Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors

Kim, Hyeonwoo; Wrann, Christiane D.; Jedrychowski, Mark P.; Vidoni, Sara; Kitase, Yukiko; Nagano, Kenichi; Zhou, Chenhe; Chou, Joshua; Parkman, Virginia-Jeni Akila; Novick, Scott J.; Strutzenberg, Timothy S.; Pascal, Bruce D.; Le, Phuong; Brooks, Daniel J.; Roche, Alexander M.; Gerber, Kaitlyn K.; Mattheis, Laura; Chen, Wenjing; Tu, Hua; Bouxsein, Mary L.; Griffin, Patrick R.; Baron, Roland; Rosen, Clifford J.; Bonewald, Lynda F.; Spiegelman, Bruce M.

doi:10.1016/j.cell.2018.10.025

Cited by 397 publications

(419 citation statements)

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“…Numerous works by us and other groups have shown that irisin targets bone tissue mainly by increasing osteoblast differentiation and activity, (9,(17)(18)(19) but new recent findings have proved that irisin also acts on osteocytes via integrin αV/β5 receptor activating phosphorylation of focal adhesion kinase (FAK) and cyclic AMP response elementbinding protein (CREB). (8) In the present study, we show that irisin treatment in MLO-Y4 osteocytes rapidly activates phosphorylation of Erk1/Erk2 after only 5 min and increases Atf4 mRNA expression after 8 hours of treatment. The irisin-mediated Atf4 upregulation occurs through Erk1/Erk2 phosphorylation (pERK) because it is inhibited by pretreatment with a selective inhibitor of MAP kinase kinases (MAPKK), thereby preventing the activation of its downstream molecule ERK.…”

Section: Discussionsupporting

confidence: 57%

“…(7) Noteworthy, it has been recently shown that another myokine, irisin, inhibited hydrogen peroxide-induced apoptosis in the MLO-Y4 (osteocyte-like) cell line. (8) Irisin, a myokine released by skeletal muscles upon muscle contraction, has been shown to exert anabolic effects in several tissues, highlighting the importance of physical activity to delay the onset of age-related diseases.…”

Section: Introductionmentioning

confidence: 99%

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Irisin Prevents Disuse-Induced Osteocyte Apoptosis

Storlino

Colaianni

Sanesi

et al. 2019

Journal of Bone and Mineral Research

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Previous results showed that intermittently administered irisin improves bone mass in normal mice and prevents the development of disuse‐induced osteoporosis and muscular atrophy in hindlimb‐suspended mice, a murine model able to mimic the absence of mechanical loading. A recent study showed that irisin increases survival of osteocytes acting through integrin αV/β5 receptors. To better understand the action of irisin on these cells, we investigated the downstream signaling cascades in osteocyte‐like cells (MLO‐Y4) treated with recombinant irisin (rec‐irisin) in vitro and we analyzed survival of osteocytes and caspase activation in cortical bone of osteoporotic mice treated with rec‐irisin in vivo. Our results revealed that rec‐irisin activated the MAP kinases Erk1 and Erk2 and increased the expression of the transcription factor Atf4 (2.5‐fold, p < .05) through an Erk‐dependent pathway in osteocytes. Some key genes expressed by MLO‐Y4 cells were modulated by long‐term irisin treatment, either continuously administered or given with intermittent short pulses. Interestingly, Sost mRNA was severely downregulated only upon intermittent irisin administration (10‐fold, p < .001). Furthermore, rec‐irisin upregulated Tfam mRNA (fourfold, p < .05) and Bcl2/Bax ratio (twofold, p < .05) in MLO‐Y4 cells. By detecting caspase‐9 and caspase‐3, we also found that rec‐irisin inhibited apoptosis induced by hydrogen peroxide and dexamethasone, respectively. In cortical bone of unloading C57BL6 mice treated with vehicle (unload‐veh), irisin prevented disuse‐induced reduction of viable osteocytes (+30% versus unload‐veh, p < .05) and increase of empty lacunae (+110% versus unload‐veh, p < .05), as well as caspase‐9 (threefold, p < .05) and caspase‐3 (twofold, p < .05) activations. Our findings revealed underlying mechanisms of irisin action on osteocytes, which increases their functions and exerts anti‐apoptotic effects, confirming that mechanosensor cells of bone are sensitive to the exercise‐mimetic myokine irisin. © 2019 American Society for Bone and Mineral Research.

