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• W3000719078 abstract "Cancer cachexia is a complex metabolic disease so far lacking effective therapy, and it accounts for approximately one third of all cancer-related deaths worldwide. The extracellular ligand Wnt7a has a dual function in skeletal muscle, inducing the anabolic AKT/mammalian target of rapamycin (mTOR) pathway in myofibers and driving muscle stem cell expansion in skeletal muscle, making it a promising candidate for treatment of muscle wasting diseases. In murine and human myotubes, Wnt7a activates the anabolic AKT/mTOR pathway, thereby preventing cachexia-induced atrophy with a single application being sufficient to prevent atrophy independently of the tumor cell type causing cachexia. Addition of Wnt7a also improved activation and differentiation of muscle stem cells in cancer cachexia, a condition under which skeletal muscle regeneration is severely impaired due to stalled muscle stem cell differentiation. Finally, we show that Wnt7a prevents cancer cachexia in an in vivo mouse model based on C26 colon carcinoma cells. Wnt7a has a dual role in cachectic skeletal muscle; that is, it effectively counteracts muscle wasting through activation of the anabolic AKT/mTOR pathway and, furthermore, reverts the loss of muscle stem cell functionality due to cancer cachexia, making Wnt7a a promising candidate for an ameliorative treatment of cancer cachexia. Cancer cachexia is a complex metabolic disease so far lacking effective therapy, and it accounts for approximately one third of all cancer-related deaths worldwide. The extracellular ligand Wnt7a has a dual function in skeletal muscle, inducing the anabolic AKT/mammalian target of rapamycin (mTOR) pathway in myofibers and driving muscle stem cell expansion in skeletal muscle, making it a promising candidate for treatment of muscle wasting diseases. In murine and human myotubes, Wnt7a activates the anabolic AKT/mTOR pathway, thereby preventing cachexia-induced atrophy with a single application being sufficient to prevent atrophy independently of the tumor cell type causing cachexia. Addition of Wnt7a also improved activation and differentiation of muscle stem cells in cancer cachexia, a condition under which skeletal muscle regeneration is severely impaired due to stalled muscle stem cell differentiation. Finally, we show that Wnt7a prevents cancer cachexia in an in vivo mouse model based on C26 colon carcinoma cells. Wnt7a has a dual role in cachectic skeletal muscle; that is, it effectively counteracts muscle wasting through activation of the anabolic AKT/mTOR pathway and, furthermore, reverts the loss of muscle stem cell functionality due to cancer cachexia, making Wnt7a a promising candidate for an ameliorative treatment of cancer cachexia. Cancer cachexia is a metabolic wasting syndrome causing a dramatic loss of skeletal muscle and fat tissue. Furthermore, it is associated with a poor prognosis for patients, reduces the quality of life, and is estimated to be the direct cause of death in one third of all cancer patients.1Fearon K. Strasser F. Anker S.D. Bosaeus I. Bruera E. Fainsinger R.L. Jatoi A. Loprinzi C. MacDonald N. Mantovani G. et al.Definition and classification of cancer cachexia: an international consensus.Lancet Oncol. 2011; 12: 489-495Abstract Full Text Full Text PDF PubMed Scopus (2471) Google Scholar, 2Fearon K.C. Glass D.J. Guttridge D.C. Cancer cachexia: mediators, signaling, and metabolic pathways.Cell Metab. 2012; 16: 153-166Abstract Full Text Full Text PDF PubMed Scopus (606) Google Scholar, 3von Haehling S. Anker M.S. Anker S.D. Prevalence and clinical impact of cachexia in chronic illness in Europe, USA, and Japan: facts and numbers update 2016.J. Cachexia Sarcopenia Muscle. 