Functional rice with tandemly repeated Cbl-b ubiquitin ligase inhibitory pentapeptide prevents denervation-induced muscle atrophy in vivo

2021 ◽  
Author(s):  
Kazuhito Akama ◽  
Yasuka Shimajiri ◽  
Kumiko Kainou ◽  
Ryota Iwasaki ◽  
Reiko Nakao ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Transgenic Rice ◽  
Muscle Atrophy ◽  
Ubiquitin Ligase ◽  
Critical Role ◽  
Phosphorylation Site ◽  
Skeletal Muscle Atrophy ◽  
Rice Seeds

Abstract Ubiquitin ligase Cbl-b play a critical role in non-loading-mediated skeletal muscle atrophy: Cbl-b ubiquitinates insulin receptor substrate-1 (IRS-1), an important insulin-like growth factor-1 signaling intermediate molecule, leading to its degradation and a resulting loss in muscle mass. We reported that intramuscular injection of a pentapeptide, DGpYMP, which acts as a mimic of the phosphorylation site in IRS-1, significantly inhibited denervation-induced skeletal muscle loss. In order to explore the possibility of the prevention of muscle atrophy by diet therapy, we examined the effects of oral administration of transgenic rice containing Cblin (Cbl-b inhibitor) peptide (DGYMP) on denervation-induced muscle mass loss in frogs. We generated transgenic rice seeds in which 15 repeats of Cblin peptides with a WQ spacer were inserted into the rice storage protein glutelin for expression. A diet of the transgenic rice seeds had significant inhibitory effects on denervation-induced atrophy of the leg skeletal muscles in frogs, compared with those receiving a diet of wild-type rice.

scholarly journals Blockade of Metallothioneins 1 and 2 Increases Skeletal Muscle Mass and Strength

2016 ◽  
Vol 37 (5) ◽  
Author(s):  
Serge Summermatter ◽  
Anais Bouzan ◽  
Eliane Pierrel ◽  
Stefan Melly ◽  
Daniela Stauffer ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Skeletal Muscle Atrophy ◽  
Intracellular Zinc ◽  
Beneficial Effects ◽  
And Function ◽  
Zinc Storage

ABSTRACT Metallothioneins are proteins that are involved in intracellular zinc storage and transport. Their expression levels have been reported to be elevated in several settings of skeletal muscle atrophy. We therefore investigated the effect of metallothionein blockade on skeletal muscle anabolism in vitro and in vivo. We found that concomitant abrogation of metallothioneins 1 and 2 results in activation of the Akt pathway and increases in myotube size, in type IIb fiber hypertrophy, and ultimately in muscle strength. Importantly, the beneficial effects of metallothionein blockade on muscle mass and function was also observed in the setting of glucocorticoid addition, which is a strong atrophy-inducing stimulus. Given the blockade of atrophy and the preservation of strength in atrophy-inducing settings, these results suggest that blockade of metallothioneins 1 and 2 constitutes a promising approach for the treatment of conditions which result in muscle atrophy.

scholarly journals Emerging Role for Linear and Circular Spermine Oxidase RNAs in Skeletal Muscle Physiopathology

2020 ◽  
Vol 21 (21) ◽  
pp. 8227
Author(s):  
Jonathan Fernando Reinoso-Sánchez ◽  
Giulia Baroli ◽  
Guglielmo Duranti ◽  
Silvia Scaricamazza ◽  
Stefania Sabatini ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Pathological Condition ◽  
Physiological State ◽  
Critical Role ◽  
Skeletal Muscle Atrophy ◽  
Circular Rnas ◽  
Spermine Oxidase ◽  
In Vivo Models

