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 FOXO signaling is required for disuse muscle atrophy and is directly regulated by Hsp70

2010 ◽  
Vol 298 (1) ◽  
pp. C38-C45 ◽  
Author(s):  
Sarah M. Senf ◽  
Stephen L. Dodd ◽  
Andrew R. Judge
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Fiber ◽  
Muscle Wasting ◽  
Dominant Negative ◽  
Disuse Muscle Atrophy ◽  
Rat Soleus Muscle ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy

The purpose of the current study was to determine whether heat shock protein 70 (Hsp70) directly regulates forkhead box O (FOXO) signaling in skeletal muscle. This aim stems from previous work demonstrating that Hsp70 overexpression inhibits disuse-induced FOXO transactivation and prevents muscle fiber atrophy. However, although FOXO is sufficient to cause muscle wasting, no data currently exist on the requirement of FOXO signaling in the progression of physiological muscle wasting, in vivo. In the current study we show that specific inhibition of FOXO, via expression of a dominant-negative FOXO3a, in rat soleus muscle during disuse prevented >40% of muscle fiber atrophy, demonstrating that FOXO signaling is required for disuse muscle atrophy. Subsequent experiments determined whether Hsp70 directly regulates FOXO3a signaling when independently activated in skeletal muscle, via transfection of FOXO3a. We show that Hsp70 inhibits FOXO3a-dependent transcription in a gene-specific manner. Specifically, Hsp70 inhibited FOXO3a-induced promoter activation of atrogin-1, but not MuRF1. Further studies showed that a FOXO3a DNA-binding mutant can activate MuRF1, but not atrogin-1, suggesting that FOXO3a activates these two genes through differential mechanisms. In summary, FOXO signaling is required for physiological muscle atrophy and is directly inhibited by Hsp70.

scholarly journals Identification and characterization of Fbxl22, a novel skeletal muscle atrophy-promoting E3 ubiquitin ligase

2020 ◽  
Vol 319 (4) ◽  
pp. C700-C719 ◽  
Author(s):  
David C. Hughes ◽  
Leslie M. Baehr ◽  
Julia R. Driscoll ◽  
Sarah A. Lynch ◽  
David S. Waddell ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Splice Variant ◽  
Splice Variants ◽  
Ring Finger ◽  
Ubiquitin Ligases ◽  
Skeletal Muscle Atrophy ◽  
E3 Ubiquitin Ligases ◽  
Muscle Mass Loss

Muscle-specific E3 ubiquitin ligases have been identified in muscle atrophy-inducing conditions. The purpose of the current study was to explore the functional role of F-box and leucine-rich protein 22 (Fbxl22), and a newly identified splice variant (Fbxl22–193), in skeletal muscle homeostasis and neurogenic muscle atrophy. In mouse C2C12 muscle cells, promoter fragments of the Fbxl22 gene were cloned and fused with the secreted alkaline phosphatase reporter gene to assess the transcriptional regulation of Fbxl22. The tibialis anterior muscles of male C57/BL6 mice (12–16 wk old) were electroporated with expression plasmids containing the cDNA of two Fbxl22 splice variants and tissues collected after 7, 14, and 28 days. Gastrocnemius muscles of wild-type and muscle-specific RING finger 1 knockout (MuRF1 KO) mice were electroporated with an Fbxl22 RNAi or empty plasmid and denervated 3 days posttransfection, and tissues were collected 7 days postdenervation. The full-length gene and novel splice variant are transcriptionally induced early (after 3 days) during neurogenic muscle atrophy. In vivo overexpression of Fbxl22 isoforms in mouse skeletal muscle leads to evidence of myopathy/atrophy, suggesting that both are involved in the process of neurogenic muscle atrophy. Knockdown of Fbxl22 in the muscles of MuRF1 KO mice resulted in significant additive muscle sparing 7 days after denervation. Targeting two E3 ubiquitin ligases appears to have a strong additive effect on protecting muscle mass loss with denervation, and these findings have important implications in the development of therapeutic strategies to treat muscle atrophy.

scholarly journals Trimetazidine Attenuates Dexamethasone-Induced Muscle Atrophy via Inhibiting NLRP3/GSDMD Pathway-Mediated Pyroptosis