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Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Irisin Prevents Disuse-Induced Osteocyte Apoptosis

Storlino

Colaianni

Sanesi

et al. 2019

Journal of Bone and Mineral Research

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“…Caco-2 cells were exposed to hypoxia for 90 min, and recent study verified that irisin can directly bind to the αv class of integrin receptors in osteocytes. 19 Previous studies have demonstrated that gut barrier dysfunction after gut IR is mainly caused by metabolic disorders and destruction of enterocytes, which can benefit from exercise. 30,31 However, the effects of irisin on the intestinal barrier have not been elucidated to date.…”

Section: Discussionmentioning

confidence: 99%

“…13 A recent study indicated that irisin restrains bone loss by binding to the αv class of integrins in osteocytes. 19 However, the effect of exogenous irisin on gut barrier function has not been elucidated to date. We therefore suggested that irisin restores gut barrier function after gut IR via activation of the integrin αvβ5-AMPK-UCP 2 pathway.…”

mentioning

confidence: 99%

Irisin reverses intestinal epithelial barrier dysfunction during intestinal injury via binding to the integrin αVβ5 receptor

Zhang

Ren

et al. 2019

J Cellular Molecular Medi

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Disruption of the gut barrier results in severe clinical outcomes with no specific treatment. Metabolic disorders and destruction of enterocytes play key roles in gut barrier dysfunction. Irisin is a newly identified exercise hormone that regulates energy metabolism. However, the effect of irisin on gut barrier function remains unknown. The therapeutic effect of irisin on gut barrier dysfunction was evaluated in gut ischemia reperfusion (IR). The direct effect of irisin on gut barrier function was studied in Caco‐2 cells. Here, we discovered that serum and gut irisin levels were decreased during gut IR and that treatment with exogenous irisin restored gut barrier function after gut IR in mice. Meanwhile, irisin decreased oxidative stress, calcium influx and endoplasmic reticulum (ER) stress after gut IR. Moreover, irisin protected mitochondrial function and reduced enterocyte apoptosis. The neutralizing antibody against irisin significantly aggravated gut injury, oxidative stress and enterocyte apoptosis after gut IR. Further studies revealed that irisin activated the AMPK‐UCP 2 pathway via binding to the integrin αVβ5 receptor. Inhibition of integrin αVβ5, AMPK or UCP 2 abolished the protective role of irisin in gut barrier function. In conclusion, exogenous irisin restores gut barrier function after gut IR via the integrin αVβ5‐AMPK‐UCP 2 pathway.

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“…It is not only a compound muscle factor medium, but also a fat factor (Kim et al, 2018). It is not only a compound muscle factor medium, but also a fat factor (Kim et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Effects of irisin on the dysfunction of blood–brain barrier in rats after focal cerebral ischemia/reperfusion

Guo

Jin

et al. 2019

Brain and Behavior

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Objective To investigate whether irisin could protect against blood–brain barrier (BBB) dysfunction following focal cerebral ischemia/reperfusion in rats. Methods and Materials Seventy‐two adult male Sprague Dawley rats weighing 280–320 g were randomly divided into three groups: sham operation group (S), focal cerebral ischemia/reperfusion group (FC), and irisin group (IR). Focal cerebral ischemia was induced by improved thread occlusion of right middle cerebral artery (MCAO) for 2 hr followed by reperfusion for 24 hr in rats. After 24 hr of reperfusion, the neurological evaluation was performed by the method of Longa's score. The histopathological changes were observed by HE staining. The brain water content was determined by detecting the wet weight and dry weight. The BBB permeability was assessed by fluorescence spectrophotometer and fluorescence microscopy for Evans blue (EB) extravasation. The activity and expression of matrix metalloproteinase‐9 (MMP‐9) in different groups were detected by immunohistochemical staining, Western blot, and gel gelatin zymography. Results After MCAO, the neurological deficit scores, the infarct volume, the brain water content, and the EB content were higher in the FC group than those in the S group (p < .05). While after irisin treatment, these indicators mentioned above were lower than those in the IR group (p < .05). Moreover, the protein expression of MMP‐9 in the cortex increased significantly after MCAO, while irisin treatment could decrease the protein expression of MMP‐9 in the cortex (p < .05). Conclusion Our data suggest that irisin can attenuate brain damage both morphologically and functionally and protect BBB from disruption after focal cerebral ischemia/reperfusion, which is highly associated with the inhibition of the expression and activity of MMP‐9 in the brain tissue.

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Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors

Cited by 397 publications

References 90 publications

Irisin Prevents Disuse-Induced Osteocyte Apoptosis

Irisin Prevents Disuse-Induced Osteocyte Apoptosis

Irisin reverses intestinal epithelial barrier dysfunction during intestinal injury via binding to the integrin αVβ5 receptor

Effects of irisin on the dysfunction of blood–brain barrier in rats after focal cerebral ischemia/reperfusion

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