scholarly journals Urotensin II Induces Mice Skeletal Muscle Atrophy Associated with Enhanced Autophagy and Inhibited Irisin Precursor (Fibronectin Type III Domain Containing 5) Expression in Chronic Renal Failure

2019 ◽  
Vol 44 (4) ◽  
pp. 479-495 ◽  
Author(s):  
Ya-Jing Pan ◽  
Si-Jia Zhou ◽  
Jin Feng ◽  
Qiong Bai ◽  
La-Ta A ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Renal Failure ◽  
Chronic Renal Failure ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
Urotensin Ii ◽  
Muscle Weight ◽  
Fibronectin Type Iii ◽  
Fibronectin Type Iii Domain ◽  
Fibronectin Type

Background/Aims: Skeletal muscle atrophy is one of the main manifestations of protein energy wasting. We hypothesized that urotensin II (UII) can lead to skeletal muscle atrophy through upregulating autophagy and affecting Irisin precursor fibronectin type III domain containing 5 (FNDC5) expressions. Methods: Three animal models (the sham operation, wild-type C57BL/6 mice with 5/6 nephrectomy, UII receptor (UT) gene knockout (UTKO) mice with 5/6 nephrectomy) were designed. Skeletal muscle weight, cross-sectional area (CSA) along with UII, FNDC5, LC3, and p62 expression were investigated. C2C12 cells were differentiated for up to 4 days into myotubes. These cells were then exposed to different UII concentrations (10–5 to 10–7 M) for 6–12 h and analyzed for the expressions of autophagic markers. These cells were also exposed to the same predetermined UII concentrations for 48–72 h and analyzed for the FNDC5 expression. Myotube diameter was measured. Results: Upregulation of UII expression in skeletal muscle tissue was accompanied by reduced muscle weight and skeletal muscle CSA in the 2 posterior limbs, upregulated autophagy markers expression, and downregulated FNDC5 expression in 5/6 nephrectomy mice. The decrease of skeletal muscle weight, skeletal muscle CSA, downregulation of FNDC5 expression, and the upregulation of autophagy markers were inhibited in UTKO with 5/6 nephrectomy mice. Our in vitrostudy showed that UII could directly decrease myotube diameter, induce autophagy markers upregulation, and inhibit expression of FNDC5. When UII receptor gene was interfered by UT-specific siRNA, UII induced autophagy markers upregulation and FNDC5 downregulation were inhibited. Conclusion: We are the first to verify UII induces mice skeletal muscle atrophy associated with enhanced skeletal muscle autophagy and inhibited FNDC5 expression in chronic renal failure.

scholarly journals Iron metabolism abnormality in skeletal muscle atrophy associated with chronic renal failure

2019 ◽  
Vol 92 (0) ◽  
pp. 3-P-078
Author(s):  
Yuya Horinouchi ◽  
Yasumasa Ikeda ◽  
Hirofumi Hamano ◽  
Masaki Imanishi ◽  
Keijo Fukushima ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Renal Failure ◽  
Chronic Renal Failure ◽  
Muscle Atrophy ◽  
Iron Metabolism ◽  
Skeletal Muscle Atrophy

scholarly journals Interaction of CREB and PGC-1α Induces Fibronectin Type III Domain-Containing Protein 5 Expression in C2C12 Myotubes

2018 ◽  
Vol 50 (4) ◽  
pp. 1574-1584 ◽  
Author(s):  
Xiu-ying Yang ◽  
Margaret C.L. Tse ◽  
Xiang Hu ◽  
Wei-hua Jia ◽  
Guan-hua Du ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Metabolic Effects ◽  
Hek293 Cells ◽  
Metabolic Phenotype ◽  
C2c12 Myotubes ◽  
Type Iii ◽  
Fibronectin Type Iii ◽  
Fibronectin Type Iii Domain ◽  
Fibronectin Type

