ashwani Mittal ◽  
Shephali Bhatnagar ◽  
Akhilesh Kumar ◽  
Estelle Lach-Trifilieff ◽  
Sandrine Wauters ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Fiber Type ◽  
Nuclear Factor Κb ◽  
Skeletal Muscle Atrophy ◽  
Muscle Proteins ◽  
Cross Sectional ◽  
Transgenic Expression ◽  
Genetic Ablation ◽  
Skeletal Muscle Wasting

Skeletal muscle atrophy occurs in a variety of clinical settings, including cachexia, disuse, and denervation. Inflammatory cytokines have been shown to be mediators of cancer cachexia; however, the role of cytokines in denervation- and immobilization-induced skeletal muscle loss remains unknown. In this study, we demonstrate that a single cytokine, TNF-like weak inducer of apoptosis (TWEAK), mediates skeletal muscle atrophy that occurs under denervation conditions. Transgenic expression of TWEAK induces atrophy, fibrosis, fiber-type switching, and the degradation of muscle proteins. Importantly, genetic ablation of TWEAK decreases the loss of muscle proteins and spared fiber cross-sectional area, muscle mass, and strength after denervation. Expression of the TWEAK receptor Fn14 (fibroblast growth factor–inducible receptor 14) and not the cytokine is significantly increased in muscle upon denervation, demonstrating an unexpected inside-out signaling pathway; the receptor up-regulation allows for TWEAK activation of nuclear factor κB, causing an increase in the expression of the E3 ubiquitin ligase MuRF1. This study reveals a novel mediator of skeletal muscle atrophy and indicates that the TWEAK–Fn14 system is an important target for preventing skeletal muscle wasting.

scholarly journals Physiology of a Microgravity Environment Invited Review: Microgravity and skeletal muscle

2000 ◽  
Vol 89 (2) ◽  
pp. 823-839 ◽  
Author(s):  
Robert H. Fitts ◽  
Danny R. Riley ◽  
Jeffrey J. Widrick
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Thin Filament ◽  
Molecular Mechanisms ◽  
Skeletal Muscle Atrophy ◽  
Microgravity Environment ◽  
Type I ◽  
Fiber Types ◽  
Maximal Velocity ◽  
Cross Sectional

Spaceflight (SF) has been shown to cause skeletal muscle atrophy; a loss in force and power; and, in the first few weeks, a preferential atrophy of extensors over flexors. The atrophy primarily results from a reduced protein synthesis that is likely triggered by the removal of the antigravity load. Contractile proteins are lost out of proportion to other cellular proteins, and the actin thin filament is lost disproportionately to the myosin thick filament. The decline in contractile protein explains the decrease in force per cross-sectional area, whereas the thin-filament loss may explain the observed postflight increase in the maximal velocity of shortening in the type I and IIa fiber types. Importantly, the microgravity-induced decline in peak power is partially offset by the increased fiber velocity. Muscle velocity is further increased by the microgravity-induced expression of fast-type myosin isozymes in slow fibers (hybrid I/II fibers) and by the increased expression of fast type II fiber types. SF increases the susceptibility of skeletal muscle to damage, with the actual damage elicited during postflight reloading. Evidence in rats indicates that SF increases fatigability and reduces the capacity for fat oxidation in skeletal muscles. Future studies will be required to establish the cellular and molecular mechanisms of the SF-induced muscle atrophy and functional loss and to develop effective exercise countermeasures.

scholarly journals β-Cryptoxanthin Improves p62 Accumulation and Muscle Atrophy in the Soleus Muscle of Senescence-Accelerated Mouse-Prone 1 Mice

Nutrients ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2180
Author(s):  
Mari Noguchi ◽  
Tomoya Kitakaze ◽  
Yasuyuki Kobayashi ◽  
Katsuyuki Mukai ◽  
Naoki Harada ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Soleus Muscle ◽  
Muscle Fibers ◽  
Skeletal Muscle Atrophy ◽  
Related Factor ◽  
Related Factors ◽  
Cross Sectional ◽  
Senescence Accelerated Mouse

