Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Evaluation of follistatin as a therapeutic in models of skeletal muscle atrophy associated with denervation and tenotomy.

ABSTRACT: Follistatin is an inhibitor of TGF-β superfamily ligands that repress skeletal muscle growth and promote muscle wasting. Accordingly, follistatin has emerged as a potential therapeutic to ameliorate the deleterious effects of muscle atrophy. However, it remains unclear whether the anabolic effects of follistatin are conserved across different modes of non-degenerative muscle wasting. In this study, the delivery of a recombinant adeno-associated viral vector expressing follistatin (rAAV:Fst) to the hind-limb musculature of mice two weeks prior to denervation or tenotomy promoted muscle hypertrophy that was sufficient to preserve muscle mass comparable to that of untreated sham-operated muscles. However, administration of rAAV:Fst to muscles at the time of denervation or tenotomy did not prevent subsequent muscle wasting. Administration of rAAV:Fst to innervated or denervated muscles increased protein synthesis, but markedly reduced protein degradation only in innervated muscles. Phosphorylation of the signalling proteins mTOR and S6RP, which are associated with protein synthesis, was increased in innervated muscles administered rAAV:Fst, but not in treated denervated muscles. These results demonstrate that the anabolic effects of follistatin are influenced by the interaction between muscle fibres and motor nerves. These findings have important implications for understanding the potential efficacy of follistatin-based therapies for non-degenerative muscle wasting.

SUBMITTER: Sepulveda PV

PROVIDER: S-EPMC4675991 | biostudies-other | 2015 Dec

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Mechanistic Role of Reactive Oxygen Species and Therapeutic Potential of Antioxidants in Denervation- or Fasting-Induced Skeletal Muscle Atrophy.

Project description:Skeletal muscle atrophy occurs under various conditions, such as disuse, denervation, fasting, aging, and various diseases. Although the underlying molecular mechanisms are still not fully understood, skeletal muscle atrophy is closely associated with reactive oxygen species (ROS) overproduction. In this study, we aimed to investigate the involvement of ROS in skeletal muscle atrophy from the perspective of gene regulation, and further examine therapeutic effects of antioxidants on skeletal muscle atrophy. Microarray data showed that the gene expression of many positive regulators for ROS production were up-regulated and the gene expression of many negative regulators for ROS production were down-regulated in mouse soleus muscle atrophied by denervation (sciatic nerve injury). The ROS level was significantly increased in denervated mouse soleus muscle or fasted C2C12 myotubes that had suffered from fasting (nutrient deprivation). These two muscle samples were then treated with N-acetyl-L-cysteine (NAC, a clinically used antioxidant) or pyrroloquinoline quinone (PQQ, a naturally occurring antioxidant), respectively. As compared to non-treatment, both NAC and PQQ treatment (1) reversed the increase in the ROS level in two muscle samples; (2) attenuated the reduction in the cross-sectional area (CSA) of denervated mouse muscle or in the diameter of fasted C2C12 myotube; (3) increased the myosin heavy chain (MHC) level and decreased the muscle atrophy F-box (MAFbx) and muscle-specific RING finger-1 (MuRF-1) levels in two muscle samples. Collectively, these results suggested that an increased ROS level was, at least partly, responsible for denervation- or fasting-induced skeletal muscle atrophy, and antioxidants might resist the atrophic effect via ROS-related mechanisms.

| S-EPMC5861206 | biostudies-literature

Direct optical activation of skeletal muscle fibres efficiently controls muscle contraction and attenuates denervation atrophy.

Project description:Neural prostheses can restore meaningful function to paralysed muscles by electrically stimulating innervating motor axons, but fail when muscles are completely denervated, as seen in amyotrophic lateral sclerosis, or after a peripheral nerve or spinal cord injury. Here we show that channelrhodopsin-2 is expressed within the sarcolemma and T-tubules of skeletal muscle fibres in transgenic mice. This expression pattern allows for optical control of muscle contraction with comparable forces to nerve stimulation. Force can be controlled by varying light pulse intensity, duration or frequency. Light-stimulated muscle fibres depolarize proportionally to light intensity and duration. Denervated triceps surae muscles transcutaneously stimulated optically on a daily basis for 10 days show a significant attenuation in atrophy resulting in significantly greater contractile forces compared with chronically denervated muscles. Together, this study shows that channelrhodopsin-2/H134R can be used to restore function to permanently denervated muscles and reduce pathophysiological changes associated with denervation pathologies.

| S-EPMC4633712 | biostudies-literature

Korean red ginseng suppresses mitochondrial apoptotic pathway in denervation-induced skeletal muscle atrophy

Project description: Not available

| S-EPMC10785417 | biostudies-literature

Denervation Atrophy of Skeletal Muscle is Not Influenced by Numb Levels in Mice.

