Oral intake of rice overexpressing ubiquitin ligase inhibitory pentapeptide prevents atrophy in denervated skeletal muscle.
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ABSTRACT:
SUBMITTER: Nakao R
PROVIDER: S-EPMC8429733 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionICU-acquired weakness (ICUAW) complicates the disease course of critically ill patients. Inflammation and acute-phase response occur directly within myocytes and contribute to ICUAW. We observed that tripartite motif-containing 62 (TRIM62), an E3 ubiquitin ligase and modifier of inflammation, is increased in the skeletal muscle of ICUAW patients. We investigated the regulation and function of muscular TRIM62 in critical illness.MethodsTwenty-six critically ill patients with Sequential Organ Failure Assessment scores ?8 underwent two skeletal muscle biopsies from the vastus lateralis at median days 5 and 15 in the ICU. Four patients undergoing elective orthopedic surgery served as controls. TRIM62 expression and protein content were analyzed in these biopsies. The kinetics of Trim62, Atrogin1 and MuRF1 expression were determined in the gastrocnemius/plantaris and tibialis anterior muscles from mouse models of inflammation-, denervation- and starvation-induced muscle atrophy to differentiate between these contributors to ICUAW. Cultured myocytes were used for mechanistic analyses.ResultsTRIM62 expression and protein content were increased early and remained elevated in muscles from critically ill patients. In all three animal models, muscular Trim62 expression was early and continuously increased. Trim62 was expressed in myocytes, and its overexpression activated the atrophy-inducing activator protein 1 signal transduction pathway. Knockdown of Trim62 by small interfering RNA inhibited lipopolysaccharide-induced interleukin 6 expression.ConclusionsTRIM62 is activated in the muscles of critically ill patients. It could play a role in the pathogenesis of ICUAW by activating and maintaining inflammation in myocytes.Trial registrationCurrent Controlled Trials ID: ISRCTN77569430 (registered 13 February 2008).
| S-EPMC4231194 | biostudies-literature
Project description:This study evaluated the effect of muscle satellite cells (MSCs) overexpressing myogenin (MyoG) on denervated muscle atrophy. Rat MSCs were isolated and transfected with the MyoG-EGFP plasmid vector GV143. MyoG-transfected MSCs (MTMs) were transplanted into rat gastrocnemius muscles at 1 week after surgical denervation. Controls included injections of untransfected MSCs or the vehicle only. Muscles were harvested and analyzed at 2, 4, and 24 weeks post-transplantation. Immunofluorescence confirmed MyoG overexpression in MTMs. The muscle wet weight ratio was significantly reduced at 2 weeks after MTM injection (67.17±6.79) compared with muscles injected with MSCs (58.83±5.31) or the vehicle (53.00±7.67; t=2.37, P=0.04 and t=3.39, P=0.007, respectively). The muscle fiber cross-sectional area was also larger at 2 weeks after MTM injection (2.63×10³±0.39×10³) compared with MSC injection (1.99×10³±0.58×10³) or the vehicle only (1.57×10³±0.47×10³; t=2.24, P=0.049 and t=4.22, P=0.002, respectively). At 4 and 24 weeks post-injection, the muscle mass and fiber cross-sectional area were similar across all three experimental groups. Immunohistochemistry showed that the MTM group had larger MyoG-positive fibers. The MTM group (3.18±1.13) also had higher expression of MyoG mRNA than other groups (1.41±0.65 and 1.03±0.19) at 2 weeks after injection (t=2.72, P=0.04). Transplanted MTMs delayed short-term atrophy of denervated muscles. This approach can be optimized as a novel stand-alone therapy or as a bridge to surgical re-innervation of damaged muscles.
| S-EPMC4742975 | biostudies-literature
Project description:Starvation, like many other catabolic conditions, induces loss of skeletal muscle mass by promoting fiber atrophy. In addition to the canonical processes, the starvation-induced response employs many distinct pathways that make it a unique atrophic program. However, in the multiplex of the underlying mechanisms, several components of starvation-induced atrophy have yet to be fully understood and their roles and interplay remain to be elucidated. Here we unveiled the role of tumor necrosis factor receptor-associated factor 6 (TRAF6), a unique E3 ubiquitin ligase and adaptor protein, in starvation-induced muscle atrophy. Targeted ablation of TRAF6 suppresses the expression of key regulators of atrophy, including MAFBx, MuRF1, p62, LC3B, Beclin1, Atg12, and Fn14. Ablation of TRAF6 also improved the phosphorylation of Akt and FoxO3a and inhibited the activation of 5' AMP-activated protein kinase in skeletal muscle in response to starvation. In addition, our study provides the first evidence of the involvement of endoplasmic reticulum stress and unfolding protein response pathways in starvation-induced muscle atrophy and its regulation through TRAF6. Finally, our results also identify lysine 63-linked autoubiquitination of TRAF6 as a process essential for its regulatory role in starvation-induced muscle atrophy.