We investigated the effects of β-cryptoxanthin on skeletal muscle atrophy in senescence-accelerated mouse-prone 1 (SAMP1) mice. For 15 weeks, SAMP1 mice were intragastrically administered vehicle or β-cryptoxanthin. At 35 weeks of age, the skeletal muscle mass in SAMP1 mice was reduced compared with that in control senescence-accelerated mouse-resistant 1 (SAMR1) mice. β-cryptoxanthin increased muscle mass with an increase in the size of muscle fibers in the soleus muscle of SAMP1 mice. The expressions of autophagy-related factors such as beclin-1, p62, LC3-I, and LC3-II were increased in the soleus muscle of SAMP1 mice; however, β-cryptoxanthin administration inhibited this increase. Unlike in SAMR1 mice, p62 was punctately distributed throughout the cytosol in the soleus muscle fibers of SAMP1 mice; however, β-cryptoxanthin inhibited this punctate distribution. The cross-sectional area of p62-positive fiber was smaller than that of p62-negative fiber, and the ratio of p62-positive fibers to p62-negative fibers was increased in SAMP1 mice. β-cryptoxanthin decreased this ratio in SAMP1 mice. Furthermore, β-cryptoxanthin decreased the autophagy-related factor expression in murine C2C12 myotube. The autophagy inhibitor bafilomycin A1, but not the proteasome inhibitor MG132, inhibited the β-cryptoxanthin-induced decrease in p62 and LC3-II expressions. These results indicate that β-cryptoxanthin inhibits the p62 accumulation in fibers and improves muscle atrophy in the soleus muscle of SAMP1 mice.

scholarly journals Nuclear factor-κB signalling and transcriptional regulation in skeletal muscle atrophy

2012 ◽  
Vol 98 (1) ◽  
pp. 19-24 ◽  
Author(s):  
Robert W. Jackman ◽  
Evangeline W. Cornwell ◽  
Chia-Ling Wu ◽  
Susan C. Kandarian
Keyword(s):  
Skeletal Muscle ◽  
Transcriptional Regulation ◽  
Muscle Atrophy ◽  
Nuclear Factor Κb ◽  
Skeletal Muscle Atrophy ◽  
Nuclear Factor

scholarly journals UBE2L3, a Partner of MuRF1/TRIM63, Is Involved in the Degradation of Myofibrillar Actin and Myosin

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1974
Author(s):  
Dulce Peris-Moreno ◽  
Mélodie Malige ◽  
Agnès Claustre ◽  
Andrea Armani ◽  
Cécile Coudy-Gandilhon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Ubiquitin Proteasome System ◽  
Contractile Proteins ◽  
Skeletal Muscle Atrophy ◽  
C2c12 Myotubes ◽  
Skeletal Muscle Wasting ◽  
Life Prognosis ◽  
Ubiquitin Conjugating Enzymes ◽  
Alpha Actin

The ubiquitin proteasome system (UPS) is the main player of skeletal muscle wasting, a common characteristic of many diseases (cancer, etc.) that negatively impacts treatment and life prognosis. Within the UPS, the E3 ligase MuRF1/TRIM63 targets for degradation several myofibrillar proteins, including the main contractile proteins alpha-actin and myosin heavy chain (MHC). We previously identified five E2 ubiquitin-conjugating enzymes interacting with MuRF1, including UBE2L3/UbcH7, that exhibited a high affinity for MuRF1 (KD = 50 nM). Here, we report a main effect of UBE2L3 on alpha-actin and MHC degradation in catabolic C2C12 myotubes. Consistently UBE2L3 knockdown in Tibialis anterior induced hypertrophy in dexamethasone (Dex)-treated mice, whereas overexpression worsened the muscle atrophy of Dex-treated mice. Using combined interactomic approaches, we also characterized the interactions between MuRF1 and its substrates alpha-actin and MHC and found that MuRF1 preferentially binds to filamentous F-actin (KD = 46.7 nM) over monomeric G-actin (KD = 450 nM). By contrast with actin that did not alter MuRF1–UBE2L3 affinity, binding of MHC to MuRF1 (KD = 8 nM) impeded UBE2L3 binding, suggesting that differential interactions prevail with MuRF1 depending on both the substrate and the E2. Our data suggest that UBE2L3 regulates contractile proteins levels and skeletal muscle atrophy.

