Pulsed ultrasound prevents lipopolysaccharide-induced muscle atrophy through inhibiting p38 MAPK phosphorylation in C2C12 myotubes

Background: Muscle atrophy, i.e., the loss of skeletal muscle mass and function, is an unresolved problem associated with aging (sarcopenia) and several pathological conditions. The imbalance between myofibrillary protein breakdown (especially the adult isoforms of myosin heavy chain, MyHC) and synthesis, and the reduction of muscle regenerative potential are main causes of muscle atrophy. Methods: Starting from one-hundred dried hydroalcoholic extracts of medical plants, we identified those able to contrast the reduction of C2C12 myotube diameter in well-characterized in vitro models mimicking muscle atrophy associated to inflammatory states, glucocorticoid treatment or nutrient deprivation. Based on their ability to rescue type II MyHC (MyHC-II) expression in atrophying conditions, six extracts with different phytochemical profiles were selected, mixed in groups of three, and tested on atrophic myotubes. The molecular mechanism underpinning the effects of the most efficacious formulation, and its efficacy on myotubes obtained from muscle biopsies of young and sarcopenic subjects were also investigated. Results: We identified WST (Withania somnifera, Silybum marianum, Trigonella foenum-graecum) formulation as extremely efficacious in protecting C2C12 myotubes against MyHC-II degradation by stimulating Akt (protein kinase B)-dependent protein synthesis and p38 MAPK (p38 mitogen-activated protein kinase)/myogenin-dependent myoblast differentiation. WST sustains trophism in C2C12 and young myotubes, and rescues the size, developmental MyHC expression and myoblast fusion in sarcopenic myotubes. Conclusion: WST strongly counteracts muscle atrophy associated to different conditions in vitro. The future validation in vivo of our results might lead to the use of WST as a food supplement to sustain muscle mass in diffuse atrophying conditions, and to reverse the age-related functional decline of human muscles, thus improving people quality of life and reducing social and health-care costs.

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Somatostatin stimulates intestinal NHE8 expression via p38 MAPK pathway

AJP Cell Physiology ◽

10.1152/ajpcell.00421.2010 ◽

2011 ◽

Vol 300 (2) ◽

pp. C375-C382 ◽

Cited By ~ 15

Author(s):

Chunhui Wang ◽

Hua Xu ◽

Huacong Chen ◽

Jing Li ◽

Bo Zhang ◽

...

Keyword(s):

P38 Mapk ◽

Mapk Pathway ◽

Somatostatin Receptor ◽

Peptide Hormone ◽

Mitogen Activated Protein Kinase ◽

Mapk Phosphorylation ◽

P38 Mapk Pathway ◽

Mitogen Activated Protein ◽

D Cells ◽

Human Intestinal Cells

Diarrhea is a common manifestation of gastrointestinal disorders. Diarrhea-induced losses of fluid and electrolyte could lead to dehydration and electrolyte imbalances, resulting in significant morbidity and mortality, especially in children living in developing countries. Somatostatin, a peptide hormone secreted by D-cells, plays an important role in regulating motility and intestinal Na+ absorption. Although octreotide, a somatostatin analog, is used to treat diarrhea, its mechanisms of action are unclear. Here we showed that octreotide increased brush-border membrane Na+/H+ exchanger 8 (NHE8) expression in the small intestine to the exclusion of other NHEs that participate in Na+ absorption. The same effect also occurred in human intestinal cells (Caco-2). We found that the increase of NHE8 expression by somatostatin required p38 mitogen-activated protein kinase (MAPK) activation. Furthermore, the somatostatin receptor SSTR2 antagonist CYN154806 could abolish somatostatin-induced NHE8 expression and p38 MAPK phosphorylation. Thus our data provided the first concrete evidence indicating that somatostatin stimulates intestinal Na+ absorption by increasing intestinal NHE8 expression through the SSTR2-p38 MAPK pathway.

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Stimulation of pro-α1(I) collagen by TGF-β1 in mesangial cells: role of the p38 MAPK pathway

AJP Renal Physiology ◽

10.1152/ajprenal.2001.280.3.f495 ◽

2001 ◽

Vol 280 (3) ◽

pp. F495-F504 ◽

Cited By ~ 92

Author(s):

Beek Yoke Chin ◽

Amir Mohsenin ◽

Su Xia Li ◽

Augustine M. K. Choi ◽

Mary E. Choi

Keyword(s):