Skeletal muscle atrophy is a pathological condition so far without effective treatment and poorly understood at a molecular level. Emerging evidence suggest a key role for circular RNAs (circRNA) during myogenesis and their deregulation has been reported to be associated with muscle diseases. Spermine oxidase (SMOX), a polyamine catabolic enzyme plays a critical role in muscle differentiation and the existence of a circRNA arising from SMOX gene has been recently identified. In this study, we evaluated the expression profile of circular and linear SMOX in both C2C12 differentiation and dexamethasone-induced myotubes atrophy. To validate our findings in vivo their expression levels were also tested in two murine models of amyotrophic lateral sclerosis: SOD1G93A and hFUS+/+, characterized by progressive muscle atrophy. During C2C12 differentiation, linear and circular SMOX show the same trend of expression. Interestingly, in atrophy circSMOX levels significantly increased compared to the physiological state, in both in vitro and in vivo models. Our study demonstrates that SMOX represents a new player in muscle physiopathology and provides a scientific basis for further investigation on circSMOX RNA as a possible new therapeutic target for the treatment of muscle atrophy.

scholarly journals Knockdown of the E3 Ubiquitin ligase UBR5 and its role in skeletal muscle anabolism

2020 ◽  
Author(s):  
Daniel C. Turner ◽  
David C. Hughes ◽  
Leslie M. Baehr ◽  
Robert A. Seaborne ◽  
Mark Viggars ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Muscle Mass ◽  
Ubiquitin Ligase ◽  
Muscle Protein ◽  
E3 Ubiquitin Ligase ◽  
Skeletal Muscle Atrophy ◽  
Human Myotubes ◽  
The Impact

AbstractUBR5 is an E3-ubiquitin-ligase positively associated with anabolism, hypertrophy and recovery from atrophy in skeletal muscle. The precise mechanisms underpinning UBR5’s role in the regulation of skeletal muscle mass remain unknown. The present study aimed to elucidate these mechanisms by silencing the UBR5 gene in-vitro and in-vivo. The siRNA-induced reduction (−77%) in UBR5 gene expression in human myotubes was prevented by mechanical loading, suggesting that UBR5 gene expression may be regulated via mechano-transduction signalling. Therefore, we electroporated a UBR5-RNAi plasmid into mouse tibialis anterior muscle in-vivo to investigate the impact of reduced UBR5 on mechano-transduction signalling MEK/ERK/p90RSK and Akt/p70S6K/4E-BP1/rpS6 pathways. Seven days post UBR5 RNAi electroporation, while reductions in overall muscle mass were not detected, mean CSA of GFP-positive fibers was reduced (−9.5%) and the number of large fibers was lower versus the control. Importantly, UBR5-RNAi significantly reduced total RNA, muscle protein synthesis, ERK1/2 and Akt phosphorylation. Whilst p90RSK phosphorylation significantly increased, total p90RSK protein levels demonstrated a 45% reduction with UBR5-RNAi. Finally, these early signalling events after 7 days of UBR5 knockdown culminated in significant reductions in muscle mass (−4.6%) and larger reductions in fiber CSA (−18.5%) after 30 days. This was associated with increased levels of the phosphatase, PP2Ac, and inappropriate chronic elevation of p70S6K and rpS6 between 7 and 30 days, and corresponding reductions in eIF4e. This study demonstrates UBR5 plays an important role in anabolism/hypertrophy, whereby knockdown of UBR5 culminates in skeletal muscle atrophy.

scholarly journals Drugs for the Treatment of Muscle Atrophy

2021 ◽  
Author(s):  
Linlin Chen ◽  
Hong Zhang ◽  
Mengyi Chi ◽  
Quanjun Yang ◽  
Cheng Guo
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Drug Target ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Mammalian Target Of Rapamycin ◽  
Proteasome Inhibitors ◽  
Skeletal Muscle Atrophy