2016; 7: 507-509Crossref PubMed Scopus (117) Google Scholar, 4Bruera E. ABC of palliative care. Anorexia, cachexia, and nutrition.BMJ. 1997; 315: 1219-1222Crossref PubMed Scopus (229) Google Scholar, 5Powers C.N. Cancer Cytopathology enters its third decade.Cancer Cytopathol. 2017; 125: 9-10Crossref PubMed Scopus (2) Google Scholar Of note, most cancer patients will suffer from cancer cachexia in an advanced state.2Fearon K.C. Glass D.J. Guttridge D.C. Cancer cachexia: mediators, signaling, and metabolic pathways.Cell Metab. 2012; 16: 153-166Abstract Full Text Full Text PDF PubMed Scopus (606) Google Scholar Cancer cachexia significantly contributes to cancer-associated co-morbidities by weakening the patients toward the point that neither chemotherapy nor surgery can be tolerated.1Fearon K. Strasser F. Anker S.D. Bosaeus I. Bruera E. Fainsinger R.L. Jatoi A. Loprinzi C. MacDonald N. Mantovani G. et al.Definition and classification of cancer cachexia: an international consensus.Lancet Oncol. 2011; 12: 489-495Abstract Full Text Full Text PDF PubMed Scopus (2471) Google Scholar,2Fearon K.C. Glass D.J. Guttridge D.C. Cancer cachexia: mediators, signaling, and metabolic pathways.Cell Metab. 2012; 16: 153-166Abstract Full Text Full Text PDF PubMed Scopus (606) Google Scholar,6Sadeghi M. Keshavarz-Fathi M. Baracos V. Arends J. Mahmoudi M. Rezaei N. Cancer cachexia: diagnosis, assessment, and treatment.Crit. Rev. Oncol. Hematol. 2018; 127: 91-104Crossref PubMed Scopus (65) Google Scholar The mechanisms by which the tumors induce loss of muscle mass and function is multifactorial, mostly caused by pro-inflammatory cytokines, with tumor necrosis factor (TNF)-α, interleukin (IL)-6, and interferon (INF)-γ being important cytokines, which are increased in cancer cachexia.2Fearon K.C. Glass D.J. Guttridge D.C. Cancer cachexia: mediators, signaling, and metabolic pathways.Cell Metab. 2012; 16: 153-166Abstract Full Text Full Text PDF PubMed Scopus (606) Google Scholar,7Mueller T.C. Bachmann J. Prokopchuk O. Friess H. Martignoni M.E. Molecular pathways leading to loss of skeletal muscle mass in cancer cachexia--can findings from animal models be translated to humans?.BMC Cancer. 2016; 16: 75Crossref PubMed Scopus (48) Google Scholar Importantly, loss of skeletal muscle mass due to cancer cachexia cannot be reversed by conventional nutritional support.8Fearon K. Cachexia: treat wasting illness on multiple fronts.Nature. 2016; 529: 156Crossref PubMed Scopus (8) Google Scholar, 9Tisdale M.J. Mechanisms of cancer cachexia.Physiol. Rev. 2009; 89: 381-410Crossref PubMed Scopus (782) Google Scholar, 10Bossola M. Marzetti E. Rosa F. Pacelli F. Skeletal muscle regeneration in cancer cachexia.Clin. Exp. Pharmacol. Physiol. 2016; 43: 522-527Crossref PubMed Scopus (19) Google Scholar Despite the widespread need for improved cachexia therapies and immense research on this topic, there remain very few treatments for this disease. Therefore, therapeutic strategies to prevent cachexia remain one of the main promising strategies.8Fearon K. Cachexia: treat wasting illness on multiple fronts.Nature. 2016; 529: 156Crossref PubMed Scopus (8) Google Scholar Skeletal muscle of patients suffering from cancer cachexia as well as mouse models of cancer cachexia display severe signs of atrophy, including the loss of muscle mass concomitant with reduced muscle functionality.11Egerman M.A. Glass D.J. Signaling pathways controlling skeletal muscle mass.Crit. Rev. Biochem. Mol. Biol. 2014; 49: 59-68Crossref PubMed Scopus (289) Google Scholar Atrophy of skeletal muscle is mostly caused by aberrant signaling pathways, which perturb the balance between anabolism and catabolism of skeletal muscle proteins. In case of cancer cachexia the balance is tipped toward catabolism; the E3-ubiquitin ligases MuRF-1 and MAFbx/Atrogin-1 are strongly upregulated, leading to protein degradation in skeletal muscle.12Bodine S.C. Baehr L.M. Skeletal muscle atrophy and the E3 ubiquitin ligases MuRF1 and MAFbx/atrogin-1.Am. J. Physiol. Endocrinol. Metab. 