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.

scholarly journals Morphological Evidence of Telocytes in Skeletal Muscle Interstitium of Exercised and Sedentary Rodents

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 807
Author(s):  
Silvia Ravalli ◽  
Concetta Federico ◽  
Giovanni Lauretta ◽  
Salvatore Saccone ◽  
Elisabetta Pricoco ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Stromal Cells ◽  
Tibialis Anterior Muscle ◽  
Skeletal Muscle Atrophy ◽  
Morphological Evidence ◽  
Double Positive ◽  
Functional Changes ◽  
Cell Niche ◽  
The Relationship

Skeletal muscle atrophy, resulting from states of hypokinesis or immobilization, leads to morphological, metabolic, and functional changes within the muscle tissue, a large variety of which are supported by the stromal cells populating the interstitium. Telocytes represent a recently discovered population of stromal cells, which has been increasingly identified in several human organs and appears to participate in sustaining cross-talk, promoting regenerative mechanisms and supporting differentiation of local stem cell niche. The aim of this morphologic study was to investigate the presence of Telocytes in the tibialis anterior muscle of healthy rats undergoing an endurance training protocol for either 4 weeks or 16 weeks compared to sedentary rats. Histomorphometric analysis of muscle fibers diameter revealed muscle atrophy in sedentary rats. Telocytes were identified by double-positive immunofluorescence staining for CD34/CD117 and CD34/vimentin. The results showed that Telocytes were significantly reduced in sedentary rats at 16 weeks, while rats subjected to regular exercise maintained a stable Telocytes population after 16 weeks. Understanding of the relationship between Telocytes and exercise offers new chances in the field of regenerative medicine, suggesting possible triggers for Telocytes in sarcopenia and other musculoskeletal disorders, promoting adapted physical activity and rehabilitation programmes in clinical practice.

scholarly journals MicroRNA 322 Aggravates Dexamethasone-Induced Muscle Atrophy by Targeting IGF1R and INSR

2020 ◽  
Vol 21 (3) ◽  
pp. 1111 ◽  
Author(s):  
Hongwei Geng ◽  
Qinglong Song ◽  
Yunyun Cheng ◽  
Haoyang Li ◽  
Rui Yang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Target Genes ◽  
Immunosuppressive Agent ◽  
Skeletal Muscle Atrophy ◽  
Luciferase Reporter ◽  
C2c12 Myotubes ◽  
High Dose ◽  
Reporter Assays ◽  
Underlying Mechanisms

Dexamethasone (Dex) has been widely used as a potent anti-inflammatory, antishock, and immunosuppressive agent. However, high dose or long-term use of Dex is accompanied by side effects including skeletal muscle atrophy, whose underlying mechanisms remain incompletely understood. A number of microRNAs (miRNAs) have been shown to play key roles in skeletal muscle atrophy. Previous studies showed significantly increased miR-322 expression in Dex-treated C2C12 myotubes. In our study, the glucocorticoid receptor (GR) was required for Dex to increase miR-322 expression in C2C12 myotubes. miR-322 mimic or miR-322 inhibitor was used for regulating the expression of miR-322. Insulin-like growth factor 1 receptor (IGF1R) and insulin receptor (INSR) were identified as target genes of miR-322 using luciferase reporter assays and played key roles in Dex-induced muscle atrophy. miR-322 overexpression promoted atrophy in Dex-treated C2C12 myotubes and the gastrocnemius muscles of mice. Conversely, miR-322 inhibition showed the opposite effects. These data suggested that miR-322 contributes to Dex-induced muscle atrophy via targeting of IGF1R and INSR. Furthermore, miR-322 might be a potential target to counter Dex-induced muscle atrophy. miR-322 inhibition might also represent a therapeutic approach for Dex-induced muscle atrophy.

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.

