Inhibition of interleukin-6 decreases atrogene expression and ameliorates tail suspension-induced skeletal muscle atrophy

Yakabe, Mitsutaka; Ogawa, Sumito; Ota, Hidetaka; Iijima, Katsuya; Eto, Masato; Ouchi, Yasuyoshi; Akishita, Masahiro

doi:10.1371/journal.pone.0191318

Cited by 58 publications

(43 citation statements)

References 52 publications

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“…Other approaches to counteract muscle atrophy in different models of wasting conditions have been recently described and include administration of β‐hydroxy β‐methylbutyrate (HMB), 1,25‐dihydroxyvitamin D, anti‐interleukin‐6 antibody treatment, IκB kinase‐β inhibition by IMD‐0354, or direct inhibition of the UPS by MG132 . In the majority of these studies, however, the pharmacological agent was administered prior to initiating muscle atrophy by hindlimb suspension or did not prevent muscle atrophy . The use of MG132 is discussed controversially with a subset of studies reporting positive effects on muscle atrophy induced by hindlimb unloading, or tumour, whereas others saw no effects .…”

Section: Discussionmentioning

confidence: 99%

“…19 This possibly relates to a diversity of underlying mechanisms, length of intervention, or pharmacokinetics, but further studies are necessary to address this in more detail. Other approaches to counteract muscle atrophy in different models of wasting conditions have been recently described and include administration of β-hydroxy β-methylbutyrate (HMB), 50 1,25-dihydroxyvitamin D, 51 anti-interleukin-6 antibody treatment, 51 IκB kinase-β inhibition by IMD-0354, 52 or direct inhibition of the UPS by MG132. [53][54][55] In the majority of these studies, however, the pharmacological agent was administered prior to initiating muscle atrophy by hindlimb suspension 51 or did not prevent muscle atrophy.…”

Section: Treatment Of Diaphragm Dysfunction and Atrophy By Compound Imentioning

confidence: 99%

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Small‐molecule‐mediated chemical knock‐down of MuRF1/MuRF2 and attenuation of diaphragm dysfunction in chronic heart failure

Adams

Bowen

Werner³

et al. 2019

J cachexia sarcopenia muscle

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Background Chronic heart failure (CHF) leads to diaphragm myopathy that significantly impairs quality of life and worsens prognosis. In this study, we aimed to assess the efficacy of a recently discovered small‐molecule inhibitor of MuRF1 in treating CHF‐induced diaphragm myopathy and loss of contractile function. Methods Myocardial infarction was induced in mice by ligation of the left anterior descending coronary artery. Sham‐operated animals (sham) served as controls. One week post‐left anterior descending coronary artery ligation animals were randomized into two groups—one group was fed control rodent chow, whereas the other group was fed a diet containing 0.1% of the compound ID#704946—a recently described MuRF1‐interfering small molecule. Echocardiography confirmed development of CHF after 10 weeks. Functional and molecular analysis of the diaphragm was subsequently performed. Results Chronic heart failure induced diaphragm fibre atrophy and contractile dysfunction by ~20%, as well as decreased activity of enzymes involved in mitochondrial energy production (P < 0.05). Treatment with compound ID#704946 in CHF mice had beneficial effects on the diaphragm: contractile function was protected, while mitochondrial enzyme activity and up‐regulation of the MuRF1 and MuRF2 was attenuated after infarct. Conclusions Our murine CHF model presented with diaphragm fibre atrophy, impaired contractile function, and reduced mitochondrial enzyme activities. Compound ID#704946 rescued from this partially, possibly by targeting MuRF1/MuRF2. However, at this stage of our study, we refrain to claim specific mechanism(s) and targets of compound ID#704946, because the nature of changes after 12 weeks of feeding is likely to be complex and is not necessarily caused by direct mechanistic effects.

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Section: Discussionmentioning

confidence: 99%

Section: Treatment Of Diaphragm Dysfunction and Atrophy By Compound Imentioning

confidence: 99%

Small‐molecule‐mediated chemical knock‐down of MuRF1/MuRF2 and attenuation of diaphragm dysfunction in chronic heart failure

Adams

Bowen

Werner³

et al. 2019

J cachexia sarcopenia muscle

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“…Chronic IL-6 injections into skeletal muscle results in muscle atrophy [37]. Muscle unloading increases IL-6 expression [33], whereas inhibiting IL-6 during unloading diminishes MuRF1 activation without any effect on the MAFbx expression [38]. IL-6 expression in myotubes is regulated by p38 MAPK [39].…”

Section: Discussionmentioning

confidence: 99%

P38α-MAPK Signaling Inhibition Attenuates Soleus Atrophy during Early Stages of Muscle Unloading