2014; 307: E469-E484Crossref PubMed Scopus (432) Google Scholar Expression of both E3-ubiquitin ligases, canonical markers for skeletal muscle atrophy, is controlled by transcription factors of the FoxO family.2Fearon K.C. Glass D.J. Guttridge D.C. Cancer cachexia: mediators, signaling, and metabolic pathways.Cell Metab. 2012; 16: 153-166Abstract Full Text Full Text PDF PubMed Scopus (606) Google Scholar,11Egerman M.A. Glass D.J. Signaling pathways controlling skeletal muscle mass.Crit. Rev. Biochem. Mol. Biol. 2014; 49: 59-68Crossref PubMed Scopus (289) Google Scholar,13Glass D.J. PI3 kinase regulation of skeletal muscle hypertrophy and atrophy.Curr. Top. Microbiol. Immunol. 2010; 346: 267-278PubMed Google Scholar,14Jagoe R.T. Goldberg A.L. What do we really know about the ubiquitin-proteasome pathway in muscle atrophy?.Curr. Opin. Clin. Nutr. Metab. Care. 2001; 4: 183-190Crossref PubMed Scopus (315) Google Scholar In addition, protein synthesis, e.g., driven by the activation of the AKT/mammalian target of rapamycin (mTOR) pathway through insulin-like growth factor-1 (IGF-1), is reduced in tumor-bearing mice suffering from cancer cachexia in various tissues, including adipose tissue and skeletal muscle.2Fearon K.C. Glass D.J. Guttridge D.C. Cancer cachexia: mediators, signaling, and metabolic pathways.Cell Metab. 2012; 16: 153-166Abstract Full Text Full Text PDF PubMed Scopus (606) Google Scholar,15Fearon K. Arends J. Baracos V. Understanding the mechanisms and treatment options in cancer cachexia.Nat. Rev. Clin. Oncol. 2013; 10: 90-99Crossref PubMed Scopus (474) Google Scholar,16Argilés J.M. Busquets S. Stemmler B. López-Soriano F.J. Cancer cachexia: understanding the molecular basis.Nat. Rev. Cancer. 2014; 14: 754-762Crossref PubMed Scopus (544) Google Scholar This combination of increased catabolism and decreased protein synthesis in skeletal muscle causes muscular atrophy. Interestingly, IGF-1 can dominantly revert AKT inhibition by myostatin in vitro but fails to do so in vivo.17Penna F. Bonetto A. Muscaritoli M. Costamagna D. Minero V.G. Bonelli G. Rossi Fanelli F. Baccino F.M. Costelli P. Muscle atrophy in experimental cancer cachexia: is the IGF-1 signaling pathway involved?.Int. J. Cancer. 2010; 127: 1706-1717Crossref PubMed Scopus (77) Google Scholar,18Trendelenburg A.U. Meyer A. Rohner D. Boyle J. Hatakeyama S. Glass D.J. Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size.Am. J. Physiol. Cell Physiol. 2009; 296: C1258-C1270Crossref PubMed Scopus (490) Google Scholar Therefore, potential treatments for cancer cachexia, which are currently being tested, include activation of the AKT/mTOR pathway or inhibition of protein degradation in skeletal muscle. Due to the aforementioned issues regarding efficiency of IGF-1 in vivo, other activators of the AKT/mTOR pathway need to be investigated on their ability to counteract muscle wasting in cancer cachexia in vivo. In cancer cachexia, myofibers in skeletal muscle become atrophic, a process that is accompanied by a reduced ability to regenerate due to impaired muscle stem cell function.19He W.A. Berardi E. Cardillo V.M. Acharyya S. Aulino P. Thomas-Ahner J. Wang J. Bloomston M. Muscarella P. Nau P. et al.NF-κB-mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia.J. Clin. Invest. 