Muscle mass is maintained through an interplay between anabolic and catabolic pathways. The ubiquitin-proteasome system plays an important role in the proteolysis progress during skeletal muscle atrophy which can be blocked by some proteasome inhibitors. But few studies have demonstrated the ability of these inhibitors to preserve muscle mass and architecture under catabolic condition in vivo. The insulin-like growth factor-1/phosphatidylinositide 3-kinases/protein kinase B/mammalian target of rapamycin (IGF-1/PI3K/Akt/mTOR) pathway was associated with anabolic pathways. The activation of IGF-1 causes muscle hypertrophy; however, it cannot be used as a drug target. Myostatin pathway maintains activation that can induce skeletal muscle atrophy involved with various transcriptional and genetic factors. Skeletal muscle atrophy is a debilitating consequence of multiple chronic diseases and conditions that involve starvation. It reduces treatment options and positive clinical outcomes as well as compromising quality of life and increasing morbidity and mortality. Though considerable research has been undertaken to find the drug target and the molecular mechanisms that improve skeletal muscle atrophy, no drug was approved to treat skeletal muscle atrophy. However, these years, the signaling pathways involved in muscle atrophy were clarified and some effective treatments were currently available to prevent, attenuate, or reverse muscle atrophy for experiment research.

Reduction of Skeletal Muscle Atrophy by a Proteasome Inhibitor in a Rat Model of Denervation

2006 ◽  
Vol 231 (3) ◽  
pp. 335-341 ◽  
Author(s):  
Blake C. Beehler ◽  
Paul G. Sleph ◽  
Latifa Benmassaoud ◽  
Gary J. Grover
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Proteasome Inhibitor ◽  
Proteasome Inhibitors ◽  
Levator Ani ◽  
Proteasome Inhibition ◽  
Skeletal Muscle Atrophy ◽  
Mrna Levels

The ubiquitin-proteasome system is the primary proteolytic pathway implicated in skeletal muscle atrophy under catabolic conditions. Although several studies showed that proteasome inhibitors reduced proteolysis under catabolic conditions, few studies have demonstrated the ability of these inhibitors to preserve skeletal muscle mass and architecture in vivo. To explore this, we studied the effect of the proteasome inhibitor Velcade (also known as PS-341 and bortezomib) in denervated skeletal muscle in rats. Rats were given vehicle or Velcade (3 mg/kg po) daily for 7 days beginning immediately after induction of muscle atrophy by crushing the sciatic nerve. At the end of the study, the rats were euthanized and the soleus and extensor digitorum longus (EDL) muscles were harvested. In vehicle-treated rats, denervation caused a 33.5 ± 2.8% and 16.2 ± 2.7% decrease in the soleus and EDL muscle wet weights (% atrophy), respectively, compared to muscles from the contralateral (innervated) limb. Velcade significantly reduced denervation-induced atrophy to 17.1 ± 3.3% in the soleus (P < 0.01), a 51.6% reduction in atrophy associated with denervation, with little effect on the EDL (9.8 ± 3.2% atrophy). Histology showed a Preservation of muscle mass and preservation of normal cellular architecture after Velcade treatment. Ubiquitin mRNA levels in denervated soleus muscle at the end of the study were significantly elevated 120 ± 25% above sham control levels and were reduced to control levels by Velcade. In contrast, testosterone proprionate (3 mg/kg sc) did not alleviate denervation-induced skeletal muscle atrophy but did prevent castration-induced levator ani atrophy, while Velcade was without effect. These results show that proteasome inhibition attenuates denervation-induced muscle atrophy in vivo in soleus muscles. However, this mechanism may not be operative in all types of atrophy.

scholarly journals IGF-1 prevents ANG II-induced skeletal muscle atrophy via Akt- and Foxo-dependent inhibition of the ubiquitin ligase atrogin-1 expression

2010 ◽  
Vol 298 (5) ◽  
pp. H1565-H1570 ◽  
Author(s):  
Tadashi Yoshida ◽  
Laura Semprun-Prieto ◽  
Sergiy Sukhanov ◽  
Patrice Delafontaine
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Critical Role ◽  
Ring Finger ◽  
Dominant Negative ◽  
Skeletal Muscle Atrophy ◽  
Ang Ii ◽  
Skeletal Muscle Wasting

