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Understanding the molecular players involved in muscle homeostasis and regeneration could help to find new therapies against muscle degenerative disorders. Previous studies revealed that the Ser\/Thr kinase p21 protein\u2010activated kinase 1 (Pak1) was specifically down\u2010regulated in the atrophying gastrocnemius of Yoshida hepatoma\u2010bearing rats. In this study, we evaluated the role of group I Paks during cancer\u2010related atrophy and muscle regeneration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We examined Pak1 expression levels in the mouse Tibialis Anterior muscles during cancer cachexia induced by grafting colon adenocarcinoma C26 cells and<jats:italic>in vitro<\/jats:italic>by dexamethasone treatment. We investigated whether the overexpression of Pak1 counteracts muscle wasting in C26\u2010bearing mice and<jats:italic>in vitro<\/jats:italic>also during interleukin\u20106 (IL6)\u2010induced or dexamethasone\u2010induced C2C12 atrophy. Moreover, we analysed the involvement of group I Paks on myogenic differentiation<jats:italic>in vivo<\/jats:italic>and<jats:italic>in vitro<\/jats:italic>using the group I chemical inhibitor IPA\u20103.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that Pak1 expression levels are reduced during cancer\u2010induced cachexia in the Tibialis Anterior muscles of colon adenocarcinoma C26\u2010bearing mice and<jats:italic>in vitro<\/jats:italic>during dexamethasone\u2010induced myotube atrophy. Electroporation of muscles of C26\u2010bearing mice with plasmids directing the synthesis of PAK1 preserves fiber size in cachectic muscles by restraining the expression of<jats:italic>atrogin\u20101<\/jats:italic>and<jats:italic>MuRF1<\/jats:italic>and possibly by inducing<jats:italic>myogenin<\/jats:italic>expression. Consistently, the overexpression of PAK1 reduces the dexamethasone\u2010induced expression of<jats:italic>MuRF1<\/jats:italic>in myotubes and increases the phospho\u2010FOXO3\/FOXO3 ratio. Interestingly, the ectopic expression of PAK1 counteracts atrophy<jats:italic>in vitro<\/jats:italic>by restraining the IL6\u2010Stat3 signalling pathway measured in luciferase\u2010based assays and by reducing rates of protein degradation in atrophying myotubes exposed to IL6. On the other hand, we observed that the inhibition of group I Paks has no effect on myotube atrophy<jats:italic>in vitro<\/jats:italic>and is associated with impaired muscle regeneration<jats:italic>in vivo<\/jats:italic>and<jats:italic>in vitro<\/jats:italic>. In fact, we found that mice treated with the group I inhibitor IPA\u20103 display a delayed recovery from cardiotoxin\u2010induced muscle injury. This is consistent with<jats:italic>in vitro<\/jats:italic>experiments showing that IPA\u20103 impairs myogenin expression and myotube formation in vessel\u2010associated myogenic progenitors, C2C12 myoblasts, and satellite cells. Finally, we observed that IPA\u20103 reduces p38\u03b1\/\u03b2 phosphorylation that is required to proceed through various stages of satellite cells differentiation: activation, asymmetric division, and ultimately myotube formation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our data provide novel evidence that is consistent with group I Paks playing a central role in the regulation of muscle homeostasis, atrophy and myogenesis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12303","type":"journal-article","created":{"date-parts":[[2018,5,21]],"date-time":"2018-05-21T10:34:34Z","timestamp":1526898874000},"page":"727-746","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Group I Paks support muscle regeneration and counteract cancer\u2010associated muscle atrophy"],"prefix":"10.1002","volume":"9","author":[{"given":"Andrea","family":"Cerquone Perpetuini","sequence":"first","affiliation":[{"name":"Department of Biology University of Rome Tor Vergata Via della ricerca scientifica 00133 Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea David","family":"Re Cecconi","sequence":"additional","affiliation":[{"name":"Department of Neurosciences IRCCS\u2010Mario Negri Institute for Pharmacological Research Via Giuseppe La Masa 20156 Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Chiappa","sequence":"additional","affiliation":[{"name":"Department of Neurosciences IRCCS\u2010Mario Negri Institute for Pharmacological Research Via Giuseppe La Masa 20156 Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia Benedetta","family":"Martinelli","sequence":"additional","affiliation":[{"name":"Department of Neurosciences IRCCS\u2010Mario Negri Institute for Pharmacological Research Via Giuseppe La Masa 20156 Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Fuoco","sequence":"additional","affiliation":[{"name":"Department of Biology University of Rome Tor Vergata Via della ricerca scientifica 00133 Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Desiderio","sequence":"additional","affiliation":[{"name":"Department of Biology University of Rome Tor Vergata Via della ricerca scientifica 00133 Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Castagnoli","sequence":"additional","affiliation":[{"name":"Department of Biology University of Rome Tor Vergata Via della ricerca scientifica 00133 Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesare","family":"Gargioli","sequence":"additional","affiliation":[{"name":"Department of Biology University of Rome Tor Vergata Via della ricerca scientifica 00133 Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Piccirillo","sequence":"additional","affiliation":[{"name":"Department of Neurosciences IRCCS\u2010Mario Negri Institute for Pharmacological Research Via Giuseppe La Masa 20156 Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianni","family":"Cesareni","sequence":"additional","affiliation":[{"name":"Department of Biology University of Rome Tor Vergata Via della ricerca scientifica 00133 Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,5,21]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.24036"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00043.2011"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI68523"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2168.1997.02525.x"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70218-7"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1155\/2016\/9579868"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.153"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.03-0610com"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1357-2725(01)00158-3"},{"key":"e_1_2_6_11_1","doi-asserted-by":"crossref","unstructured":"BokochGM.Biology of the p21\u2010activated kinases. 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