2013; 123: 4821-4835Crossref PubMed Scopus (196) Google Scholar Cancer cachexia is also associated with muscle damage resulting in muscle stem cell activation. Although muscle stem cells are activated due to muscle damage in cancer cachexia, they cannot fully differentiate due to the aberrant expression of Pax7, a transcription factor normally responsible for self-renewal of muscle stem cells.19He W.A. Berardi E. Cardillo V.M. Acharyya S. Aulino P. Thomas-Ahner J. Wang J. Bloomston M. Muscarella P. Nau P. et al.NF-κB-mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia.J. Clin. Invest. 2013; 123: 4821-4835Crossref PubMed Scopus (196) Google Scholar Regeneration of skeletal muscle is dependent on the presence and full functionality of muscle stem cells, a tightly regulated process that depends on the precise and dynamic integration of multiple signals, allowing the self-renewal and progression of myogenic precursor cells in the myogenic lineage.20Schmidt M. Schüler S.C. Hüttner S.S. von Eyss B. von Maltzahn J. Adult stem cells at work: regenerating skeletal muscle.Cell. Mol. Life Sci. 2019; 76: 2559-2570Crossref PubMed Scopus (38) Google Scholar Differentiation of muscle stem cells is impaired, thereby causing a stalling of regeneration and resulting in impairments reminiscent of regeneration in the aged. Geriatric muscle stem cells become overly quiescent, resulting in senescence as well as impaired activation and differentiation.20Schmidt M. Schüler S.C. Hüttner S.S. von Eyss B. von Maltzahn J. Adult stem cells at work: regenerating skeletal muscle.Cell. Mol. Life Sci. 2019; 76: 2559-2570Crossref PubMed Scopus (38) Google Scholar,21Sousa-Victor P. Gutarra S. García-Prat L. Rodriguez-Ubreva J. Ortet L. Ruiz-Bonilla V. Jardí M. Ballestar E. González S. Serrano A.L. et al.Geriatric muscle stem cells switch reversible quiescence into senescence.Nature. 2014; 506: 316-321Crossref PubMed Scopus (497) Google Scholar Wnt signaling plays a crucial role during embryonic development but also in the maintenance of skeletal muscle in the adult.22von Maltzahn J. Chang N.C. Bentzinger C.F. Rudnicki M.A. Wnt signaling in myogenesis.Trends Cell Biol. 2012; 22: 602-609Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar Wnt proteins constitute a large family of secreted glycoproteins that are related to the Drosophila wingless gene.23Sethi J.K. Vidal-Puig A. Wnt signalling and the control of cellular metabolism.Biochem. J. 2010; 427: 1-17Crossref PubMed Scopus (145) Google Scholar In mammals, the Wnt family comprises 19 members that share homologies in their amino acid sequence but often have fundamentally distinct signaling properties. Nevertheless, they all share a signal sequence for secretion, several glycosylation sites, and a characteristic distribution of 22 cysteine residues.24Nusse R. Wnt signaling and stem cell control.Cell Res. 2008; 18: 523-527Crossref PubMed Scopus (413) Google Scholar Wnt proteins typically bind to Frizzled (Fzd) receptors located in the plasma membrane of target cells.25Niehrs C. The complex world of WNT receptor signalling.Nat. Rev. Mol. Cell Biol. 2012; 13: 767-779Crossref PubMed Scopus (803) Google Scholar Wnt-receptor interactions can elicit various intracellular responses, with the best understood and most widely studied being the activation of β-catenin/TCF transcriptional complexes, also known as canonical Wnt signaling.26Clevers H. Nusse R. Wnt/β-catenin signaling and disease.Cell. 2012; 149: 1192-1205Abstract Full Text Full Text PDF PubMed Scopus (3453) Google Scholar In skeletal muscle Wnt ligands control the expression of MRFs (myogenic regulatory factors) as well as the differentiation and self-renewal of muscle stem cells.22von Maltzahn J. Chang N.C. Bentzinger C.F. Rudnicki M.A. Wnt signaling in myogenesis.Trends Cell Biol. 2012; 22: 602-609Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar The differentiation process of