{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T19:48:43Z","timestamp":1776282523211,"version":"3.50.1"},"reference-count":85,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T00:00:00Z","timestamp":1709856000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T00:00:00Z","timestamp":1709856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Ministry of Economy and Competitiveness | Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI21\/01596"],"award-info":[{"award-number":["PI21\/01596"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>During aging, muscle regenerative capacities decline, which is concomitant with the loss of satellite cells that enter in a state of irreversible senescence. However, what mechanisms are involved in myogenic senescence and differentiation are largely unknown. Here, we showed that early-passage or \u201cyoung\u201d C2C12 myoblasts activated the redox-sensitive p66Shc signaling pathway, exhibited a strong antioxidant protection and a bioenergetic profile relying predominantly on OXPHOS, responses that decrease progressively during differentiation. Furthermore, autophagy was increased in myotubes. Otherwise, late-passage or \u201csenescent\u201d myoblasts led to a highly metabolic profile, relying on both OXPHOS and glycolysis, that may be influenced by the loss of SQSTM1\/p62 which tightly regulates the metabolic shift from aerobic glycolysis to OXPHOS. Furthermore, during differentiation of late-passage C2C12 cells, both p66Shc signaling and autophagy were impaired and this coincides with reduced myogenic capacity. Our findings recognized that the lack of p66Shc compromises the proliferation and the onset of the differentiation of C2C12 myoblasts. Moreover, the Atg7 silencing favored myoblasts growth, whereas interfered in the viability of differentiated myotubes. Then, our work demonstrates that the p66Shc signaling pathway, which highly influences cellular metabolic status and oxidative environment, is critical for the myogenic commitment and differentiation of C2C12 cells. Our findings also support that autophagy is essential for the metabolic switch observed during the differentiation of C2C12 myoblasts, confirming how its regulation determines cell fate. The regulatory roles of p66Shc and autophagy mechanisms on myogenesis require future attention as possible tools that could predict and measure the aging-related state of frailty and disability.<\/jats:p>","DOI":"10.1038\/s41419-024-06582-0","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T15:02:26Z","timestamp":1709910146000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["p66Shc signaling and autophagy impact on C2C12 myoblast differentiation during senescence"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4687-6230","authenticated-orcid":false,"given":"Yaiza","family":"Potes","sequence":"first","affiliation":[]},{"given":"Juan C.","family":"Bermejo-Millo","sequence":"additional","affiliation":[]},{"given":"Catarina","family":"Mendes","sequence":"additional","affiliation":[]},{"given":"Jos\u00e9 P.","family":"Castel\u00e3o-Baptista","sequence":"additional","affiliation":[]},{"given":"Andrea","family":"D\u00edaz-Luis","sequence":"additional","affiliation":[]},{"given":"Zulema","family":"P\u00e9rez-Mart\u00ednez","sequence":"additional","affiliation":[]},{"given":"Juan J.","family":"Solano","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7014-4614","authenticated-orcid":false,"given":"Vilma A.","family":"Sard\u00e3o","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5201-9948","authenticated-orcid":false,"given":"Paulo J.","family":"Oliveira","sequence":"additional","affiliation":[]},{"given":"Beatriz","family":"Caballero","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Coto-Montes","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1993-6725","authenticated-orcid":false,"given":"Ignacio","family":"Vega-Naredo","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2024,3,8]]},"reference":[{"key":"6582_CR1","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1038\/nature13013","volume":"506","author":"P Sousa-Victor","year":"2014","unstructured":"Sousa-Victor P, Gutarra S, Garcia-Prat L, Rodriguez-Ubreva J, Ortet L, Ruiz-Bonilla V, et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature. 