Congestive heart failure is associated with activation of the renin-angiotensin system and skeletal muscle wasting. Angiotensin II (ANG II) has been shown to increase muscle proteolysis and decrease circulating and skeletal muscle IGF-1. We have shown previously that skeletal muscle-specific overexpression of IGF-1 prevents proteolysis and apoptosis induced by ANG II. These findings indicated that downregulation of IGF-1 signaling in skeletal muscle played an important role in the wasting effect of ANG II. However, the signaling pathways and mechanisms whereby IGF-1 prevents ANG II-induced skeletal muscle atrophy are unknown. Here we show ANG II-induced transcriptional regulation of two ubiquitin ligases atrogin-1 and muscle ring finger-1 (MuRF-1) that precedes the reduction of skeletal muscle IGF-1 expression, suggesting that activation of atrogin-1 and MuRF-1 is an initial mechanism leading to skeletal muscle atrophy in response to ANG II. IGF-1 overexpression in skeletal muscle prevented ANG II-induced skeletal muscle wasting and the expression of atrogin-1, but not MuRF-1. Dominant-negative Akt and constitutively active Foxo-1 blocked the ability of IGF-1 to prevent ANG II-mediated upregulation of atrogin-1 and skeletal muscle wasting. Our findings demonstrate that the ability of IGF-1 to prevent ANG II-induced skeletal muscle wasting is mediated via an Akt- and Foxo-1-dependent signaling pathway that results in inhibition of atrogin-1 but not MuRF-1 expression. These data suggest strongly that atrogin-1 plays a critical role in mechanisms of ANG II-induced wasting in vivo.

scholarly journals Lifelong Aerobic Exercise Alleviates Sarcopenia by Activating Autophagy and Inhibiting Protein Degradation via the AMPK/PGC-1α Signaling Pathway

Metabolites ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 323
Author(s):  
Jiling Liang ◽  
Hu Zhang ◽  
Zhengzhong Zeng ◽  
Liangwen Wu ◽  
Ying Zhang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Aerobic Exercise ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Skeletal Muscle Mass ◽  
Critical Role ◽  
Treadmill Running ◽  
Skeletal Muscle Atrophy

Sarcopenia is an aging-induced syndrome characterized by a progressive reduction of skeletal muscle mass and strength. Increasing evidence has attested that appropriate and scientific exercise could induce autophagy or optimize the functional status of autophagy, which plays a critical role in senescent muscular dystrophy. As a publicly recognized strategy for extending lifespan and improving the health of the elderly, the underlying mechanisms of lifelong regular aerobic exercise for the prevention of sarcopenia have not been fully elucidated. To explore the role of lifelong aerobic exercise in the beneficial regulation of autophagic signaling pathways in senescent skeletal muscle, the natural aging mice were used as the sarcopenia model and subjected to lifelong treadmill running to evaluate corresponding parameters related to skeletal muscle atrophy and autophagic signaling pathways. Compared with the young control mice, the aged mice showed a significant reduction in skeletal muscle mass, gastrocnemius muscle weight/body weight (GMW/BW) ratio, and cross-sectional areas (CSA) of skeletal muscle fibers (p < 0.01). In contrast, lifelong aerobic exercise effectively rescued these reduced biomarkers associated with muscle atrophy. Moreover, as shown in the activated AMPK/PGC-1α signaling pathway, lifelong aerobic exercise successfully prevented the aging-induced impairment of the ubiquitin-proteasome system (UPS), excessive apoptosis, defective autophagy, and mitochondrial dysfunction. The exercise-induced autophagy suppressed the key regulatory components of the UPS, inhibited excessive apoptosis, and optimized mitochondrial quality control, thereby preventing and delaying aging-induced skeletal muscle atrophy.