Project description:Skeletal muscle undergoes rapid and extensive atrophy following nerve transection though the underlying mechanisms remain incompletely understood. We previously showed transiently elevated Notch 1 signaling in denervated skeletal muscle that was abrogated by administration of nandrolone (an anabolic steroid) combined with replacement doses of testosterone. Numb is an adaptor molecule present in myogenic precursors and skeletal muscle fibers that is vital for normal tissue repair after muscle injury and for skeletal muscle contractile function. It is unclear whether the increase in Notch signaling observed in denervated muscle contributes to denervation and whether expression of Numb in myofibers slows denervation atrophy. To address these questions, the degree of denervation atrophy, Notch signaling, and Numb expression was studied over time after denervation in C57B6J mice treated with nandrolone, nandrolone plus testosterone or vehicle. Nandrolone increased Numb expression and reduced Notch signaling. Neither nandrolone alone nor nandrolone plus testosterone changed the rate of denervation atrophy. We next compared rates of denervation atrophy between mice with conditional, tamoxifen-inducible knockout of Numb in myofibers and genetically identical mice treated with vehicle. Numb cKO had no effect on denervation atrophy in this model. Taken together, the data indicate that loss of Numb in myofibers does not alter the course of denervation atrophy and that upregulation of Numb and blunting of the denervation-atrophy induced activation of Notch do not change the course of denervation atrophy.

| S-EPMC9969502 | biostudies-literature

Microarray Analysis of Gene Expression Provides New Insights Into Denervation-Induced Skeletal Muscle Atrophy.

Project description:Denervation induces skeletal muscle atrophy, accompanied by complex biochemical and physiological changes, with potentially devastating outcomes even an increased mortality. Currently, however, there remains a paucity of effective strategies to treat skeletal muscle atrophy. Therefore, it is required to understand the molecular mechanisms of skeletal muscle atrophy and formulate new treatment strategies. In this study, we investigated the transcriptional profile of denervated skeletal muscle after peripheral nerve injury in rats. The cDNA microarray analysis showed that a huge number of genes in tibialis anterior (TA) muscles were differentially expressed at different times after sciatic nerve transection. Notably, the 24 h of denervation might be a critical time point for triggering TA muscle atrophy. According to the data from self-organizing map (SOM), Pearson correlation heatmap, principal component analysis (PCA), and hierarchical clustering analysis, three nodal transitions in gene expression profile of the denervated TA muscle might partition the period of 0.25 h-28 days post nerve injury into four distinct transcriptional phases. Moreover, the four transcriptional phases were designated as "oxidative stress stage", "inflammation stage", "atrophy stage" and "atrophic fibrosis stage", respectively, which was concluded from Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene ontology (GO) analyses at each transcriptional phase. Importantly, the differentially expressed genes at 24 h post sciatic nerve transection seemed to be mainly involved in inflammation, which might be a critical process in denervation-induced muscle atrophy. Overall, our study would contribute to the understanding of molecular aspects of denervation-induced muscle atrophy, and may also provide a new insight into the time window for targeted therapy.

| S-EPMC6798177 | biostudies-literature

Denervation causes fiber atrophy and myosin heavy chain co-expression in senescent skeletal muscle.

Project description:Although denervation has long been implicated in aging muscle, the degree to which it is causes the fiber atrophy seen in aging muscle is unknown. To address this question, we quantified motoneuron soma counts in the lumbar spinal cord using choline acetyl transferase immunhistochemistry and quantified the size of denervated versus innervated muscle fibers in the gastrocnemius muscle using the in situ expression of the denervation-specific sodium channel, Nav?.?, in young adult (YA) and senescent (SEN) rats. To gain insights into the mechanisms driving myofiber atrophy, we also examined the myofiber expression of the two primary ubiquitin ligases necessary for muscle atrophy (MAFbx, MuRF1). MN soma number in lumbar spinal cord declined 27% between YA (638±34 MNs×mm?¹) and SEN (469±13 MNs×mm?¹). Nav?.? positive fibers (1548±70 ?m²) were 35% smaller than Nav?.? negative fibers (2367±78 ?m²; P<0.05) in SEN muscle, whereas Nav?.? negative fibers in SEN were only 7% smaller than fibers in YA (2553±33 ?m²; P<0.05) where no Nav?.? labeling was seen, suggesting denervation is the primary cause of aging myofiber atrophy. Nav?.? positive fibers had higher levels of MAFbx and MuRF1 (P<0.05), consistent with involvement of the proteasome proteolytic pathway in the atrophy of denervated muscle fibers in aging muscle. In summary, our study provides the first quantitative assessment of the contribution of denervation to myofiber atrophy in aging muscle, suggesting it explains the majority of the atrophy we observed. This striking result suggests a renewed focus should be placed on denervation in seeking understanding of the causes of and treatments for aging muscle atrophy.

| S-EPMC3250397 | biostudies-literature

Salidroside Attenuates Denervation-Induced Skeletal Muscle Atrophy Through Negative Regulation of Pro-inflammatory Cytokine.