2020 ◽  
Author(s):  
Li Wang ◽  
Ming-Qing He ◽  
Xi-Yu Shen ◽  
Kang-Zhen Zhang ◽  
Can Zhao ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Ring Finger ◽  
Muscle Performance ◽  
Skeletal Muscle Atrophy ◽  
C2c12 Myotubes ◽  
High Dose ◽  
Therapeutic Compound

Skeletal muscle atrophy is one of the major side effects of high dose or sustained usage of glucocorticoids. Pyroptosis is a novel form of pro-inflammatory programmed cell death that may contribute to skeletal muscle injury. Trimetazidine, a well-known anti-anginal agent, can also improve skeletal muscle performance both in human and mice. We here showed that dexamethasone induced atrophy, evidenced by the increase of muscle atrophy F-box (Atrogin-1) and muscle ring finger 1 (MuRF1) expression , and the decrease of myotube diameter in C2C12 myotubes. Dexamethasone also induced pyroptosis, indicated by upregulated pyroptosis-related protein NLRP3, Caspase-1 and GSDMD. Knockdown of NLRP3 or GSDMD attenuated dexamethasone-induced myotube pyroptosis and atrophy. Trimetazidine administration ameliorated dexamethasone-induced muscle atrophy both in vivo and in vitro. Moreover, trimetazidine improved exercise tolerance, as evidenced by increased running distance and running time, as well as increased skeletal muscle mass in dexamethasone-treated mice. Mechanically, trimetazidine could reverse dexamethasone-induced activation of pyroptosis both in C2C12 myotubes and in mice. Taken together, our present study demonstrated that NLRP3/GSDMD pathway-mediated pyroptosis was involved in dexamethasone-induced skeletal muscle atrophy. Trimetazidine could partially alleviate dexamethasone-induced skeletal muscle atrophy, and increase the diameter of C2C12 myotubes via inhibiting pyroptosis. Thus, trimetazidine might be a potential therapeutic compound for the prevention of muscle atrophy in glucocorticoid-treated patients.

scholarly journals Emerging Strategies Targeting Catabolic Muscle Stress Relief

2020 ◽  
Vol 21 (13) ◽  
pp. 4681 ◽  
Author(s):  
Mattia Scalabrin ◽  
Volker Adams ◽  
Siegfried Labeit ◽  
T. Scott Bowen
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Treatment Strategies ◽  
Ring Finger ◽  
Ubiquitin Proteasome System ◽  
Functional Mobility ◽  
Skeletal Muscle Wasting ◽  
Therapeutic Concepts ◽  
Ubiquitin Proteasome

Skeletal muscle wasting represents a common trait in many conditions, including aging, cancer, heart failure, immobilization, and critical illness. Loss of muscle mass leads to impaired functional mobility and severely impedes the quality of life. At present, exercise training remains the only proven treatment for muscle atrophy, yet many patients are too ill, frail, bedridden, or neurologically impaired to perform physical exertion. The development of novel therapeutic strategies that can be applied to an in vivo context and attenuate secondary myopathies represents an unmet medical need. This review discusses recent progress in understanding the molecular pathways involved in regulating skeletal muscle wasting with a focus on pro-catabolic factors, in particular, the ubiquitin-proteasome system and its activating muscle-specific E3 ligase RING-finger protein 1 (MuRF1). Mechanistic progress has provided the opportunity to design experimental therapeutic concepts that may affect the ubiquitin-proteasome system and prevent subsequent muscle wasting, with novel advances made in regards to nutritional supplements, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) inhibitors, myostatin antibodies, β2 adrenergic agonists, and small-molecules interfering with MuRF1, which all emerge as a novel in vivo treatment strategies for muscle wasting.

Endotoxin-induced skeletal muscle wasting is prevented by angiotensin-(1–7) through a p38 MAPK-dependent mechanism

2015 ◽  
Vol 129 (6) ◽  
pp. 461-476 ◽  
Author(s):  
María Gabriela Morales ◽  
Hugo Olguín ◽  
Gabriella Di Capua ◽  
Enrique Brandan ◽  
Felipe Simon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
P38 Mapk ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Skeletal Muscle Atrophy ◽  
Skeletal Muscle Wasting ◽  
Catabolic Response ◽  
Dependent Mechanism

In this study we determined that angiotensin-(1–7) is a novel peptide that prevents the skeletal muscle atrophy observed in a model of sepsis by inhibiting the catabolic response developed in skeletal muscle and improving its performance.