muscle stem cells is mostly regulated by canonical Wnt signaling while self-renewal is controlled by non-canonical Wnt signaling, namely Wnt7a.27Le Grand F. Jones A.E. Seale V. Scimè A. Rudnicki M.A. Wnt7a activates the planar cell polarity pathway to drive the symmetric expansion of satellite stem cells.Cell Stem Cell. 2009; 4: 535-547Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar, 28Bentzinger C.F. Wang Y.X. von Maltzahn J. Soleimani V.D. Yin H. Rudnicki M.A. Fibronectin regulates Wnt7a signaling and satellite cell expansion.Cell Stem Cell. 2013; 12: 75-87Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 29Jones A.E. Price F.D. Le Grand F. Soleimani V.D. Dick S.A. Megeney L.A. Rudnicki M.A. Wnt/β-catenin controls follistatin signalling to regulate satellite cell myogenic potential.Skelet. Muscle. 2015; 5: 14Crossref PubMed Scopus (49) Google Scholar In muscle stem cells Wnt7a has a dual role. On the one hand, it increases the number of symmetric satellite stem cell divisions, a subpopulation of muscle stem cells with high engraftment potential.30Kuang S. Kuroda K. Le Grand F. Rudnicki M.A. Asymmetric self-renewal and commitment of satellite stem cells in muscle.Cell. 2007; 129: 999-1010Abstract Full Text Full Text PDF PubMed Scopus (852) Google Scholar Satellite stem cells can give rise to either daughter satellite stem cells or differentiate into committed progenitor cells, a process that is important for proper regeneration of skeletal muscle. On the other hand, Wnt7a increases the directed migration of muscle stem cells, thereby improving regeneration of skeletal muscle.28Bentzinger C.F. Wang Y.X. von Maltzahn J. Soleimani V.D. Yin H. Rudnicki M.A. Fibronectin regulates Wnt7a signaling and satellite cell expansion.Cell Stem Cell. 2013; 12: 75-87Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar,31Bentzinger C.F. von Maltzahn J. Dumont N.A. Stark D.A. Wang Y.X. Nhan K. Frenette J. Cornelison D.D. Rudnicki M.A. Wnt7a stimulates myogenic stem cell motility and engraftment resulting in improved muscle strength.J. Cell Biol. 2014; 205: 97-111Crossref PubMed Scopus (90) Google Scholar Interestingly, in skeletal muscle Wnt7a always signals through the Fzd7 receptor. In muscle stem cells this leads to the activation of the PCP (planar cell polarity) signaling pathway and the activation of Rho/Rac. In myofibers Wnt7a drives the activation of the AKT/mTOR pathway, leading to the induction of myofiber hypertrophy.27Le Grand F. Jones A.E. Seale V. Scimè A. Rudnicki M.A. Wnt7a activates the planar cell polarity pathway to drive the symmetric expansion of satellite stem cells.Cell Stem Cell. 2009; 4: 535-547Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar,31Bentzinger C.F. von Maltzahn J. Dumont N.A. Stark D.A. Wang Y.X. Nhan K. Frenette J. Cornelison D.D. Rudnicki M.A. Wnt7a stimulates myogenic stem cell motility and engraftment resulting in improved muscle strength.J. Cell Biol. 2014; 205: 97-111Crossref PubMed Scopus (90) Google Scholar, 32von Maltzahn J. Bentzinger C.F. Rudnicki M.A. Wnt7a-Fzd7 signalling directly activates the Akt/mTOR anabolic growth pathway in skeletal muscle.Nat. Cell Biol. 2011; 14: 186-191Crossref PubMed Scopus (135) Google Scholar, 33von Maltzahn J. Zinoviev R. Chang N.C. Bentzinger C.F. Rudnicki M.A. A truncated Wnt7a retains full biological activity in skeletal muscle.Nat. Commun. 