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 A cell-autonomous role for the glucocorticoid receptor in skeletal muscle atrophy induced by systemic glucocorticoid exposure

2012 ◽  
Vol 302 (10) ◽  
pp. E1210-E1220 ◽  
Author(s):  
Monica L. Watson ◽  
Leslie M. Baehr ◽  
Holger M. Reichardt ◽  
Jan P. Tuckermann ◽  
Sue C. Bodine ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucocorticoid Receptor ◽  
Muscle Atrophy ◽  
Target Genes ◽  
Prolonged Exposure ◽  
Skeletal Muscle Atrophy ◽  
High Dose ◽  
Nerve Lesion ◽  
Nutritional Deprivation

Glucocorticoids (GCs) are important regulators of skeletal muscle mass, and prolonged exposure will induce significant muscle atrophy. To better understand the mechanism of skeletal muscle atrophy induced by elevated GC levels, we examined three different models: exogenous synthetic GC treatment [dexamethasone (DEX)], nutritional deprivation, and denervation. Specifically, we tested the direct contribution of the glucocorticoid receptor (GR) in skeletal muscle atrophy by creating a muscle-specific GR-knockout mouse line (MGRe3KO) using Cre-lox technology. In MGRe3KO mice, we found that the GR is essential for muscle atrophy in response to high-dose DEX treatment. In addition, DEX regulation of multiple genes, including two important atrophy markers, MuRF1 and MAFbx, is eliminated completely in the MGRe3KO mice. In a condition where endogenous GCs are elevated, such as nutritional deprivation, induction of MuRF1 and MAFbx was inhibited, but not completely blocked, in MGRe3KO mice. In response to sciatic nerve lesion and hindlimb muscle denervation, muscle atrophy and upregulation of MuRF1 and MAFbx occurred to the same extent in both wild-type and MGRe3KO mice, indicating that a functional GR is not required to induce atrophy under these conditions. Therefore, we demonstrate conclusively that the GR is an important mediator of skeletal muscle atrophy and associated gene expression in response to exogenous synthetic GCs in vivo and that the MGRe3KO mouse is a useful model for studying the role of the GR and its target genes in multiple skeletal muscle atrophy models.

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 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 UBE2E1 Is Preferentially Expressed in the Cytoplasm of Slow-Twitch Fibers and Protects Skeletal Muscles from Exacerbated Atrophy upon Dexamethasone Treatment

Cells ◽  
2018 ◽  
Vol 7 (11) ◽  
pp. 214 ◽  
Author(s):  
Cécile Polge ◽  
Julien Aniort ◽  
Andrea Armani ◽  
Agnès Claustre ◽  
Cécile Coudy-Gandilhon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Tibialis Anterior Muscle ◽  
Ubiquitin Proteasome System ◽  
Skeletal Muscle Atrophy ◽  
C2c12 Myotubes ◽  
Type I ◽  
Dexamethasone Treatment ◽  
Sarcomeric Protein

Skeletal muscle mass is reduced during many diseases or physiological situations (disuse, aging), which results in decreased strength and increased mortality. Muscle mass is mainly controlled by the ubiquitin-proteasome system (UPS), involving hundreds of ubiquitinating enzymes (E2s and E3s) that target their dedicated substrates for subsequent degradation. We recently demonstrated that MuRF1, an E3 ubiquitin ligase known to bind to sarcomeric proteins (telethonin, α-actin, myosins) during catabolic situations, interacts with 5 different E2 enzymes and that these E2-MuRF1 couples are able to target telethonin, a small sarcomeric protein, for degradation. Amongst the E2s interacting with MuRF1, E2E1 was peculiar as the presence of the substrate was necessary for optimal MuRF1-E2E1 interaction. In this work, we focused on the putative role of E2E1 during skeletal muscle atrophy. We found that E2E1 expression was restricted to type I and type IIA muscle fibers and was not detectable in type IIB fibers. This strongly suggests that E2E1 targets are fiber-specific and may be strongly linked to the contractile and metabolic properties of the skeletal muscle. However, E2E1 knockdown was not sufficient for preserving the protein content in C2C12 myotubes subjected to a catabolic state (dexamethasone treatment), suggesting that E2E1 is not involved in the development of muscle atrophy. By contrast, E2E1 knockdown aggravated the atrophying process in both catabolic C2C12 myotubes and the Tibialis anterior muscle of mice, suggesting that E2E1 has a protective effect on muscle mass.

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 Identification of potential target genes associated with the reversion of androgen-dependent skeletal muscle atrophy

2019 ◽  
Vol 663 ◽  
pp. 173-182 ◽  
Author(s):  
Priscila de O. Coelho ◽  
Flavia A. Guarnier ◽  
Leonardo Bruno Figueiredo ◽  
Livia S. Zaramela ◽  
Enio S.A. Pacini ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Target Genes ◽  
Skeletal Muscle Atrophy ◽  
Potential Target
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