Background/Aims: Fibronectin type III domain-containing protein 5 (FNDC5), also known as irisin, is a myokine secreted from muscle in response to exercise. However, the molecular mechanisms that regulate FNDC5 expression and the functional significance of irisn in skeletal muscle remain unknown. In this study, we explored the potential pathways that induce FNDC5 expression and delineated the metabolic effects of irisin on skeletal muscle. Methods: C2C12 myotubes were treated with drugs at various concentrations and durations. The expression and activation of genes were measured by real-time polymerase chain reaction (qRT-PCR) and Western blotting. Oxidative phosphorylation was quantified by measuring the oxygen consumption rate (OCR). Results: We found that the exercise-mimicking treatment (cAMP, forskolin and isoproterenol) increased Fndc5 expression in C2C12 myotubes. CREB over-expressed C2C12 myotubes displayed higher Fndc5 expression. CREB over-expression also promoted peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) expression. PGC-1α-induced Fndc5 expression was blocked when the dominant negative form of CREB (S133A) was present. PGC-1α mutation (S570A) also decreased Fndc5 expression. Immunoprecipitation showed that overexpressed PGC-1α complexed with CREB in HEK293 cells. C2C12 myotubes treated with forskolin also increased endogenous CREB and PGC-1α binding. Functionally, irisin treatment increased mitochondrial respiration, enhanced ATP production, promoted fatty acid oxidation but decreased glycolysis in myotubes. Conclusion: Our observation indicates that cAMP-mediated PGC-1α/CREB interaction triggers Fndc5 expression, which acts as an autocrine/paracrine to shape the metabolic phenotype of myotubes.

scholarly journals Forkhead box O3 plays a role in skeletal muscle atrophy through expression of E3 ubiquitin ligases MuRF-1 and atrogin-1 in Cushing’s syndrome

2017 ◽  
Vol 312 (6) ◽  
pp. E495-E507 ◽  
Author(s):  
Seol-Hee Kang ◽  
Hae-Ahm Lee ◽  
Mina Kim ◽  
Eunjo Lee ◽  
Uy Dong Sohn ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Cushing’S Syndrome ◽  
Ubiquitin Ligases ◽  
Cushing's Syndrome ◽  
Skeletal Muscle Atrophy ◽  
E3 Ubiquitin Ligases ◽  
Sprague Dawley ◽  
Muscle Weight ◽  
Forkhead Box

Cushing’s syndrome is caused by overproduction of the adrenocorticotropic hormone (ACTH), which stimulates the adrenal grand to make cortisol. Skeletal muscle wasting occurs in pathophysiological response to Cushing’s syndrome. The forkhead box (FOX) protein family has been implicated as a key regulator of muscle loss under conditions such as diabetes and sepsis. However, the mechanistic role of the FOXO family in ACTH-induced muscle atrophy is not understood. We hypothesized that FOXO3a plays a role in muscle atrophy through expression of the E3 ubiquitin ligases, muscle RING finger protein-1 (MuRF-1), and atrogin-1 in Cushing’s syndrome. For establishment of a Cushing’s syndrome animal model, Sprague-Dawley rats were implanted with osmotic minipumps containing ACTH (40 ng·kg−1·day−1). ACTH infusion significantly reduced muscle weight. In ACTH-infused rats, MuRF-1, atrogin-1, and FOXO3a were upregulated and the FOXO3a promoter was targeted by the glucocorticoid receptor (GR). Transcriptional activity and expression of FOXO3a were significantly decreased by the GR antagonist RU486. Treatment with RU486 reduced MuRF-1 and atrogin-1 expression in accordance with reduced enrichment of FOXO3a and Pol II on the promoters. Knockdown of FOXO3a prevented dexamethasone-induced MuRF-1 and atrogin-1 expression. These results indicate that FOXO3a plays a role in muscle atrophy through expression of MuRF-1 and atrogin-1 in Cushing’s syndrome.

scholarly journals Metronidazole Causes Skeletal Muscle Atrophy and Modulates Muscle Chronometabolism

2018 ◽  
Vol 19 (8) ◽  
pp. 2418 ◽  
Author(s):  
Ravikumar Manickam ◽  
Hui Oh ◽  
Chek Tan ◽  
Eeswari Paramalingam ◽  
Walter Wahli
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Metabolic Regulation ◽  
Target Genes ◽  
Clock Genes ◽  
Tibialis Anterior Muscle ◽  
Skeletal Muscle Atrophy ◽  
Muscle Weight ◽  
Expression Of Genes ◽  
Specific Pathogen

