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 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 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 Upregulation of Heme Oxygenase-1 by Hemin Alleviates Sepsis-Induced Muscle Wasting in Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Xiongwei Yu ◽  
Wenjun Han ◽  
Changli Wang ◽  
Daming Sui ◽  
Jinjun Bian ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Heme Oxygenase ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Cecal Ligation ◽  
Skeletal Muscle Atrophy ◽  
Enzyme Linked Immunosorbent Assay ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Sod Activity

Hemin, an inducer of heme oxygenase-1 (HO-1), can enhance the activation of HO-1. HO-1 exhibits a variety of activities, such as anti-inflammatory, antioxidative, and antiapoptotic functions. The objective of this study was to investigate the effects of hemin on sepsis-induced skeletal muscle wasting and to explore the mechanisms by which hemin exerts its effects. Cecal ligation and perforation (CLP) was performed to create a sepsis mouse model. Mice were randomly divided into four groups: control, CLP, CLP plus group, and CLP-hemin-ZnPP (a HO-1 inhibitor). The weight of the solei from the mice was measured, and histopathology was examined. Cytokines were measured by enzyme-linked immunosorbent assay (ELISA). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting were used to assess the expression levels of HO-1 and atrogin-1. Furthermore, we investigated the antioxidative effects of HO-1 by detecting malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. CLP led to dramatic skeletal muscle weakness and atrophy, but pretreatment with hemin protected mice against CLP-mediated muscle atrophy. Hemin also induced high HO-1 expression, which resulted in suppressed proinflammatory cytokine and reactive oxygen species (ROS) production. The expression of MuRF1 and atrogin-1, two ubiquitin ligases of the ubiquitin-proteasome system- (UPS-) mediated proteolysis, was also inhibited by increased HO-1 levels. Hemin-mediated increases in HO-1 expression exert protective effects on sepsis-induced skeletal muscle atrophy at least partly by inhibiting the expression of proinflammatory cytokines, UPS-mediated proteolysis, and ROS activation. Therefore, hemin might be a new treatment target against sepsis-induced skeletal muscle atrophy.

scholarly journals Exercise as an anti-inflammatory therapy for cancer cachexia: a focus on interleukin-6 regulation

2020 ◽  
Vol 318 (2) ◽  
pp. R296-R310 ◽  
Author(s):  
Hélène N. Daou
Keyword(s):  
Skeletal Muscle ◽  
Systemic Inflammation ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Skeletal Muscle Atrophy ◽  
Ampk Signaling ◽  
Skeletal Muscle Wasting ◽  
Skeletal Muscle Loss ◽  
Anti Inflammatory ◽  
Tumor Growth And Metastasis

Cancer cachexia is a complicated disorder of extreme, progressive skeletal muscle wasting. It is directed by metabolic alterations and systemic inflammation dysregulation. Numerous studies have demonstrated that increased systemic inflammation promotes this type of cachexia and have suggested that cytokines are implicated in the skeletal muscle loss. Exercise is firmly established as an anti-inflammatory therapy that can attenuate or even reverse the process of muscle wasting in cancer cachexia. The interleukin IL-6 is generally considered to be a key player in the development of the microenvironment of malignancy; it promotes tumor growth and metastasis by acting as a bridge between chronic inflammation and cancerous tissue and it also induces skeletal muscle atrophy and protein breakdown. Paradoxically, a beneficial role for IL-6 has also been identified recently, and that is its status as a “founding member” of the myokine class of proteins. Skeletal muscle is an important source of circulating IL-6 in people who participate in exercise training. IL-6 acts as an anti-inflammatory myokine by inhibiting TNFα and improving glucose uptake through the stimulation of AMPK signaling. This review discusses the action of IL-6 in skeletal muscle tissue dysfunction and the role of IL-6 as an “exercise factor” that modulates the immune system. This review also sheds light on the main considerations related to the treatment of muscle wasting in cancer cachexia.