scholarly journals Effect of Quercetin on Dexamethasone-Induced C2C12 Skeletal Muscle Cell Injury

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3267 ◽  
Author(s):  
Chun Chen ◽  
Jai-Sing Yang ◽  
Chi-Cheng Lu ◽  
Yu-Jen Chiu ◽  
Hung-Che Chen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Fruits And Vegetables ◽  
Cell Injury ◽  
C2c12 Cells ◽  
Skeletal Muscle Atrophy ◽  
Protective Effects ◽  
Cross Sectional ◽  
Hydroxyl Free Radical ◽  
C2c12 Skeletal Muscle Cells

Glucocorticoids are widely used anti-inflammatory drugs in clinical settings. However, they can induce skeletal muscle atrophy by reducing fiber cross-sectional area and myofibrillar protein content. Studies have proven that antioxidants can improve glucocorticoid-induced skeletal muscle atrophy. Quercetin is a potent antioxidant flavonoid widely distributed in fruits and vegetables and has shown protective effects against dexamethasone-induced skeletal muscle atrophy. In this study, we demonstrated that dexamethasone significantly inhibited cell growth and induced cell apoptosis by stimulating hydroxyl free radical production in C2C12 skeletal muscle cells. Our results evidenced that quercetin increased C2C12 skeletal cell viability and exerted antiapoptotic effects on dexamethasone-treated C2C12 cells by regulating mitochondrial membrane potential (ΔΨm) and reducing oxidative species. Quercetin can protect against dexamethasone-induced muscle atrophy by regulating the Bax/Bcl-2 ratio at the protein level and abnormal ΔΨm, which leads to the suppression of apoptosis.

scholarly journals Serum Creatinine as a Potential Biomarker of Skeletal Muscle Atrophy in Non-small Cell Lung Cancer Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Willian das Neves ◽  
Christiano R. R. Alves ◽  
Ana Paula de Souza Borges ◽  
Gilberto de Castro
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Serum Creatinine ◽  
Muscle Atrophy ◽  
Normal Serum ◽  
Skeletal Muscle Atrophy ◽  
Cross Sectional ◽  
Tissue Area ◽  
Nsclc Patients ◽  
Low Serum

Objectives: Identifying simple biomarkers to determine muscle atrophy in non-small-cell lung cancer (NSCLC) patients remains a critical research gap. Since creatinine is mainly a product from intramuscular creatine metabolism, we tested the hypothesis that low serum creatinine levels would be associated to skeletal muscle atrophy in NSCLC patients.Materials and Methods: This is a prospective cohort study including 106 treatment-naive patients with histologically confirmed stage IV NSCLC. All patients performed routine serum creatinine laboratory tests. We divided patients into two groups based on low (<0.7 mg/dL for male and <0.5 mg/dL for female) or normal creatinine levels. We compared body mass index (BMI), psoas muscle cross-sectional area, adipose tissue area and complete blood counts between groups.Results: Male and female NSCLC patients with low serum creatinine levels had low muscle cross-sectional area as compared to patients with normal serum creatinine levels. Male NSCLC patients with low serum creatinine also displayed reduced BMI, reduced adipose tissue area, and elevated systemic inflammation compared to NSCLC patients with normal serum creatinine levels. There were no significant differences between female groups for BMI, adipose tissue area and inflammatory markers.Conclusions: Serum creatinine is a potential prognostic biomarker of skeletal muscle atrophy in NSCLC patients. Since serum creatinine is a simple and accessible measurement, we suggest that it should be monitored in longitudinal follow-up of NSCLC patients as a biomarker of muscle atrophy.