Project description:Skeletal muscle atrophy is associated with pro-inflammatory cytokines. Salidroside is a biologically active ingredient of Rhodiola rosea, which exhibits anti-inflammatory property. However, there is little known about the effect of salidroside on denervation-induced muscle atrophy. Therefore, the present study aimed to determine whether salidroside could protect against denervation-induced muscle atrophy and to clarify potential molecular mechanisms. Denervation caused progressive accumulation of inflammatory factors in skeletal muscle, especially interleukin 6 (IL6) and its receptor, and recombinant murine IL6 (rmIL6) local infusion could induce target muscle atrophy, suggesting that denervation induced inflammation in target muscles and the inflammation may trigger muscle wasting. Salidroside alleviated denervation-induced muscle atrophy and inhibited the production of IL6. Furthermore, the inhibition of phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the decreased levels of suppressor of cytokine signaling (SOCS3), muscle RING finger protein-1 (MuRF1), atrophy F-box (atrogin-1), microtubule-associated protein light chain 3 beta (LC3B) and PTEN-induced putative kinase (PINK1) were observed in denervated muscles that were treated with salidroside. Finally, all of these responses to salidroside were replicated in neutralizing antibody against IL6. Taken together, these results suggest that salidroside alleviates denervation-induced inflammation response, thereby inhibits muscle proteolysis and muscle atrophy. Therefore, it was assumed that salidroside might be a potential therapeutic candidate to prevent muscle wasting.

| S-EPMC6604664 | biostudies-literature

Dynamic changes in the mouse skeletal muscle proteome during denervation-induced atrophy.

Project description:Loss of neuronal stimulation enhances protein breakdown and reduces protein synthesis, causing rapid loss of muscle mass. To elucidate the pathophysiological adaptations that occur in atrophying muscles, we used stable isotope labelling and mass spectrometry to quantify protein expression changes accurately during denervation-induced atrophy after sciatic nerve section in the mouse gastrocnemius muscle. Additionally, mice were fed a stable isotope labelling of amino acids in cell culture (SILAC) diet containing 13C6-lysine for 4, 7 or 11 days to calculate relative levels of protein synthesis in denervated and control muscles. Ubiquitin remnant peptides (K-ε-GG) were profiled by immunoaffinity enrichment to identify potential substrates of the ubiquitin-proteasomal pathway. Of the 4279 skeletal muscle proteins quantified, 850 were differentially expressed significantly within 2 weeks after denervation compared with control muscles. Moreover, pulse labelling identified Lys6 incorporation in 4786 proteins, of which 43 had differential Lys6 incorporation between control and denervated muscle. Enrichment of diglycine remnants identified 2100 endogenous ubiquitination sites and revealed a metabolic and myofibrillar protein diglycine signature, including myosin heavy chains, myomesins and titin, during denervation. Comparative analysis of these proteomic data sets with known atrogenes using a random forest approach identified 92 proteins subject to atrogene-like regulation that have not previously been associated directly with denervation-induced atrophy. Comparison of protein synthesis and proteomic data indicated that upregulation of specific proteins in response to denervation is mainly achieved by protein stabilization. This study provides the first integrated analysis of protein expression, synthesis and ubiquitin signatures during muscular atrophy in a living animal.

| S-EPMC5536905 | biostudies-other

Intramuscular injection of skeletal muscle derived extracellular matrix mitigates denervation atrophy after sciatic nerve transection.

Project description:Peripheral nerve injury and the associated muscle atrophy has an estimated annual healthcare burden of $150 billion dollars in the United States. When considering the total annual health-related spending of $3.5 trillion, these pathologies alone occupy about 4.3%. The prevalence of these ailments is rooted, at least in part, in the lack of specific preventative therapies that can be administered to muscle while it remains in the denervated state. To address this, skeletal muscle-derived ECM (skECM) was injected directly in denervated muscle with postoperative analysis performed at 20 weeks, including gait analysis, force production, cytokine quantification, and histological analysis. skECM was shown to be superior against non-injected muscle controls showing no difference in contraction force to uninjured muscle at 20 weeks. Cytokines IL-1β, IL-18, and IFNγ appeared to mediate regeneration with statistical regression implicating these cytokines as strong predictors of muscle contraction, showing significant linear correlation.

| S-EPMC8458676 | biostudies-literature

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

Project description: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.

| S-EPMC7600733 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data