α-Ionone attenuates high-fat diet-induced skeletal muscle wasting in mice via activation of cAMP signaling

2019 ◽  
Vol 10 (2) ◽  
pp. 1167-1178 ◽  
Author(s):  
Tao Tong ◽  
Minji Kim ◽  
Taesun Park
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
High Fat Diet ◽  
Muscle Wasting ◽  
Camp Signaling ◽  
High Fat ◽  
Skeletal Muscle Wasting ◽  
Naturally Occurring ◽  
Flavoring Agent

α-Ionone, a naturally occurring flavoring agent, attenuates muscle atrophy in HFD-fed mice via activation of cAMP signaling.

scholarly journals MuRF1/TRIM63, Master Regulator of Muscle Mass

2020 ◽  
Vol 21 (18) ◽  
pp. 6663 ◽  
Author(s):  
Dulce Peris-Moreno ◽  
Daniel Taillandier ◽  
Cécile Polge
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Muscle Wasting ◽  
Skeletal Muscle Atrophy ◽  
Cardiac Functions ◽  
Important Player ◽  
Cardiac Muscles ◽  
Inhibitory Molecules

The E3 ubiquitin ligase MuRF1/TRIM63 was identified 20 years ago and suspected to play important roles during skeletal muscle atrophy. Since then, numerous studies have been conducted to decipher the roles, molecular mechanisms and regulation of this enzyme. This revealed that MuRF1 is an important player in the skeletal muscle atrophy process occurring during catabolic states, making MuRF1 a prime candidate for pharmacological treatments against muscle wasting. Indeed, muscle wasting is an associated event of several diseases (e.g., cancer, sepsis, diabetes, renal failure, etc.) and negatively impacts the prognosis of patients, which has stimulated the search for MuRF1 inhibitory molecules. However, studies on MuRF1 cardiac functions revealed that MuRF1 is also cardioprotective, revealing a yin and yang role of MuRF1, being detrimental in skeletal muscle and beneficial in the heart. This review discusses data obtained on MuRF1, both in skeletal and cardiac muscles, over the past 20 years, regarding the structure, the regulation, the location and the different functions identified, and the first inhibitors reported, and aim to draw the picture of what is known about MuRF1. The review also discusses important MuRF1 characteristics to consider for the design of future drugs to maintain skeletal muscle mass in patients with different pathologies.

scholarly journals PO-094 p38 MAPK controls of E3-ligases expression and soleus atrophy attenuation in rat upon hindlimb unloading

2018 ◽  
Vol 1 (3) ◽  
Author(s):  
Tatiana Nemirovskaya ◽  
Svetlana Belova ◽  
Boris Shenkman ◽  
Ekaterina Mochalova
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
P38 Mapk ◽  
Muscle Atrophy ◽  
Mapk Signaling ◽  
Hindlimb Unloading ◽  
Hindlimb Suspension ◽  
Skeletal Muscle Atrophy ◽  
Control Group ◽  
E3 Ligases