2013; 4: 2869Crossref PubMed Scopus (29) Google Scholar Therefore, Wnt7a is a potent new candidate for treatment of skeletal muscle of individuals suffering from cancer cachexia since the binding of one extracellular ligand to one receptor activates three different signaling pathways, thereby enhancing muscle mass and muscle stem cell functionality. This is particularly important since not only muscle mass is severely reduced in patients suffering from cancer cachexia, but also muscle regeneration is impaired. The latter one is especially important in cases when tumors are resected and surrounding skeletal muscles are damaged either due to stretching or even incisions. In this study, we demonstrate that Wnt7a counteracts cancer cachexia-induced muscle loss through activation of the AKT/mTOR pathway independent of the tumor type causing cachexia. We show that myotube size is increased after addition of Wnt7a, which can be inhibited by addition of rapamycin. Of note, Wnt7a prevents myotube atrophy in murine and human myogenic cells, demonstrating high translational potential for ameliorative treatments of cancer cachexia patients. Furthermore, we show that Wnt7a increases the number of muscle stem cells by driving planar muscle stem cell divisions. Furthermore, the number of muscle stem cells is enhanced after addition of Wnt7a concomitant with an increase in further differentiated cells, suggesting that Wnt7a also improves the differentiation process of muscle stem cells, which is impaired in cancer cachexia. Finally, we demonstrate that Wnt7a prevents myofiber atrophy and loss of muscle stem cells in vivo using a C26 colon cancer mouse model. Wnt7a is a known activator of the anabolic AKT/mTOR pathway in skeletal muscle.32von Maltzahn J. Bentzinger C.F. Rudnicki M.A. Wnt7a-Fzd7 signalling directly activates the Akt/mTOR anabolic growth pathway in skeletal muscle.Nat. Cell Biol. 2011; 14: 186-191Crossref PubMed Scopus (135) Google Scholar We first asked whether Wnt7a can prevent atrophy of myotubes caused by cancer cachexia (Figure 1A; Figure S1A). Therefore, we used a well-established cell culture system using primary murine myoblasts incubated with supernatant from either C26 colon carcinoma cells or LL2 Lewis lung carcinoma cells, two independent cell lines known to contain a cocktail of cachexia-inducing cytokines.34Seto D.N. Kandarian S.C. Jackman R.W. A key role for leukemia inhibitory factor in C26 cancer cachexia.J. Biol. Chem. 2015; 290: 19976-19986Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar As expected, myotubes incubated with C26 or LL2 supernatant developed myotube atrophy, as demonstrated by a decrease in myotube diameter of 24% and 29%, respectively (Figures 1B and 1C; Figures S1B and S1C). Notably, a single treatment with Wnt7a or IGF-1 prevented development of myotube atrophy independent of the cancer type inducing cachexia-dependent atrophy (Figures 1B and 1C; Figures S1B and S1C). Importantly, the diameter of myotubes in cancer cachexia treated with either a single dose of Wnt7a or IGF-1 was similar to control conditions, independently of the tumor cell type causing cachexia. Our previous studies have demonstrated that Wnt7a induces hypertrophy through the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway via the Fzd7 receptor.32von Maltzahn J. Bentzinger C.F. Rudnicki M.A. Wnt7a-Fzd7 signalling directly activates the Akt/mTOR anabolic growth pathway in skeletal muscle.Nat. Cell Biol. 2011; 14: 186-191Crossref PubMed Scopus (135) Google Scholar To investigate whether activation of the anabolic AKT/mTOR pathway is the main pathway driving Wnt7a-induced prevention of myotube atrophy in cancer cachexia, we used rapamycin, a well-known inhibitor of mTOR activity.35Ballou L.M. Lin R.Z. Rapamycin and mTOR kinase inhibitors.J. Chem. Biol. 2008; 1: 27-36Crossref PubMed Google Scholar Indeed, inhibition of mTOR activity completely blunted the ability of Wnt7a to counteract myotube atrophy in cancer cachexia (Figures 2A–2D), independent of the tumor cell type. This suggests that Wnt7a drives the activation of the anabolic AKT/mTOR pathway in cancer