Aerobic Exercise and Pharmacological Treatments Counteract Cachexia by Modulating Autophagy in Colon Cancer

Pigna, Eva; Berardi, Emanuele; Aulino, Paola; Rizzuto, Emanuele; Zampieri, Sandra; Carraro, Ugo; Kern, Helmut; Merigliano, Stefano; Gruppo, Mario; Mericskay, Mathias; Li, Zhenlin; Rocchi, Marco; Barone, Rosario; Macaluso, Filippo; Felice, Valentina Di; Adamo, Sergio; Coletti, Dario; Moresi, Viviana

doi:10.1038/srep26991

Cited by 162 publications

(210 citation statements)

References 59 publications

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“…In contrast, aerobic training has been shown to confer several benefits including maintenance of physical function and reduced hepatosplenomegaly [14]. Furthermore, others reported aerobic exercise to not only inhibit muscle atrophy, but also prolong the survival time of C26 mice [16]. These results suggest differential adaptations to the classical modes of exercise training in rodent models of cancer cachexia.…”

Section: Introductionmentioning

confidence: 37%

Bone mineral density and content are differentially impacted by aerobic and resistance training in the colon-26 mouse model of cancer cachexia

et al. 2017

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Background: Cancer cachexia is a debilitating paraneoplastic syndrome featuring unintended weight loss and skeletal muscle atrophy. Evidence suggests that bone health may also be compromised, further limiting mobility and quality of life. Aerobic and resistance training was recently reported to differentially affect skeletal muscle adaptations in cancer cachectic mice. The purpose of this investigation was to assess the effects of aerobic and resistance training on bone mineral density (BMD) and bone mineral content (BMC) in mice with colon-26 (C26) tumor-induced cachexia. Methods: Twelve-month old Balb/c mice were aerobic-trained (wheel running 5 days/week) or resistance-trained (weighted ladder climbing 3days/week) for 8 weeks prior to C26 cell injection, followed by an additional three weeks of exercise. BMD and BMC were assessed pre-and post-training by dual-energy x-ray absorptiometry. Results: Resistance-trained C26 mice lost total BMD by 7% (p = 0.06), which did not occur in aerobic-trained C26 mice. In terms of pelvic bone, both resistance-and aerobic-trained C26 mice had significantly lower BMD values (−12%, p = 0.01 and −6%, p = 0.04, respectively), albeit to a lesser degree in aerobic-trained C26 mice. Furthermore, resistance-trained C26 mice tended to lose total BMC (−12%), whereas aerobic-trained C26 mice maintained total BMC. In mice without C26 tumors, resistance training significantly increased total BMD (+13%, p = 0.001). Conclusions: Aerobic and resistance training may differentially affect bone status in C26 cancer cachexia, with high resistance loading possibly being detrimental to total and pelvis BMD, a region expected to bear significant loading stress and contribute substantially to overall mobility. Because resistance training improved BMD in tumor-free mice, the C26 tumor burden appeared to impair the beneficial effect of resistance training on bone mass.

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Section: Introductionmentioning

confidence: 37%

Bone mineral density and content are differentially impacted by aerobic and resistance training in the colon-26 mouse model of cancer cachexia

et al. 2017

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“…Indeed, if UPS or autophagic hyper-activation leads to muscle atrophy [54,55], their impairment in conditions in which they must be activated is deleterious for skeletal muscle [56,57]. While control mice activated the proteasome and degraded MHC upon denervation, HDAC4mKO mice did not show either proteasome activation or decrease in MHC levels, until 4 weeks following denervation, indicating an impairment in the ubiquitin-proteasome system response.…”

Section: Discussionmentioning

confidence: 99%

HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses

et al. 2018

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Background: Denervation triggers numerous molecular responses in skeletal muscle, including the activation of catabolic pathways and oxidative stress, leading to progressive muscle atrophy. Histone deacetylase 4 (HDAC4) mediates skeletal muscle response to denervation, suggesting the use of HDAC inhibitors as a therapeutic approach to neurogenic muscle atrophy. However, the effects of HDAC4 inhibition in skeletal muscle in response to long-term denervation have not been described yet. Methods: To further study HDAC4 functions in response to denervation, we analyzed mutant mice in which HDAC4 is specifically deleted in skeletal muscle. Results: After an initial phase of resistance to neurogenic muscle atrophy, skeletal muscle with a deletion of HDAC4 lost structural integrity after 4 weeks of denervation. Deletion of HDAC4 impaired the activation of the ubiquitin-proteasome system, delayed the autophagic response, and dampened the OS response in skeletal muscle. Inhibition of the ubiquitinproteasome system or the autophagic response, if on the one hand, conferred resistance to neurogenic muscle atrophy; on the other hand, induced loss of muscle integrity and inflammation in mice lacking HDAC4 in skeletal muscle. Moreover, treatment with the antioxidant drug Trolox prevented loss of muscle integrity and inflammation in in mice lacking HDAC4 in skeletal muscle, despite the resistance to neurogenic muscle atrophy. Conclusions: These results reveal new functions of HDAC4 in mediating skeletal muscle response to denervation and lead us to propose the combined use of HDAC inhibitors and antioxidant drugs to treat neurogenic muscle atrophy.

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“…Autophagy may induce apoptosis and tolerance to nutritional deficiency of colon cancer cells, and elevated autophagy activity may lead to colon cancer (19). Studies have identified that the expression of Atg key proteins, including LC3 and Beclin-1 increase during the early, and advanced stages of colon cancer (7).…”

Section: Discussionmentioning

confidence: 99%

Wogonoside inhibits cell growth and induces mitochondrial-mediated autophagy-related apoptosis in human colon cancer cells through the PI3K/AKT/mTOR/p70S6K signaling pathway

et al. 2018

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Abstract. Wogonoside, the main effective constituent of traditional Chinese medicine Scutellaria, belongs to the glucuronide family, with various functions, including detoxification, anti-inflammation and nourishing gallbladder, lowering blood pressure, diuresis and anti-allergic reactions. However, the effects of wogonoside on human colon cancer cells remain unclear. The present study aimed to investigate the anticancer effect of wogonoside on human colon cancer cells in vitro and its anticancer mechanisms. The results demonstrated that wogonoside significantly inhibited cell growth, induced apoptosis and mitochondrial-mediated autophagy of colon cancer cells. Furthermore, the results revealed that wogonoside significantly increased caspase-3 and caspase-9 expression levels, induced apoptosis regulator Bax/Bcl-2 and microtubule-associated protein 1A/1B-light chain 3 protein expression, suppressed the phosphatidylinositol 3 kinase (PI3K)/RAC-α serine/threonine-protein kinase (Akt)/mechanistic target of rapamycin (mTOR)/p70 S6 kinase (p70S6K) signaling pathway and induced p62 protein expression in colon cancer cells. In conclusion, these results demonstrated that wogonoside inhibits cell growth and induces mitochondrial mediated autophagy-related apoptosis in human colon cancer cells through modulation of the PI3K/Akt/mTOR/p70S6K signaling pathway.

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Aerobic Exercise and Pharmacological Treatments Counteract Cachexia by Modulating Autophagy in Colon Cancer

Cited by 162 publications

References 59 publications

Bone mineral density and content are differentially impacted by aerobic and resistance training in the colon-26 mouse model of cancer cachexia

Bone mineral density and content are differentially impacted by aerobic and resistance training in the colon-26 mouse model of cancer cachexia

HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses

Wogonoside inhibits cell growth and induces mitochondrial-mediated autophagy-related apoptosis in human colon cancer cells through the PI3K/AKT/mTOR/p70S6K signaling pathway

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