scholarly journals Polyglutamine-Expanded Androgen Receptor Alteration of Skeletal Muscle Homeostasis and Myonuclear Aggregation Are Affected by Sex, Age and Muscle Metabolism

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 325 ◽  
Author(s):  
Mathilde Chivet ◽  
Caterina Marchioretti ◽  
Marco Pirazzini ◽  
Diana Piol ◽  
Chiara Scaramuzzino ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Androgen Receptor ◽  
Muscle Atrophy ◽  
Fiber Type ◽  
Sodium Dodecyl ◽  
Premature Death ◽  
Motor Dysfunction ◽  
Skeletal Muscle Atrophy ◽  
Muscle Pathology ◽  
Gain Of Function

Polyglutamine (polyQ) expansions in the androgen receptor (AR) gene cause spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease characterized by lower motor neuron (MN) loss and skeletal muscle atrophy, with an unknown mechanism. We generated new mouse models of SBMA for constitutive and inducible expression of mutant AR and performed biochemical, histological and functional analyses of phenotype. We show that polyQ-expanded AR causes motor dysfunction, premature death, IIb-to-IIa/IIx fiber-type change, glycolytic-to-oxidative fiber-type switching, upregulation of atrogenes and autophagy genes and mitochondrial dysfunction in skeletal muscle, together with signs of muscle denervation at late stage of disease. PolyQ expansions in the AR resulted in nuclear enrichment. Within the nucleus, mutant AR formed 2% sodium dodecyl sulfate (SDS)-resistant aggregates and inclusion bodies in myofibers, but not spinal cord and brainstem, in a process exacerbated by age and sex. Finally, we found that two-week induction of expression of polyQ-expanded AR in adult mice was sufficient to cause premature death, body weight loss and muscle atrophy, but not aggregation, metabolic alterations, motor coordination and fiber-type switch, indicating that expression of the disease protein in the adulthood is sufficient to recapitulate several, but not all SBMA manifestations in mice. These results imply that chronic expression of polyQ-expanded AR, i.e. during development and prepuberty, is key to induce the full SBMA muscle pathology observed in patients. Our data support a model whereby chronic expression of polyQ-expanded AR triggers muscle atrophy through toxic (neomorphic) gain of function mechanisms distinct from normal (hypermorphic) gain of function mechanisms.

Endotoxin-induced skeletal muscle wasting is prevented by angiotensin-(1–7) through a p38 MAPK-dependent mechanism

2015 ◽  
Vol 129 (6) ◽  
pp. 461-476 ◽  
Author(s):  
María Gabriela Morales ◽  
Hugo Olguín ◽  
Gabriella Di Capua ◽  
Enrique Brandan ◽  
Felipe Simon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
P38 Mapk ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Skeletal Muscle Atrophy ◽  
Skeletal Muscle Wasting ◽  
Catabolic Response ◽  
Dependent Mechanism

In this study we determined that angiotensin-(1–7) is a novel peptide that prevents the skeletal muscle atrophy observed in a model of sepsis by inhibiting the catabolic response developed in skeletal muscle and improving its performance.

Muscle protection during hibernation of Daurian ground squirrels (Spermophilus dauricus): role of atrogin-1, MuRF1, and fiber-type transition

2016 ◽  
Vol 94 (9) ◽  
pp. 619-629 ◽  
Author(s):  
Kai Dang ◽  
Ban Feng ◽  
Yunfang Gao ◽  
Naifei Hu ◽  
Shanfeng Jiang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Muscle Atrophy ◽  
Hind Limb ◽  
Fiber Type ◽  
Ground Squirrels ◽  
Skeletal Muscle Atrophy ◽  
Type I ◽  
Protective Mechanisms ◽  
Edl Muscle

