The
            <scp>AMPK</scp>
            agonist 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation‐associated cachectic muscle wasting

Hall, Derek T; Griss, Takla; Jennifer, F.; Sánchez, Brenda Janice; Sadek, Jason; Tremblay, Anne Marie K; Mubaid, Souad; Omer, Amr; Ford, Rebecca J.; Bédard, Nathalie; Pause, Arnim; Wing, Simon S.; Marco, Sergio Di; Steinberg, Gregory R.; Jones, Russell G.; Gallouzi, Imed Eddine

doi:10.15252/emmm.201708307

Cited by 64 publications

(89 citation statements)

References 95 publications

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“…To identify the network of mRNAs that associate with HuR during muscle wasting, we used C2C12 myotubes treated with or without IFNγ/TNFα to perform RNA immunoprecipitation (RIP) coupled to cDNA microarray experiments using an anti-HuR monoclonal antibody (3A2) (12,23,24,27). This in vitro cell model of muscle wasting is routinely used to mimic the effects of cytokines on muscle fibers, as seen during cachectic conditions (7,12,28,29) (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

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HuR counteracts miR-330 to promote STAT3 translation during inflammation-induced muscle wasting

Mubaid

Jennifer

Omer

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Debilitating cancer-induced muscle wasting, a syndrome known as cachexia, is lethal. Here we report a posttranscriptional pathway involving the RNA-binding protein HuR as a key player in the onset of this syndrome. Under these conditions, HuR switches its function from a promoter of muscle fiber formation to become an inducer of muscle loss. HuR binds to the STAT3 (signal transducer and activator of transcription 3) mRNA, which encodes one of the main effectors of this condition, promoting its expression both in vitro and in vivo. While HuR does not affect the stability and the cellular movement of this transcript, HuR promotes the translation of the STAT3 mRNA by preventing miR-330 (microRNA 330)–mediated translation inhibition. To achieve this effect, HuR directly binds to a U-rich element in the STAT3 mRNA-3′untranslated region (UTR) located within the vicinity of the miR-330 seed element. Even though the binding sites of HuR and miR-330 do not overlap, the recruitment of either one of them to the STAT3-3′UTR negatively impacts the binding and the function of the other factor. Therefore, together, our data establish the competitive interplay between HuR and miR-330 as a mechanism via which muscle fibers modulate, in part, STAT3 expression to determine their fate in response to promoters of muscle wasting.

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Section: Resultsmentioning

confidence: 99%

“…2D). Using the Lewis lung carcinoma (LLC) model of cancer inflammation-induced muscle wasting (29,32), we observed that the genetic ablation of HuR protected muHuR-KO mice from the LLC tumor-induced muscle loss that is normally observed in the control mice ( Fig. 2 E and F).…”

Section: Hur Promotes Stat3 Expression During Muscle Wasting Both In mentioning

confidence: 99%

HuR counteracts miR-330 to promote STAT3 translation during inflammation-induced muscle wasting

Mubaid

Jennifer

Omer

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Activators of AMPK, inflammatory www.nature.com/scientificreports www.nature.com/scientificreports/ cytokines and metformin, decreased the rate of protein synthesis. However, treatment with AICAR and A-769662, which activate AMPK, restored the levels of phosphorylated S6K and S6 proteins, which are markers of protein synthesis 32 . These findings suggested that AMPK activation induced by AICAR and A-769662 could restore protein synthesis in skeletal muscle.…”

Section: Discussionmentioning

confidence: 97%

“…Additionally, TGF-β1 mRNA and protein expression are significantly increased in skeletal muscles of humans and mice with ALS, and because of this characteristic, TGF-β1 could be used as a muscle biomarker for ALS disease 10 . Previous studies have shown that AMPK activation can prevent muscle wasting induced by inflammation through inhibition of the iNOS/NO pathway 32 . Therefore, we investigated whether hUCB-MSCs could inhibit the iNOS/NO pathway and found that hUCB-MSCs could prevent muscle atrophy by reducing nitrite concentration and iNOS protein levels in in vitro and in vivo studies ( Figs.…”

Section: Discussionmentioning

confidence: 99%

Repeated intramuscular transplantations of hUCB-MSCs improves motor function and survival in the SOD1 G93A mice through activation of AMPK