Objective Unloading causes rapid skeletal muscle atrophy mainly due to the increased protein degradation. Muscle proteolysis results from the activation of ubiquitin-proteasome systems. The ubiquitination proteins are carried out by muscle-specific E3 ubiquitin ligases – MuRF-1 and MAFbx. It is known that MuRF-1 and MAFbx expression significantly increases on the third day of muscle unloading. We tested the hypothesis that p38 MAPK participates in the regulation of E3 ligases expression and the development of skeletal muscle atrophy during unloading. To check this idea we inhibited p38 MAPK by VX-745. Methods 21 male Wistar rats were divided into 3 groups (7 rats in each group): intact control (C), rats suspended for 3 days (HS) and rats suspended and injected i.p. with VX-745 (10 mg/kg/day) (VX). The hindlimb suspension was carried out according to Morey-Holton technique. The animals were anaesthetised with an i.p. injection of tribromoethanol (240 mg/kg). Under anesthesia, the m.soleus were excised, frozen in liquid nitrogen, and stored at -80°C until further analysis. All procedures with the animals were approved by the Biomedicine Ethics Committee of the Institute of Biomedical Problems of the Russian Academy of Sciences/Physiology section of the Russian Bioethics Committee. The statistical analysis was performed using the REST 2009 v.2.0.12 and Origin Pro programs at the significance level set at 0,05. The results are given as median in percent and interquartile range (0.25-0.75). Results The muscle weight in HS group was significantly reduced (72,3±2,5 mg) compared to C (83,0±3 mg), p<0.05, while the soleus weight of VX group didn’t differ from the control (84.2±5 mg). The MuRF1 mRNA expression was elevated dramatically in HS group (165 (138-210) %) when compared with the control (100 (64.6-112.5) %), p<0.05.  In the VX group the level of MuRF1 mRNA expression (127 (105-138) %) didn’t differ from the control group. The MAFbx mRNA expression was observed to increase equally in both suspended groups (294 (265-342) % and (271 (239-309) %).) vs C (100 (91-106) %) so, VX-745 administration did not have any significant effect on its expression. We also found that the level of ubiquitin mRNA expression in the soleus of HS rats was higher (423 (325-485) %) in comparison with the C group (100 (78-166) %, p<0.05) while VX-745 injection prevented increasing the  mRNA ubiquitin expression (200 (190-237) %). We discovered that the elevation of calpain-1 mRNA expression upon HS was prevented by VX-745 administration and its level didn’t differ from the control group (C - 100 (97-105) %, HS – 120 (116-133) %, VX - 107 (100-115) %, p<0.05). Conclusions Thus, the results indicate that the p38 MAPK signaling pathway takes part in the regulation of E3-ligase MuRF1 but not MAFbx expression. The p38 MAPK inhibition prevents muscle atrophy and the elevation of ubiquitin and calpain mRNA expression at the early stage of hindlimb unloading. This work was supported by RFBR grant No.17-04-01838.

scholarly journals UBE2L3, a Partner of MuRF1/TRIM63, Is Involved in the Degradation of Myofibrillar Actin and Myosin

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1974
Author(s):  
Dulce Peris-Moreno ◽  
Mélodie Malige ◽  
Agnès Claustre ◽  
Andrea Armani ◽  
Cécile Coudy-Gandilhon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Ubiquitin Proteasome System ◽  
Contractile Proteins ◽  
Skeletal Muscle Atrophy ◽  
C2c12 Myotubes ◽  
Skeletal Muscle Wasting ◽  
Life Prognosis ◽  
Ubiquitin Conjugating Enzymes ◽  
Alpha Actin

The ubiquitin proteasome system (UPS) is the main player of skeletal muscle wasting, a common characteristic of many diseases (cancer, etc.) that negatively impacts treatment and life prognosis. Within the UPS, the E3 ligase MuRF1/TRIM63 targets for degradation several myofibrillar proteins, including the main contractile proteins alpha-actin and myosin heavy chain (MHC). We previously identified five E2 ubiquitin-conjugating enzymes interacting with MuRF1, including UBE2L3/UbcH7, that exhibited a high affinity for MuRF1 (KD = 50 nM). Here, we report a main effect of UBE2L3 on alpha-actin and MHC degradation in catabolic C2C12 myotubes. Consistently UBE2L3 knockdown in Tibialis anterior induced hypertrophy in dexamethasone (Dex)-treated mice, whereas overexpression worsened the muscle atrophy of Dex-treated mice. Using combined interactomic approaches, we also characterized the interactions between MuRF1 and its substrates alpha-actin and MHC and found that MuRF1 preferentially binds to filamentous F-actin (KD = 46.7 nM) over monomeric G-actin (KD = 450 nM). By contrast with actin that did not alter MuRF1–UBE2L3 affinity, binding of MHC to MuRF1 (KD = 8 nM) impeded UBE2L3 binding, suggesting that differential interactions prevail with MuRF1 depending on both the substrate and the E2. Our data suggest that UBE2L3 regulates contractile proteins levels and skeletal muscle atrophy.

