Irisin prevents and restores bone loss and muscle atrophy in hind-limb suspended mice

Colaianni, Graziana; Mongelli, Teresa; Cuscito, Concetta; Pignataro, Patrizia; Lippo, Luciana; Spiro, Giovanna; Notarnicola, Angela; Severi, Ilenia; Passeri, Giovanni; Mori, Giorgio; Brunetti, Giacomina; Moretti, Biagio; Tarantino, Umberto; Colucci, Silvia; Reseland, Janne Elin; Vettor, Roberto; Cinti, Saverio; Grano, Maria

doi:10.1038/s41598-017-02557-8

Cited by 230 publications

(203 citation statements)

References 47 publications

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“…We have previously shown that treatment with rec-irisin in vivo increased the gene expression of mitochondrial transcription factor A (Tfam) in skeletal muscle of unloaded mice. (10) Here we found that short treatment (8 hours) with rec-irisin increased the expression of Tfam (fourfold, p < .05) (Fig. 3A) and upregulated the pro-survival Bcl2/Bax ratio (twofold, p < .05) (Fig.…”

Section: Irisin Inhibits Apoptosis Modulating Caspase-9 and Caspase-3mentioning

confidence: 64%

“…Massive apoptosis has been observed in Tfam knockout embryos, suggesting that this transcription factor might be a key regulator in preventing activation of the mitochondrial pathway of cell death . In addition, our previous findings showed that irisin treatment in vivo increased mitochondrial biogenesis and upregulated the expression of the mitochondrial transcription factor Tfam in atrophic skeletal muscle . This led us to hypothesize that irisin might have been primarily involved in the mitochondrial (intrinsic) pathway.…”

Section: Discussionmentioning

confidence: 91%

“…Earlier study from our group clearly demonstrated that irisin treatment was effective in preventing bone loss during unloading. (10) Following this evidence, we proceeded to determine whether irisin influences osteocyte function by preserving their survival in the absence of load. As shown in Fig.…”

Section: Journal Of Bone and Mineral Researchmentioning

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: Irisin Inhibits Apoptosis Modulating Caspase-9 and Caspase-3mentioning

confidence: 64%

Section: Discussionmentioning

confidence: 91%

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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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“…Although irisin targets bone resorption, intermittent treatment with irisin has been shown to improve bone density and strength (Colaianni et al, 2015; Colaianni et al, 2017). Considered within the light of our data, this may seem counter-intuitive.…”

Section: Introductionmentioning

confidence: 99%

Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors

Kim

Wrann²,

Jedrychowski

et al. 2018

Cell

395

365

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Summary Irisin is secreted by muscle, increased with exercise and mediates certain favorable effects of physical activity. In particular, irisin has been shown to have beneficial effects in adipose tissues, brain and bone. However, the skeletal response to exercise is less clear and the receptor for irisin has not been identified. Here we show that irisin binds to proteins of the αV class of integrins and biophysical studies identify interacting surfaces between irisin and αV/β5 integrin. Chemical inhibition of the αV integrins blocks signaling and function by irisin in osteocytes and fat cells. Irisin increases both osteocytic survival and production of sclerostin, a local modulator of bone remodeling. Genetic ablation of FNDC5/irisin completely blocks osteocytic osteolysis induced by ovariectomy, preventing bone loss and supporting an important role for irisin in skeletal remodeling. The identification of the irisin receptor should greatly facilitate our understanding of irisin’s function in exercise and human health.

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“…Reduced muscle mass might be the cause of lower irisin levels in PD patients with PEW. As a myokine factor, irisin regulates skeletal muscle metabolism, which reduces muscle atrophy in mice [20]. Moreover, it was observed that the decrease of myosin type II expression was completely prevented by r-Irisin administration in mice.…”

Section: Discussionmentioning

confidence: 83%

Irisin and Volume Overload are Associated with Protein Energy Wasting in Peritoneal Dialysis Patients

Zhou

Han

Zhang

et al. 2017

Kidney Blood Press Res

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Background/Aims: Protein energy wasting (PEW) is a common medical phenomenon that is observed in maintenance dialysis patients. PEW also increases morbidity and mortality of these patients. Its pathogenesis is unclear. We hypothesize that serum irisin levels and volume overload may induce PEW in peritoneal dialysis (PD) patients. The aim of this study is to measure serum irisin levels, evaluate volume status of PD patients, and study their correlations with PEW in PD patients. Methods: This study is a cross-sectional study with 160 PD patients from the PD center of Peking University Third Hospital and 35 healthy control subjects. PD patients were divided into PEW group and non-PEW group according to PEW diagnosis criteria. Serum irisin concentrations were measured by ELISA. Volume overload status (volume overload is defined as overhydration value ≥2 liters) of PD patients was analyzed by bioelectrical impedance. Results: The serum irisin levels were significantly lower in PD patients compared with those of the controls (113.2±11.8 ng/ml vs. 464.2±37.4 ng/ml, P<0.01). The serum irisin levels were lower in PD patients with PEW than those of the patients without PEW (106.5±15.2 ng/ml vs. 117.4±17.6 ng/ml, P<0.01). PEW is more prevalent in patients with volume overload than patients without volume overload (62.5% vs. 43.1%, x 2 =5.756, P=0.016); however, no direct relationship was found between irisin levels and volume overload status. The independent influencing factors of PEW were serum irisin, serum albumin, and volume overload. Conclusion: Our results are the first to provide clinical evidence of the association between serum irisin, volume overload, and PEW in PD patients. PEW may inhibit the release or synthesis of irisin from skeletal muscles, and volume overload may aggravate PEW in PD patients.

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Irisin prevents and restores bone loss and muscle atrophy in hind-limb suspended mice

Cited by 230 publications

References 47 publications

Irisin Prevents Disuse-Induced Osteocyte Apoptosis

Irisin Prevents Disuse-Induced Osteocyte Apoptosis

Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors

Irisin and Volume Overload are Associated with Protein Energy Wasting in Peritoneal Dialysis Patients

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