| S-EPMC3302447 | biostudies-literature
Project description:We identify sestrins, a family of stress-inducible metabolic regulators, as protective factors against muscle wasting. Sestrin expression decreases during inactivity and its genetic deficiency exacerbates muscle wasting; conversely, sestrin overexpression suffices to prevent atrophy.
2019-09-05 | GSE136866 | GEO
Project description:Denervation of skeletal muscles induces atrophy, preceded by changes in sarcolemma permeability of causes not yet completely understood. Here, we show that denervation-induced Evans blue dye uptake in vivo of fast, but not slow, myofibers was acutely inhibited by connexin (Cx) hemichannel/pannexin1 (Panx1) channel and purinergic ionotropic P2X7 receptor (P2X7R) blockers. Denervated myofibers showed up-regulation of Panx1 and de novo expression of Cx39, Cx43, and Cx45 hemichannels as well as P2X7Rs and transient receptor potential subfamily V, member 2, channels, all of which are permeable to small molecules. The sarcolemma of freshly isolated WT myofibers from denervated muscles also showed high hemichannel-mediated permeability that was slightly reduced by blockade of Panx1 channels or the lack of Panx1 expression, but was completely inhibited by Cx hemichannel or P2X7R blockers, as well as by degradation of extracellular ATP. However, inhibition of transient receptor potential subfamily V, member 2, channels had no significant effect on membrane permeability. Moreover, activation of the transcription factor NF?B and higher mRNA levels of proinflammatory cytokines (TNF-? and IL-1?) were found in denervated WT but not Cx43/Cx45-deficient muscles. The atrophy observed after 7 d of denervation was drastically reduced in Cx43/Cx45-deficient but not Panx1-deficient muscles. Therefore, expression of Cx hemichannels and P2X7R promotes a feed-forward mechanism activated by extracellular ATP, most likely released through hemichannels, that activates the inflammasome. Consequently, Cx hemichannels are potential targets for new therapeutic agents to prevent or reduce muscle atrophy induced by denervation of diverse etiologies.
| S-EPMC3791696 | biostudies-literature
Project description:Treatment options for denervated skeletal muscle atrophy are limited, in part because the underlying molecular mechanisms are not well understood. Unlike previous transcriptomics studies conducted in rodent models of peripheral nerve injury, in the present study, we performed high-throughput sequencing with denervated atrophic biceps muscle and normal (non-denervated) sternocleidomastoid muscle samples obtained from four brachial plexus injury (BPI) patients. We also investigated whether Ficus carica L. (FCL.) extract can suppress denervated muscle atrophy in a mouse model, along with the mechanism of action. We identified 1471 genes that were differentially expressed between clinical specimens of atrophic and normal muscle, including 771 that were downregulated and 700 that were upregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the differentially expressed genes were mainly enriched in the GO terms "structural constituent of muscle," "Z disc," "M band," and "striated muscle contraction," as well as "Cell adhesion molecules," "Glycolysis/Gluconeogenesis," "Peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway," and "P53 signaling pathway." In experiments using mice, the reduction in wet weight and myofiber diameter in denervated muscle was improved by FCL. extract compared to saline administration, which was accompanied by downregulation of the proinflammatory cytokines interleukin (IL)-1β and IL-6. Moreover, although both denervated groups showed increased nuclear factor (NF)-κB activation and PPARα expression, the degree of NF-κB activation was lower while PPARα and inhibitor of NF-κB IκBα expression was higher in FCL. extract-treated mice. Thus, FCL. extract suppresses denervation-induced inflammation and attenuates muscle atrophy by enhancing PPARα expression and inhibiting NF-κB activation. These findings suggest that FCL. extract has therapeutic potential for preventing denervation-induced muscle atrophy caused by peripheral nerve injury or disease.