scholarly journals The TWEAK–Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice

2010 ◽  
Vol 188 (6) ◽  
pp. 833-849 ◽  
Author(s):  
Ashwani Mittal ◽  
Shephali Bhatnagar ◽  
Akhilesh Kumar ◽  
Estelle Lach-Trifilieff ◽  
Sandrine Wauters ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Fiber Type ◽  
Nuclear Factor Κb ◽  
Skeletal Muscle Atrophy ◽  
Muscle Proteins ◽  
Cross Sectional ◽  
Transgenic Expression ◽  
Genetic Ablation ◽  
Skeletal Muscle Wasting

Skeletal muscle atrophy occurs in a variety of clinical settings, including cachexia, disuse, and denervation. Inflammatory cytokines have been shown to be mediators of cancer cachexia; however, the role of cytokines in denervation- and immobilization-induced skeletal muscle loss remains unknown. In this study, we demonstrate that a single cytokine, TNF-like weak inducer of apoptosis (TWEAK), mediates skeletal muscle atrophy that occurs under denervation conditions. Transgenic expression of TWEAK induces atrophy, fibrosis, fiber-type switching, and the degradation of muscle proteins. Importantly, genetic ablation of TWEAK decreases the loss of muscle proteins and spared fiber cross-sectional area, muscle mass, and strength after denervation. Expression of the TWEAK receptor Fn14 (fibroblast growth factor–inducible receptor 14) and not the cytokine is significantly increased in muscle upon denervation, demonstrating an unexpected inside-out signaling pathway; the receptor up-regulation allows for TWEAK activation of nuclear factor κB, causing an increase in the expression of the E3 ubiquitin ligase MuRF1. This study reveals a novel mediator of skeletal muscle atrophy and indicates that the TWEAK–Fn14 system is an important target for preventing skeletal muscle wasting.

scholarly journals Lithium Chloride Protects against Sepsis-Induced Skeletal Muscle Atrophy and Cancer Cachexia

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1017
Author(s):  
Ji-Hyung Lee ◽  
Seon-Wook Kim ◽  
Jun-Hyeong Kim ◽  
Hyun-Jun Kim ◽  
JungIn Um ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Lithium Chloride ◽  
Muscle Atrophy ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Therapeutic Effects ◽  
In Vivo Models ◽  
Skeletal Muscle Wasting ◽  
Chloride Treatment

Inflammation-mediated skeletal muscle wasting occurs in patients with sepsis and cancer cachexia. Both conditions severely affect patient morbidity and mortality. Lithium chloride has previously been shown to enhance myogenesis and prevent certain forms of muscular dystrophy. However, to our knowledge, the effect of lithium chloride treatment on sepsis-induced muscle atrophy and cancer cachexia has not yet been investigated. In this study, we aimed to examine the effects of lithium chloride using in vitro and in vivo models of cancer cachexia and sepsis. Lithium chloride prevented wasting in myotubes cultured with cancer cell-conditioned media, maintained the expression of the muscle fiber contractile protein, myosin heavy chain 2, and inhibited the upregulation of the E3 ubiquitin ligase, Atrogin-1. In addition, it inhibited the upregulation of inflammation-associated cytokines in macrophages treated with lipopolysaccharide. In the animal model of sepsis, lithium chloride treatment improved body weight, increased muscle mass, preserved the survival of larger fibers, and decreased the expression of muscle-wasting effector genes. In a model of cancer cachexia, lithium chloride increased muscle mass, enhanced muscle strength, and increased fiber cross-sectional area, with no significant effect on tumor mass. These results indicate that lithium chloride exerts therapeutic effects on inflammation-mediated skeletal muscle wasting, such as sepsis-induced muscle atrophy and cancer cachexia.

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