We investigated the mechanism of protection from skeletal muscle atrophy in the hind limb extensor digitorum longus (EDL) muscle of hibernating Daurian ground squirrels (Spermophilus dauricus Brandt, 1843). The effects of unrestrained hibernation and 14 day hind limb unloading (HLU) on EDL were studied in three seasons (summer, autumn, and winter). Atrogin-1 and MuRF1 mRNA skeletal muscle expression, wet muscle mass, and muscle to body mass ratios were unchanged during hibernation in all three seasons. EDL mass measurements decreased following HLU and atrogin-1 and MuRF1 mRNA expression increased. In summer, atrogin-1 and MuRF1 mRNA expression increased by 85% and 75%, respectively; in autumn, by 95% and 69%, respectively; and in winter, by 91% and 65%, respectively (P < 0.05). In the HLU group, microscopic skeletal muscle changes were present, including a reduction in the percentage of type-I skeletal muscle fibers. Fat storage in Daurian ground squirrels and a shorter photoperiod during hibernation did not affect the protective mechanisms that prevented skeletal muscle atrophy. The results of this study suggest that the stable expression of atrogin-1 and MuRF1 and the transition from fast glycolytic fibers to slow oxidative fibers are associated with a lack of skeletal muscle atrophy in the hibernating Daurian ground squirrel.

scholarly journals HDAC4 Knockdown Alleviates Denervation-Induced Muscle Atrophy by Inhibiting Myogenin-Dependent Atrogene Activation

2021 ◽  
Vol 15 ◽  
Author(s):  
Wenjing Ma ◽  
Yong Cai ◽  
Yuntian Shen ◽  
Xin Chen ◽  
Lilei Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscular Atrophy ◽  
Underlying Mechanism ◽  
Skeletal Muscle Atrophy ◽  
Regulation Mechanism ◽  
Type I ◽  
Muscle Adaptation ◽  
Cross Sectional

Denervation can activate the catabolic pathway in skeletal muscle and lead to progressive skeletal muscle atrophy. At present, there is no effective treatment for muscle atrophy. Histone deacetylase 4 (HDAC4) has recently been found to be closely related to muscle atrophy, but the underlying mechanism of HDAC4 in denervation-induced muscle atrophy have not been described clearly yet. In this study, we found that the expression of HDAC4 increased significantly in denervated skeletal muscle. HDAC4 inhibition can effectively diminish denervation-induced muscle atrophy, reduce the expression of muscle specific E3 ubiquitin ligase (MuRF1 and MAFbx) and autophagy related proteins (Atg7, LC3B, PINK1 and BNIP3), inhibit the transformation of type I fibers to type II fibers, and enhance the expression of SIRT1 and PGC-1 α. Transcriptome sequencing and bioinformatics analysis was performed and suggested that HDAC4 may be involved in denervation-induced muscle atrophy by regulating the response to denervation involved in the regulation of muscle adaptation, cell division, cell cycle, apoptotic process, skeletal muscle atrophy, and cell differentiation. STRING analysis showed that HDAC4 may be involved in the process of muscle atrophy by directly regulating myogenin (MYOG), cell cycle inhibitor p21 (CDKN1A) and salt induced kinase 1 (SIK1). MYOG was significantly increased in denervated skeletal muscle, and MYOG inhibition could significantly alleviate denervation-induced muscle atrophy, accompanied by the decreased MuRF1 and MAFbx. MYOG overexpression could reduce the protective effect of HDAC4 inhibition on denervation-induced muscle atrophy, as evidenced by the decreased muscle mass and cross-sectional area of muscle fibers, and the increased mitophagy. Taken together, HDAC4 inhibition can alleviate denervation-induced muscle atrophy by reducing MYOG expression, and HDAC4 is also directly related to CDKN1A and SIK1 in skeletal muscle, which suggests that HDAC4 inhibitors may be a potential drug for the treatment of neurogenic muscle atrophy. These results not only enrich the molecular regulation mechanism of denervation-induced muscle atrophy, but also provide the experimental basis for HDAC4-MYOG axis as a new target for the prevention and treatment of muscular atrophy.

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