Belova

Mochalova

Kostrominova

et al. 2020

IJMS

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To test the hypothesis that p38α-MAPK plays a critical role in the regulation of E3 ligase expression and skeletal muscle atrophy during unloading, we used VX-745, a selective p38α inhibitor. Three groups of rats were used: non-treated control (C), 3 days of unloading/hindlimb suspension (HS), and 3 days HS with VX-745 inhibitor (HSVX; 10 mg/kg/day). Total weight of soleus muscle in HS group was reduced compared to C (72.3 ± 2.5 vs 83.0 ± 3 mg, respectively), whereas muscle weight in the HSVX group was maintained (84.2 ± 5 mg). The expression of muscle RING-finger protein-1 (MuRF1) mRNA was significantly increased in the HS group (165%), but not in the HSVX group (127%), when compared with the C group. The expression of muscle-specific E3 ubiquitin ligases muscle atrophy F-box (MAFbx) mRNA was increased in both HS and HSVX groups (294% and 271%, respectively) when compared with C group. The expression of ubiquitin mRNA was significantly higher in the HS (423%) than in the C and HSVX (200%) groups. VX-745 treatment blocked unloading-induced upregulation of calpain-1 mRNA expression (HS: 120%; HSVX: 107%). These results indicate that p38α-MAPK signaling regulates MuRF1 but not MAFbx E3 ligase expression and inhibits skeletal muscle atrophy during early stages of unloading.

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“…Studies indicate that inflammation is an important mechanism leading to muscle atrophy. For example, the expression of interleukin‐6 (IL‐6, an inflammatory cytokine) is elevated in immobilized muscle or skin, and inhibition of IL‐6 decreases atrogene expression and ameliorates tail suspension‐induced skeletal muscle atrophy (Guo et al, ; Kang & Ji, ; Yakabe et al, ). Previous research has also shown that hindlimb unloading (7 d) can result in a 10‐fold increase in the activity of NF‐κB in the SOL muscle of rats, as well as a marked increase in the nuclear levels of p50 (Hunter et al, ).…”

Section: Discussionmentioning

confidence: 99%

Unexpected regulation pattern of the IKKβ/NF‐κB/MuRF1 pathway with remarkable muscle plasticity in the Daurian ground squirrel (Spermophilus dauricus)

Wei¹,

Gong²,

Fu³

et al. 2018

Journal Cellular Physiology

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As a typical hibernator, the Daurian ground squirrel (Spermophilus dauricus) spends considerable time in a state of reduced activity with prolonged fasting. Despite this, they experience little muscle atrophy and have thus become an interesting anti-disuse muscle atrophy model. The IKKβ/NF-κB signaling pathway is significant to muscle atrophy due to the protein degradation resulting from the upregulation of the E3 ubiquitin ligase MuRF1. The current study showed that the IKKβ/NF-κB signaling pathway and MuRF1 maintained relatively steady mRNA and protein expression levels, with little muscle atrophy observed in the soleus (slow-twitch, SOL) or extensor digitorum longus (fast-twitch, EDL) during hibernation (HIB); however, mRNA expression significantly increased in the SOL and EDL muscle during interbout arousal (IBA), as did the MuRF1 mRNA level in the SOL and MuRF1 protein level in the EDL. Interestingly, the expressions of p50 and MuRF1 significantly increased during HIB in the gastrocnemius (mixed muscle, GAS) and showed moderate atrophy, but dramatically decreased during IBA. Elevated IKKβ and p50 mRNA and protein expression in the cardiac muscle (CM) during HIB did not accompany increased MuRF1 expression or muscle wasting. Importantly, almost all increased or decreased indicators in the tested tissues recovered to pre-hibernation levels after HIB. This is the first study to report on the unexpected regulation of the IKKβ/NF-κB/MuRF1 pathway with remarkable muscle plasticity in Daurian ground squirrels during hibernation. Furthermore, we found that different types of muscles exhibited different strategies to cope with prolonged hibernation-induced disuse muscle atrophy.

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Inhibition of interleukin-6 decreases atrogene expression and ameliorates tail suspension-induced skeletal muscle atrophy

Cited by 58 publications

References 52 publications

Small‐molecule‐mediated chemical knock‐down of MuRF1/MuRF2 and attenuation of diaphragm dysfunction in chronic heart failure

Small‐molecule‐mediated chemical knock‐down of MuRF1/MuRF2 and attenuation of diaphragm dysfunction in chronic heart failure

P38α-MAPK Signaling Inhibition Attenuates Soleus Atrophy during Early Stages of Muscle Unloading

Unexpected regulation pattern of the IKKβ/NF‐κB/MuRF1 pathway with remarkable muscle plasticity in the Daurian ground squirrel (Spermophilus dauricus)

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