P38 Mapk ◽

Intracellular Signaling ◽

Mesangial Cells ◽

Mapk Pathway ◽

Dominant Negative ◽

Glomerular Mesangial Cells ◽

Mapk Activation ◽

Mapk Phosphorylation ◽

Collagen Mrna

Transforming growth factor-β1(TGF-β1) is a potent inducer of extracellular matrix protein synthesis and a key mediator of renal fibrosis. However, the intracellular signaling mechanisms by which TGF-β1stimulates this process remain incompletely understood. In this report, we examined the role of a major stress-activated intracellular signaling cascade, belonging to the mitogen-activated protein kinase (MAPK) superfamily, in mediating TGF-β1 responses in rat glomerular mesangial cells, using dominant-negative inhibition of TGF-β1 signaling receptors. We first stably transfected rat glomerular mesangial cells with a kinase-deleted mutant TGF-β type II receptor (TβR-IIM) designed to inhibit TGF-β1 signaling in a dominant-negative fashion. Next, expression of TβR-IIM mRNA was confirmed by Northern analysis. Cell surface expression and ligand binding of TβR-IIM protein were demonstrated by affinity cross-linking with 125I-labeled-TGF-β1. TGF-β1 rapidly induced p38 MAPK phosphorylation in wild-type and empty vector (pcDNA3)-transfected control mesangial cells. Interestingly, transfection with dominant-negative TβR-IIM failed to block TGF-β1-induced p38 MAPK phosphorylation. Moreover, dominant-negative TβR-IIMfailed to block TGF-β1-stimulated pro-α1(I) collagen mRNA expression and cellular protein synthesis, whereas TGF-β1-induced extracellular signal-regulated kinase (ERK) 1/ERK2 activation and antiproliferative responses were blocked by TβR-IIM. In the presence of a specific inhibitor of p38 MAPK, SB-203580, TGF-β1 was unable to stimulate pro-α1(I) collagen mRNA expression in the control and TβR-IIM-transfected mesangial cells. Finally, we confirmed that both p38 MAPK activation and pro-α1(I) collagen stimulation were TGF-β1 effects that were abrogated by dominant-negative inhibition of TGF-β type I receptor. Thus we show first demonstration of p38 MAPK activation by TGF-β1 in mesangial cells, and, given the rapid kinetics, this TGF-β1 effect is likely a direct one. Furthermore, our findings suggest that the p38 MAPK pathway functions as a component in the signaling of pro-α1(I) collagen induction by TGF-β1 in mesangial cells.

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Angiotensin (1-7) prevents angiotensin II-induced nociceptive behaviour via inhibition of p38 MAPK phosphorylation mediated through spinal Mas receptors in mice

European Journal of Pain ◽

10.1002/ejp.512 ◽

2014 ◽

Vol 18 (10) ◽

pp. 1471-1479 ◽

Cited By ~ 23

Author(s):

W. Nemoto ◽

Y. Ogata ◽

O. Nakagawasai ◽

F. Yaoita ◽

T. Tadano ◽

...

Keyword(s):

Angiotensin Ii ◽

P38 Mapk ◽

Mapk Phosphorylation ◽

Nociceptive Behaviour

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Biochanin A Alleviates Cerebral Ischemia/Reperfusion Injury by Suppressing Endoplasmic Reticulum Stress-Induced Apoptosis and p38MAPK Signaling Pathway In Vivo and In Vitro

Frontiers in Endocrinology ◽

10.3389/fendo.2021.646720 ◽

2021 ◽

Vol 12 ◽

Author(s):

Min-min Guo ◽

Sheng-biao Qu ◽

Hui-ling Lu ◽

Wen-bo Wang ◽

Mu-Liang He ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

P38 Mapk ◽

Ischemia Reperfusion ◽

Biochanin A ◽

Neurological Deficits ◽

Mapk Phosphorylation ◽

Cerebral Ischemia Reperfusion

We have previously shown that biochanin A exhibits neuroprotective properties in the context of cerebral ischemia/reperfusion (I/R) injury. The mechanistic basis for such properties, however, remains poorly understood. This study was therefore designed to explore the manner whereby biochanin A controls endoplasmic reticulum (ER) stress, apoptosis, and inflammation within fetal rat primary cortical neurons in response to oxygen-glucose deprivation/reoxygenation (OGD/R) injury, and in a rat model of middle cerebral artery occlusion and reperfusion (MCAO/R) injury. For the OGD/R in vitro model system, cells were evaluated after a 2 h OGD following a 24 h reoxygenation period, whereas in vivo neurological deficits were evaluated following 2 h of ischemia and 24 h of reperfusion. The expression of proteins associated with apoptosis, ER stress (ERS), and p38 MAPK phosphorylation was evaluated in these samples. Rats treated with biochanin A exhibited reduced neurological deficits relative to control rats following MCAO/R injury. Additionally, GRP78 and CHOP levels rose following I/R modeling both in vitro and in vivo, whereas biochanin A treatment was associated with reductions in CHOP levels but further increases in GRP78 levels. In addition, OGD/R or MCAO/R were associated with markedly enhanced p38 MAPK phosphorylation that was alleviated by biochanin A treatment. Similarly, OGD/R or MCAO/R injury resulted in increases in caspase-3, caspase-12, and Bax levels as well as decreases in Bcl-2 levels, whereas biochanin A treatment was sufficient to reverse these phenotypes. Together, these findings thus demonstrate that biochanin A can alleviate cerebral I/R-induced damage at least in part via suppressing apoptosis, ER stress, and p38 MAPK signaling, thereby serving as a potent neuroprotective agent.