scholarly journals Tail suspension is useful as a sarcopenia model in rats

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Akira Nemoto ◽  
Toru Goyagi
Keyword(s):  
Skeletal Muscle ◽  
Muscle Contraction ◽  
Experimental Model ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Whole Body ◽  
Skeletal Muscle Atrophy ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Simple Method

Abstract Background Sarcopenia promotes skeletal muscle atrophy and exhibits a high mortality rate. Its elucidation is of the highest clinical importance, but an animal experimental model remains controversial. In this study, we investigated a simple method for studying sarcopenia in rats. Results Muscle atrophy was investigated in 24-week-old, male, tail-suspended (TS), Sprague Dawley and spontaneously hypertensive rats (SHR). Age-matched SD rats were used as a control group. The skeletal muscle mass weight, muscle contraction, whole body tension (WBT), cross-sectional area (CSA), and Muscle RING finger-1 (MuRF-1) were assessed. Enzyme-linked immunosorbent assay was used to evaluate the MuRF-1 levels. Two muscles, the extensor digitorum longus and soleus muscles, were selected for representing fast and slow muscles, respectively. All data, except CSA, were analyzed by a one-way analysis of variance, whereas CSA was analyzed using the Kruskal-Wallis test. Muscle mass weight, muscle contraction, WBT, and CSA were significantly lower in the SHR (n = 7) and TS (n = 7) groups than in the control group, whereas MuRF-1 expression was dominant. Conclusions TS and SHR presented sarcopenic phenotypes in terms of muscle mass, muscle contraction and CSA. TS is a useful technique for providing muscle mass atrophy and weakness in an experimental model of sarcopenia in rats.

scholarly journals Knockdown of the E3 ubiquitin ligase UBR5 and its role in skeletal muscle anabolism

2021 ◽  
Vol 320 (1) ◽  
pp. C45-C56
Author(s):  
David C. Hughes ◽  
Daniel C. Turner ◽  
Leslie M. Baehr ◽  
Robert A. Seaborne ◽  
Mark Viggars ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Ubiquitin Ligase ◽  
Fluorescent Protein ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Tibialis Anterior Muscle ◽  
E3 Ubiquitin Ligase ◽  
Skeletal Muscle Atrophy ◽  
The Impact

UBR5 is an E3 ubiquitin ligase positively associated with anabolism, hypertrophy, and recovery from atrophy in skeletal muscle. The precise mechanisms underpinning UBR5’s role in the regulation of skeletal muscle mass remain unknown. The present study aimed to elucidate these mechanisms by silencing the UBR5 gene in vivo. To achieve this aim, we electroporated a UBR5-RNAi plasmid into mouse tibialis anterior muscle to investigate the impact of reduced UBR5 on anabolic signaling MEK/ERK/p90RSK and Akt/GSK3β/p70S6K/4E-BP1/rpS6 pathways. Seven days after UBR5 RNAi electroporation, although reductions in overall muscle mass were not detected, the mean cross-sectional area (CSA) of green fluorescent protein (GFP)-positive fibers were reduced (−9.5%) and the number of large fibers were lower versus the control. Importantly, UBR5-RNAi significantly reduced total RNA, muscle protein synthesis, ERK1/2, Akt, and GSK3β activity. Although p90RSK phosphorylation significantly increased, total p90RSK protein levels demonstrated a 45% reduction with UBR5-RNAi. Finally, these early events after 7 days of UBR5 knockdown culminated in significant reductions in muscle mass (−4.6%) and larger reductions in fiber CSA (−18.5%) after 30 days. This was associated with increased levels of phosphatase PP2Ac and inappropriate chronic elevation of p70S6K and rpS6 between 7 and 30 days, as well as corresponding reductions in eIF4e. This study demonstrates that UBR5 plays an important role in anabolism/hypertrophy, whereby knockdown of UBR5 culminates in skeletal muscle atrophy.

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