cachexia rather than inhibiting catabolic pathways such as activation of MAFbx/Atrogin-1 and MuRF-1.36Foletta V.C. White L.J. Larsen A.E. Léger B. Russell A.P. The role and regulation of MAFbx/atrogin-1 and MuRF1 in skeletal muscle atrophy.Pflugers Arch. 2011; 461: 325-335Crossref PubMed Scopus (202) Google Scholar This is further supported by previous reports showing that phosphorylated (p-)AKT and p-mTOR levels are decreased in myotubes cultured in cancer cachexia conditions.37Liu D. Qiao X. Ge Z. Shang Y. Li Y. Wang W. Chen M. Si S. Chen S.Z. IMB0901 inhibits muscle atrophy induced by cancer cachexia through MSTN signaling pathway.Skelet. Muscle. 2019; 9: 8Crossref PubMed Scopus (15) Google Scholar,38Lokireddy S. Wijesoma I.W. Bonala S. Wei M. Sze S.K. McFarlane C. Kambadur R. Sharma M. Retraction.Biochem. J. 2016; 473: 1111Crossref PubMed Scopus (0) Google Scholar As a control, we used IGF-1, which is known to activate the AKT/mTOR pathway via the IGF receptor.13Glass D.J. PI3 kinase regulation of skeletal muscle hypertrophy and atrophy.Curr. Top. Microbiol. Immunol. 2010; 346: 267-278PubMed Google Scholar As expected, inhibition of mTOR activity by rapamycin also fully blunted the prevention of myotube atrophy (Figures 2A–2D; Figure S2). In conclusion, we demonstrate that Wnt7a counteracts myotube atrophy induced by cancer cachexia through activation of the AKT/mTOR pathway independent of the cachexia-inducing tumor type. Cancer cachexia affects myofibers, causing atrophy. Furthermore, cancer cachexia impairs muscle stem cell function, in particular through inhibiting muscle stem cell differentiation.19He W.A. Berardi E. Cardillo V.M. Acharyya S. Aulino P. Thomas-Ahner J. Wang J. Bloomston M. Muscarella P. Nau P. et al.NF-κB-mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia.J. Clin. Invest. 2013; 123: 4821-4835Crossref PubMed Scopus (196) Google Scholar Muscle stem cells can undergo symmetric planar and asymmetric apical-basal divisions needed for proper regeneration of skeletal muscle after injury.30Kuang S. Kuroda K. Le Grand F. Rudnicki M.A. Asymmetric self-renewal and commitment of satellite stem cells in muscle.Cell. 2007; 129: 999-1010Abstract Full Text Full Text PDF PubMed Scopus (852) Google Scholar Therefore, we first asked whether the first division of muscle stem cells is affected by cancer cachexia (Figure 3A). Indeed, we found a slight reduction of 31% (C26 cells) and 26% (LL/2 cells) in the number of planar muscle stem cell divisions after 42 h of culture (Figures 3B and 3C) in cancer cachexia independent of the tumor cell type. Strikingly, the amount of apical-basal muscle stem cell divisions was reduced by 75% (C26 cells) and 73% (LL/2 cells) when muscle stem cells were cultured under cancer cachexia conditions (Figures 3D and 3E). Wnt7a was shown to drive planar symmetric satellite stem cell divisions, a subpopulation of muscle stem cells significantly contributing to the muscle stem cell reservoir, through activation of planar cell polarity (PCP) signaling.27Le Grand F. Jones A.E. Seale V. Scimè A. Rudnicki M.A. Wnt7a activates the planar cell polarity pathway to drive the symmetric expansion of satellite stem cells.Cell Stem Cell. 2009; 4: 535-547Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar Therefore, we asked whether Wnt7a would also increase the number of planar muscle stem cell divisions in cancer cachexia, thereby boosting the muscle stem cell pool. Indeed, addition of recombinant Wnt7a protein significantly increased the amount of muscle stem cell divisions with a planar orientation of the division axis in cancer cachexia (Figures 3B and 3C; increase by 2.6-fold or 2.9-fold, respectively), while IGF-1 did not have any effect. In agreement with the data from Le