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 A Critical Role for Muscle Ring Finger-1 in Acute Lung Injury–associated Skeletal Muscle Wasting

2012 ◽  
Vol 185 (8) ◽  
pp. 825-834 ◽  
Author(s):  
D. Clark Files ◽  
Franco R. D'Alessio ◽  
Laura F. Johnston ◽  
Priya Kesari ◽  
Neil R. Aggarwal ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Muscle Wasting ◽  
Critical Role ◽  
Ring Finger ◽  
Skeletal Muscle Wasting

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 Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting

2011 ◽  
Vol 300 (6) ◽  
pp. H1973-H1982 ◽  
Author(s):  
Astrid Breitbart ◽  
Mannix Auger-Messier ◽  
Jeffery D. Molkentin ◽  
Joerg Heineke
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Muscle Growth ◽  
Skeletal Muscle Atrophy ◽  
Cardiac Cachexia ◽  
Heart Failure Patients ◽  
Skeletal Muscle Growth ◽  
Skeletal Muscle Wasting

A significant proportion of heart failure patients develop skeletal muscle wasting and cardiac cachexia, which is associated with a very poor prognosis. Recently, myostatin, a cytokine from the transforming growth factor-β (TGF-β) family and a known strong inhibitor of skeletal muscle growth, has been identified as a direct mediator of skeletal muscle atrophy in mice with heart failure. Myostatin is mainly expressed in skeletal muscle, although basal expression is also detectable in heart and adipose tissue. During pathological loading of the heart, the myocardium produces and secretes myostatin into the circulation where it inhibits skeletal muscle growth. Thus, genetic elimination of myostatin from the heart reduces skeletal muscle atrophy in mice with heart failure, whereas transgenic overexpression of myostatin in the heart is capable of inducing muscle wasting. In addition to its endocrine action on skeletal muscle, cardiac myostatin production also modestly inhibits cardiomyocyte growth under certain circumstances, as well as induces cardiac fibrosis and alterations in ventricular function. Interestingly, heart failure patients show elevated myostatin levels in their serum. To therapeutically influence skeletal muscle wasting, direct inhibition of myostatin was shown to positively impact skeletal muscle mass in heart failure, suggesting a promising strategy for the treatment of cardiac cachexia in the future.

scholarly journals Linalool Prevents Cisplatin Induced Muscle Atrophy by Regulating IGF-1/Akt/FoxO Pathway

2020 ◽  
Vol 11 ◽  
Author(s):  
Hong Zhang ◽  
Mengyi Chi ◽  
Linlin Chen ◽  
Xipeng Sun ◽  
Lili Wan ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Cancer Cachexia ◽  
Ring Finger ◽  
Skeletal Muscle Atrophy ◽  
Lewis Lung Cancer ◽  
Muscle Weight ◽  
C2c12 Myotube

Skeletal muscle atrophy is an important feature of cancer cachexia, which can be induced by chemotherapy, and affects the survival and quality of life of cancer patients seriously. No specific drugs for cancer cachexia have been applied in clinical practice. This study explored the therapeutic effect of linalool (LIN) on cisplatin (DDP) induced skeletal muscle atrophy. In vivo, LIN can improve skeletal muscle weight loss, anorexia, muscle strength decline and other cachexia symptoms caused by cisplatin treatment in a Lewis lung cancer tumor bearing mouse model, and cause no adverse effects on the anti-tumour effect. LIN treatment decreased the expression of muscle RING-finger protein-1 (MuRF1) and Atrogin1(MAFbx) in muscle, and the activation of insulin-like growth factor-1 (IGF-1)/protein kinase B (Akt)/forkhead box O (FoxO) pathway was observed. In vitro, LIN alleviated DDP induced C2C12 myotube atrophy, and IGF-1 receptor inhibitor Picropodophyllin (PIC), which had no adverse effect on C2C12 myotube cells, could reverse the protective effect of LIN. These results indicate that LIN down-regulates the expression of Atrogin1 and MuRF1 through the IGF-1/Akt/FoxO pathway, alleviating DDP-induced muscle atrophy and improving cachexia symptoms. LIN has the potential to be developed as a drug against cancer cachexia.

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