Kook

Lee

Shin

et al. 2020

Sci Rep

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by loss of motor neurons and degeneration of neuromuscular junctions. to improve disease progression, previous studies have suggested many options that have shown beneficial effects in diseases, especially stem cell therapy. in this study, we used repeated intramuscular transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) and observed positive effects on muscle atrophy and oxidative stress. in an in vivo study, motor function, body weight and survival rate were assessed, and skeletal muscle tissues were analyzed by western blotting and immunohistochemistry. After intramuscular transplantation, the hUcB-MScs survived within the skeletal muscle for at least 1 week. Transplantation ameliorated muscle atrophy and the rate of neuromuscular degeneration in skeletal muscle through reductions in intracellular RoS levels. Both expression of skeletal muscle atrophy markers, muscle atrophy F-box (MAFbx)/atrogin1 and muscle RING finger 1 (MuRF1), were also reduced; however, the reductions were not significant. Moreover, transplantation of hUCB-MSCs improved protein synthesis and inhibited the inoS/no signaling pathway through AMpK activation. our results suggest that repeated intramuscular transplantation of hUcB-MScs can be a practical option for stem cell therapy for ALS.

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“…Third, dorsomorphin was not a specific AMPK inhibitor which also inhibits BMP signaling and the VEGF type 2 receptor [36][37][38]. Notwithstanding its limitation, dorsomorphin was still used to inhibit AMPK in recent studies [39,40] since it remains the only small molecule that has been found to inhabit AMPK signaling [41]. However, it would be more specific to apply AMPK knockout mouse models to examine the specific role of AMPK in mediating the chondroprotective and pain relief effects of metformin; thus, future studies are still warranted to explore.…”

Section: Limitationsmentioning

confidence: 99%

Exploration of metformin as novel therapy for osteoarthritis: preventing cartilage degeneration and reducing pain behavior

Ding

Terkeltaub

et al. 2020

Arthritis Res Ther

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Background: Metformin could activate adenosine monophosphate-activated protein kinase (AMPK) which was postulated as a potential therapeutic target for osteoarthritis. This study aimed to examine the effects of metformin on cartilage and pain in osteoarthritis mouse model. Methods: Eighty 10-week-old male C57BL/6 mice were randomized to 6 groups: non-operation, sham-operation, destabilization of the medial meniscus (DMM)-operation with intragastric saline/metformin, and DMM-operation with intraarticular saline/metformin. Articular cartilage degeneration was examined by scanning electron microscopy (SEM) and graded using the scoring system recommended by Osteoarthritis Research Society International (OARSI). Mechanical withdrawal threshold and hind paw weight distribution were measured to assess the pain-related behavior. Cell Counting Kit-8 assay, quantificational real-time polymerase chain reaction, and western blot analysis were conducted to examine the anabolic and anti-catabolic effect of metformin and the role of AMPK in mediating its effects on interleukin-1β stimulated primary mice chondrocytes. Results: Compared with mice receiving intragastric and intraarticular saline, mice in both intragastric and intraarticular metformin displayed attenuated articular cartilage degeneration, indicated by less cartilage damage under SEM and significantly lower OARSI scores. A higher paw withdrawal threshold and a decreased weightbearing asymmetry were observed in the intragastric and intraarticular metformin mice compared with their corresponding saline groups in DMM model of osteoarthritis. In vitro experiments showed that metformin not only decreased the level of matrix metalloproteinase 13, but also elevated type II collagen production through activating AMPK pathway. Conclusions: Metformin attenuates osteoarthritis structural worsening and modulates pain, suggesting its potential for osteoarthritis prevention or treatment.

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The AMPK agonist 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation‐associated cachectic muscle wasting

Cited by 64 publications

References 95 publications

HuR counteracts miR-330 to promote STAT3 translation during inflammation-induced muscle wasting

HuR counteracts miR-330 to promote STAT3 translation during inflammation-induced muscle wasting

Repeated intramuscular transplantations of hUCB-MSCs improves motor function and survival in the SOD1 G93A mice through activation of AMPK

Exploration of metformin as novel therapy for osteoarthritis: preventing cartilage degeneration and reducing pain behavior

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