Antibiotics lead to increased susceptibility to colonization by pathogenic organisms, with different effects on the host-microbiota relationship. Here, we show that metronidazole treatment of specific pathogen-free (SPF) mice results in a significant increase of the bacterial phylum Proteobacteria in fecal pellets. Furthermore, metronidazole in SPF mice decreases hind limb muscle weight and results in smaller fibers in the tibialis anterior muscle. In the gastrocnemius muscle, metronidazole causes upregulation of Hdac4, myogenin, MuRF1, and atrogin1, which are implicated in skeletal muscle neurogenic atrophy. Metronidazole in SPF mice also upregulates skeletal muscle FoxO3, described as involved in apoptosis and muscle regeneration. Of note, alteration of the gut microbiota results in increased expression of the muscle core clock and effector genes Cry2, Ror-β, and E4BP4. PPARγ and one of its important target genes, adiponectin, are also upregulated by metronidazole. Metronidazole in germ-free (GF) mice increases the expression of other core clock genes, such as Bmal1 and Per2, as well as the metabolic regulators FoxO1 and Pdk4, suggesting a microbiota-independent pharmacologic effect. In conclusion, metronidazole in SPF mice results in skeletal muscle atrophy and changes the expression of genes involved in the muscle peripheral circadian rhythm machinery and metabolic regulation.

Deficiency of inducible nitric oxide synthase attenuates immobilization-induced skeletal muscle atrophy in mice

2012 ◽  
Vol 113 (1) ◽  
pp. 114-123 ◽  
Author(s):  
Sang-Keun Bae ◽  
Hey-Na Cha ◽  
Tae-Jin Ju ◽  
Yong-Woon Kim ◽  
Hee Sun Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Inducible Nitric Oxide Synthase ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
Muscle Weight ◽  
Protein Levels ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

The present study examined the effects of inducible nitric oxide synthase (iNOS) deficiency on skeletal muscle atrophy in single leg-immobilized iNOS knockout (KO) and wild-type (WT) mice. The left leg was immobilized for 1 wk, and the right leg was used as the control. Muscle weight and contraction-stimulated glucose uptake were reduced by immobilization in WT mice, which was accompanied with increased iNOS expression in skeletal muscle. Deficiency of iNOS attenuated muscle weight loss and the reduction in contraction-stimulated glucose uptake by immobilization. Phosphorylation of Akt, mTOR, and p70S6K was reduced to a similar extent by immobilization in both WT and iNOS KO mice. Immobilization decreased FoxO1 phosphorylation and increased mRNA and protein levels of MuRF1 and atrogin-1 in WT mice, which were attenuated in iNOS KO mice. Aconitase and superoxide dismutase activities were reduced by immobilization in WT mice, and deficiency of iNOS normalized these enzyme activities. Increased nitrotyrosine and carbonylated protein levels by immobilization in WT mice were reversed in iNOS KO mice. Phosphorylation of ERK and p38 was increased by immobilization in WT mice, which was reduced in iNOS KO mice. Immobilization-induced muscle atrophy was also attenuated by an iNOS-specific inhibitor N6-(1-iminoethyl)-l-lysine, and this finding was accompanied by increased FoxO1 phosphorylation and reduced MuRF1 and atrogin-1 levels. These results suggest that deficiency of iNOS attenuates immobilization-induced skeletal muscle atrophy through reduced oxidative stress, and iNOS-induced oxidative stress may be required for immobilization-induced skeletal muscle atrophy.

scholarly journals Small-Molecule Chemical Knockdown of MuRF1 in Melanoma Bearing Mice Attenuates Tumor Cachexia Associated Myopathy

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2272
Author(s):  
Volker Adams ◽  
Victoria Gußen ◽  
Sergey Zozulya ◽  
André Cruz ◽  
Anselmo Moriscot ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Citrate Synthase ◽  
Malignant Tumors ◽  
Ubiquitin Proteasome System ◽  
Muscle Performance ◽  
Skeletal Muscle Atrophy ◽  
Muscle Weight ◽  
Ubiquitin Proteasome ◽  
Progressive Weakness