Grand et al.,27Le Grand F. Jones A.E. Seale V. Scimè A. Rudnicki M.A. Wnt7a activates the planar cell polarity pathway to drive the symmetric expansion of satellite stem cells.Cell Stem Cell. 2009; 4: 535-547Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar we did not find an increase in the number of apical-basal divisions after addition of Wnt7a recombinant protein (Figures 3D and 3E). Of note, also IGF-1 did not affect apical-basal muscle stem cell divisions. It was shown earlier that muscle stem cell activation is impaired in cancer cachexia. We confirmed this finding and found that even the first division of muscle stem cells is impaired due to cancer cachexia. Therefore, we measured the number of single muscle stem cells after 42 h of culture (Figures 3F and 3G), a time point when properly activated muscle stem cells have already undergone their first round of division and can be found as duplexes on their adjacent myofibers. In this study, we found a significant increase in the amount of single muscle stem cells per myofiber of 56% (C26 cells) or 82% (LL/2 cells) when extensor digitorum longus (EDL) myofiber cultures were performed in cancer cachexia conditions, suggesting that activation of muscle stem cells is severely impaired. We then asked whether addition of recombinant Wnt7a protein could counteract this hampered activation. Indeed, the number of single muscle stem cells per myofiber was decreased by 28% (C26 cells) or 48% (LL/2 cells) when a single Wnt7a treatment was applied (Figures 3F and 3G), suggesting that Wnt7a can overcome the impaired activation of muscle stem cells caused by cachexia-inducing factors. Also in this study, IGF-1 did not affect muscle stem cell functionality. Cancer cachexia affects muscle stem cell function by impairing activation and differentiation.19He W.A. Berardi E. Cardillo V.M. Acharyya S. Aulino P. Thomas-Ahner J. Wang J. Bloomston M. Muscarella P. Nau P. et al.NF-κB-mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia.J. Clin. Invest. 2013; 123: 4821-4835Crossref PubMed Scopus (196) Google Scholar The ability of muscle stem cells to undergo differentiation is a prerequisite for the formation of new myofibers, thereby facilitating regeneration of skeletal muscle.20Schmidt M. Schüler S.C. Hüttner S.S. von Eyss B. von Maltzahn J. Adult stem cells at work: regenerating skeletal muscle.Cell. Mol. Life Sci. 2019; 76: 2559-2570Crossref PubMed Scopus (38) Google Scholar Therefore, we investigated whether Wnt7a can improve muscle stem cell differentiation in cancer cachexia (Figure 4A; Figure S3A). First, we confirmed impaired activation and differentiation of muscle cells after 72 h in culture as measured by the decreased number of clusters per myofiber (decrease by 57% and 30%, respectively), a reduced number of cells per cluster (decrease by 20% and 10%, respectively), and reduced numbers of MyoD-only cells per cluster (decrease by 76% or 62% respectively), with the latter ones denominating differentiating muscle stem cells (Figures 4B 4F; Figures S3B and S3C). Importantly, Wnt7a increased the number of clusters per myofiber (Figure 4B; Figure S3B) by 2.5-fold (C26 cells) or 1.6-fold (LL/2 cells), further supporting the notion that addition of Wnt7a recombinant protein improves activation of muscle stem cells in cancer cachexia. Of note, the increase in cluster numbers per myofiber through Wnt7a" @default.
• W3000719078 created "2020-01-23" @default.
• W3000719078 creator A5020019518 @default.
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• W3000719078 date "2020-03-01" @default.
• W3000719078 modified "2023-09-24" @default.
• W3000719078 title "Wnt7a Counteracts Cancer Cachexia" @default.
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