| S-EPMC7744683 | biostudies-literature
Project description:Sestrin prevents skeletal muscle atrophy
| PRJNA563889 | ENA
Project description:BackgroundHeart failure (HF) is known to lead to skeletal muscle atrophy and dysfunction. However, intracellular mechanisms underlying HF-induced myopathy are not fully understood. We hypothesized that HF would increase oxidative stress and ubiquitin-proteasome system (UPS) activation in skeletal muscle of sympathetic hyperactivity mouse model. We also tested the hypothesis that aerobic exercise training (AET) would reestablish UPS activation in mice and human HF.Methods/principal findingsTime-course evaluation of plantaris muscle cross-sectional area, lipid hydroperoxidation, protein carbonylation and chymotrypsin-like proteasome activity was performed in a mouse model of sympathetic hyperactivity-induced HF. At the 7(th) month of age, HF mice displayed skeletal muscle atrophy, increased oxidative stress and UPS overactivation. Moderate-intensity AET restored lipid hydroperoxides and carbonylated protein levels paralleled by reduced E3 ligases mRNA levels, and reestablished chymotrypsin-like proteasome activity and plantaris trophicity. In human HF (patients randomized to sedentary or moderate-intensity AET protocol), skeletal muscle chymotrypsin-like proteasome activity was also increased and AET restored it to healthy control subjects' levels.ConclusionsCollectively, our data provide evidence that AET effectively counteracts redox imbalance and UPS overactivation, preventing skeletal myopathy and exercise intolerance in sympathetic hyperactivity-induced HF in mice. Of particular interest, AET attenuates skeletal muscle proteasome activity paralleled by improved aerobic capacity in HF patients, which is not achieved by drug treatment itself. Altogether these findings strengthen the clinical relevance of AET in the treatment of HF.
| S-EPMC3411696 | biostudies-literature
Project description:BackgroundSestrin2 (SESN2), a stress-inducible protein, has been reported to protect against denervated muscle atrophy through unfolded protein response and mitophagy, while its role in myofiber type transition remains unknown.MethodsA mouse sciatic nerve transection model was created to evaluate denervated muscle atrophy. Myofiber type transition was confirmed by western blot, fluorescence staining, ATP quantification, and metabolic enzyme activity analysis. Adeno-associated virus (AAV) was adopted to achieve SESN2 knockdown and overexpression in gastrocnemius. AMPK/PGC-1α signal was detected by western blot and activated with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). C2C12 myotubes with rotenone treatment were adopted for in vitro experiments.ResultsSESN2 was found to be upregulated in denervated skeletal muscles and rotenone-treated C2C12 cells. Knockdown of SESN2 aggravated muscle atrophy and accelerated myofiber type transition from slow-twitch to fast-twitch. Moreover, AMPK/PGC-1α signaling was proven to be activated by SESN2 after denervation, which further induced the expression of hypoxia-inducible factor HIF2α. Exogenous activation of AMPK/PGC-1α signaling could counteract the addition of slow-to-fast myofiber shift caused by SESN2 knockdown and lead to the retainment of muscle mass after denervation.ConclusionCollectively, the present study indicates that SESN2 prevents myofiber type transition from slow-twitch to fast-twitch and preserves muscle mass in denervated atrophy via AMPK/PGC-1α signaling. These findings contribute to a better understanding of the pathogenesis of muscle atrophy and provide novel insights into the role of SESN2 in myofiber type transition.
| S-EPMC9361691 | biostudies-literature
Project description:The ubiquitin ligase CHIP (carboxyl terminus of Hsp70-interacting protein) regulates protein quality control, and CHIP deletion accelerates aging and reduces the life span in mice. Here, we reveal a mechanism for CHIP's influence on longevity by demonstrating that CHIP stabilizes the sirtuin family member SirT6, a lysine deacetylase/ADP ribosylase involved in DNA repair, metabolism, and longevity. In CHIP-deficient cells, SirT6 protein half-life is substantially reduced due to increased proteasome-mediated degradation, but CHIP overexpression in these cells increases SirT6 protein expression without affecting SirT6 transcription. CHIP noncanonically ubiquitinates SirT6 at K170, which stabilizes SirT6 and prevents SirT6 canonical ubiquitination by other ubiquitin ligases. In CHIP-depleted cells, SirT6 K170 mutation increases SirT6 half-life and prevents proteasome-mediated degradation. The global decrease in SirT6 expression in the absence of CHIP is associated with decreased SirT6 promoter occupancy, which increases histone acetylation and promotes downstream gene transcription in CHIP-depleted cells. Cells lacking CHIP are hypersensitive to DNA-damaging agents, but DNA repair and cell viability are rescued by enforced expression of SirT6. The discovery of this CHIP-SirT6 interaction represents a novel protein-stabilizing mechanism and defines an intersection between protein quality control and epigenetic regulation to influence pathways that regulate the biology of aging.
| S-EPMC3838192 | biostudies-literature