Patients with malignant tumors frequently suffer during disease progression from a syndrome referred to as cancer cachexia (CaCax): CaCax includes skeletal muscle atrophy and weakness, loss of bodyweight, and fat tissues. Currently, there are no FDA (Food and Drug Administration) approved treatments available for CaCax. Here, we studied skeletal muscle atrophy and dysfunction in a murine CaCax model by injecting B16F10 melanoma cells into mouse thighs and followed mice during melanoma outgrowth. Skeletal muscles developed progressive weakness as detected by wire hang tests (WHTs) during days 13–23. Individual muscles analyzed at day 24 had atrophy, mitochondrial dysfunction, augmented metabolic reactive oxygen species (ROS) stress, and a catabolically activated ubiquitin proteasome system (UPS), including upregulated MuRF1. Accordingly, we tested as an experimental intervention of recently identified small molecules, Myomed-205 and -946, that inhibit MuRF1 activity and MuRF1/MuRF2 expression. Results indicate that MuRF1 inhibitor fed attenuated induction of MuRF1 in tumor stressed muscles. In addition, the compounds augmented muscle performance in WHTs and attenuated muscle weight loss. Myomed-205 and -946 also rescued citrate synthase and complex-1 activities in tumor-stressed muscles, possibly suggesting that mitochondrial-metabolic and muscle wasting effects in this CaCax model are mechanistically connected. Inhibition of MuRF1 during tumor cachexia may represent a suitable strategy to attenuate skeletal muscle atrophy and dysfunction.

scholarly journals Daily Oral Administration of Protease-Treated Royal Jelly Protects Against Denervation-Induced Skeletal Muscle Atrophy

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3089
Author(s):  
Tomohiko Shirakawa ◽  
Aki Miyawaki ◽  
Takuma Matsubara ◽  
Nobuaki Okumura ◽  
Hideto Okamoto ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Royal Jelly ◽  
Muscle Metabolism ◽  
Sebacic Acid ◽  
C2c12 Cells ◽  
Skeletal Muscle Atrophy ◽  
Muscle Weight ◽  
Age Related ◽  
Myoblast Cells

Honeybees produce royal jelly (RJ) from their cephalic glands. Royal jelly is a source of nutrition for the queen honey bee throughout its lifespan and is also involved in fertility and longevity. Royal jelly has long been considered beneficial to human health. We recently observed that RJ delayed impairment of motor function during aging, affecting muscle fiber size. However, how RJ affects skeletal muscle metabolism and the functional component of RJ is as of yet unidentified. We demonstrate that feeding mice with RJ daily prevents a decrease in myofiber size following denervation without affecting total muscle weight. RJ did not affect atrophy-related genes but stimulated the expression of myogenesis-related genes, including IGF-1 and IGF receptor. Trans-10-hydroxy-2-decenoic acid (10H2DA) and 10-hydroxydecanoic acid (10HDAA), two major fatty acids contained in RJ. After ingestion, 10H2DA and 10HDAA are metabolized into 2-decenedioic acid (2DA) and sebacic acid (SA) respectively. We found that 10H2DA, 10HDAA, 2DA, and SA all regulated myogenesis of C2C12 cells, murine myoblast cells. These novel findings may be useful for potential preventative and therapeutic applications for muscle atrophy disease included in Sarcopenia, an age-related decline in skeletal muscle mass and strength.

scholarly journals Deletion of NAD(P)H Oxidase 2 Prevents Angiotensin II-Induced Skeletal Muscle Atrophy

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Tomoyasu Kadoguchi ◽  
Shingo Takada ◽  
Takashi Yokota ◽  
Takaaki Furihata ◽  
Junichi Matsumoto ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Angiotensin Ii ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
Muscle Weight ◽  
Cross Sectional ◽  
Akt Phosphorylation ◽  
Protein Synthesis And Degradation ◽  
Synthesis And Degradation

Skeletal muscle atrophy is induced by an imbalance between protein synthesis and degradation. Our previous studies reported that angiotensin II (AII) directly induced muscle atrophy in mice. This study investigated the role of NAD(P)H oxidase 2 (Nox2) activation by AII in the induction of skeletal muscle atrophy. For 4 weeks, either saline (vehicle: V) or AII (1000 ng kg−1 min−1) was infused into male wild-type (WT) and Nox2 knockout (KO) mice via osmotic minipumps. Experiments were performed in the following 4 groups: WT + V, KO + V, WT + AII, and KO + AII. Body weight, muscle weight, and myocyte cross-sectional area were significantly decreased in WT + AII compared to WT + V mice, and these changes were not observed in KO + AII mice. Akt phosphorylation of Ser473 and p70S6K of Thr389 was decreased, gene expression levels of MuRF-1 and atrogin-1 were increased in WT + AII compared to WT + V, and these changes were significantly attenuated in KO + AII mice. The deletion of Nox2 prevented AII-induced skeletal muscle atrophy via improving the balance between protein synthesis and degradation. Therefore, Nox2 may be a therapeutic target for AII-induced skeletal muscle atrophy.

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