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The TGFβ-induced phosphorylation and activation of p38 mitogen-activated protein kinase is mediated by MAP3K4 and MAP3K10 but not TAK1

Open Biology ◽

10.1098/rsob.130067 ◽

2013 ◽

Vol 3 (6) ◽

pp. 130067 ◽

Cited By ~ 16

Author(s):

Gopal P. Sapkota

Keyword(s):

Protein Kinase ◽

P38 Mapk ◽

Transforming Growth Factor Beta ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Transforming Growth Factor ◽

Mitogen Activated Protein Kinase ◽

Mapk Phosphorylation ◽

Mesenchymal Transition ◽

Mitogen Activated Protein

The signalling pathways downstream of the transforming growth factor beta (TGFβ) family of cytokines play critical roles in all aspects of cellular homeostasis. The phosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) has been implicated in TGFβ-induced epithelial-to-mesenchymal transition and apoptosis. The precise molecular mechanisms by which TGFβ cytokines induce the phosphorylation and activation of p38 MAPK are unclear. In this study, I demonstrate that TGFβ-activated kinase 1 (TAK1/MAP3K7) does not play a role in the TGFβ-induced phosphorylation and activation of p38 MAPK in MEFs and HaCaT keratinocytes. Instead, RNAi -mediated depletion of MAP3K4 and MAP3K10 results in the inhibition of the TGFβ-induced p38 MAPK phosphorylation. Furthermore, the depletion of MAP3K10 from cells homozygously knocked-in with a catalytically inactive mutant of MAP3K4 completely abolishes the TGFβ-induced phosphorylation of p38 MAPK, implying that among MAP3Ks, MAP3K4 and MAP3K10 are sufficient for mediating the TGFβ-induced activation of p38 MAPK.

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The intrathecal administration of losartan, an AT1 receptor antagonist, produces an antinociceptive effect through the inhibiton of p38 MAPK phosphorylation in the mouse formalin test

Neuroscience Letters ◽

10.1016/j.neulet.2014.11.018 ◽

2015 ◽

Vol 585 ◽

pp. 17-22 ◽

Cited By ~ 10

Author(s):

Wataru Nemoto ◽

Yoshiki Ogata ◽

Osamu Nakagawasai ◽

Fukie Yaoita ◽

Takeshi Tanado ◽

...

Keyword(s):

Receptor Antagonist ◽

P38 Mapk ◽

Formalin Test ◽

Antinociceptive Effect ◽

Intrathecal Administration ◽

At1 Receptor ◽

Mapk Phosphorylation

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Protective Effect of Pyropia yezoensis Peptide on Dexamethasone-Induced Myotube Atrophy in C2C12 Myotubes

Marine Drugs ◽

10.3390/md17050284 ◽

2019 ◽

Vol 17 (5) ◽

pp. 284 ◽

Cited By ~ 4

Author(s):

Min-Kyeong Lee ◽

Jeong-Wook Choi ◽

Youn Hee Choi ◽

Taek-Jeong Nam

Keyword(s):

Skeletal Muscle ◽

Growth Factor ◽

Signaling Pathway ◽

Muscle Atrophy ◽

Skeletal Muscle Atrophy ◽

C2c12 Myotubes ◽

Protective Effects ◽

Factor I ◽

Igf I ◽

Foxo Signaling Pathway

Dexamethasone (DEX), a synthetic glucocorticoid, causes skeletal muscle atrophy. This study examined the protective effects of Pyropia yezoensis peptide (PYP15) against DEX-induced myotube atrophy and its association with insulin-like growth factor-I (IGF-I) and the Akt/mammalian target of rapamycin (mTOR)-forkhead box O (FoxO) signaling pathway. To elucidate the molecular mechanisms underlying the effects of PYP15 on DEX-induced myotube atrophy, C2C12 myotubes were treated for 24 h with 100 μM DEX in the presence or absence of 500 ng/mL PYP15. Cell viability assays revealed no PYP15 toxicity in C2C12 myotubes. PYP15 activated the insulin-like growth factor-I receptor (IGF-IR) and Akt-mTORC1 signaling pathway in DEX-induced myotube atrophy. In addition, PYP15 markedly downregulated the nuclear translocation of transcription factors FoxO1 and FoxO3a, and inhibited 20S proteasome activity. Furthermore, PYP15 inhibited the autophagy-lysosomal pathway in DEX-stimulated myotube atrophy. Our findings suggest that PYP15 treatment protected against myotube atrophy by regulating IGF-I and the Akt-mTORC1-FoxO signaling pathway in skeletal muscle. Therefore, PYP15 treatment appears to exert protective effects against skeletal muscle atrophy.

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