2014;506:316\u201321.","journal-title":"Nature"},{"key":"6582_CR2","doi-asserted-by":"publisher","first-page":"S943","DOI":"10.1007\/s100720070008","volume":"21","author":"S Di Donna","year":"2000","unstructured":"Di Donna S, Renault V, Forestier C, Piron-Hamelin G, Thiesson D, et al. Regenerative capacity of human satellite cells: the mitotic clock in cell transplantation. Neurol Sci. 2000;21:S943\u201351.","journal-title":"Neurol Sci"},{"key":"6582_CR3","doi-asserted-by":"publisher","first-page":"3773","DOI":"10.1002\/jcb.23308","volume":"112","author":"AP Sharples","year":"2011","unstructured":"Sharples AP, Al-Shanti N, Lewis MP, Stewart CE. Reduction of myoblast differentiation following multiple population doublings in mouse C2 C12 cells: a model to investigate ageing? J Cell Biochem. 2011;112:3773\u201385.","journal-title":"J Cell Biochem"},{"key":"6582_CR4","doi-asserted-by":"publisher","first-page":"3050","DOI":"10.1242\/dev.137075","volume":"143","author":"JS Yu","year":"2016","unstructured":"Yu JS, Cui W. Proliferation, survival and metabolism: the role of PI3K\/AKT\/mTOR signalling in pluripotency and cell fate determination. Development. 2016;143:3050\u201360.","journal-title":"Development"},{"key":"6582_CR5","doi-asserted-by":"publisher","first-page":"32","DOI":"10.3389\/fphys.2014.00032","volume":"5","author":"R Koopman","year":"2014","unstructured":"Koopman R, Ly CH, Ryall JG. A metabolic link to skeletal muscle wasting and regeneration. Front Physiol. 2014;5:32.","journal-title":"Front Physiol"},{"key":"6582_CR6","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1016\/j.cmet.2015.02.002","volume":"21","author":"A Moussaieff","year":"2015","unstructured":"Moussaieff A, Rouleau M, Kitsberg D, Cohen M, Levy G, Barasch D, et al. Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab. 2015;21:392\u2013402.","journal-title":"Cell Metab"},{"key":"6582_CR7","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1007\/s12015-009-9058-0","volume":"5","author":"JM Facucho-Oliveira","year":"2009","unstructured":"Facucho-Oliveira JM, St John JC. The relationship between pluripotency and mitochondrial DNA proliferation during early embryo development and embryonic stem cell differentiation. Stem Cell Rev. 2009;5:140\u201358.","journal-title":"Stem Cell Rev"},{"key":"6582_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1890","volume":"3","author":"M Latil","year":"2012","unstructured":"Latil M, Rocheteau P, Chatre L, Sanulli S, Memet S, Ricchetti M, et al. Skeletal muscle stem cells adopt a dormant cell state post mortem and retain regenerative capacity. Nat Commun. 2012;3:903.","journal-title":"Nat Commun"},{"key":"6582_CR9","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/593267","volume":"2013","author":"A Wagatsuma","year":"2013","unstructured":"Wagatsuma A, Sakuma K. Mitochondria as a potential regulator of myogenesis. Scientific World J. 2013;2013:593267.","journal-title":"Scientific World J"},{"key":"6582_CR10","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1111\/acel.12091","volume":"12","author":"TD Pugh","year":"2013","unstructured":"Pugh TD, Conklin MW, Evans TD, Polewski MA, Barbian HJ, Pass R, et al. A shift in energy metabolism anticipates the onset of sarcopenia in rhesus monkeys. Aging Cell. 2013;12:672\u201381.","journal-title":"Aging Cell"},{"key":"6582_CR11","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1515\/hsz-2012-0247","volume":"394","author":"R Calvani","year":"2013","unstructured":"Calvani R, Joseph AM, Adhihetty PJ, Miccheli A, Bossola M, Leeuwenburgh C, et al. Mitochondrial pathways in sarcopenia of aging and disuse muscle atrophy. Biol Chem. 2013;394:393\u2013414.","journal-title":"Biol Chem"},{"key":"6582_CR12","doi-asserted-by":"publisher","first-page":"2782","DOI":"10.15252\/embj.201488278","volume":"33","author":"AH Tang","year":"2014","unstructured":"Tang AH, Rando TA. Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation. EMBO J. 2014;33:2782\u201397.","journal-title":"EMBO J"},{"key":"6582_CR13","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1002\/path.2697","volume":"221","author":"D Glick","year":"2010","unstructured":"Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol. 2010;221:3\u201312.","journal-title":"J Pathol"},{"key":"6582_CR14","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1007\/s00418-013-1170-1","volume":"141","author":"M Garcia-Macia","year":"2014","unstructured":"Garcia-Macia M, Rubio-Gonzalez A, de Luxan-Delgado B, Potes Y, Rodriguez-Gonzalez S, de Gonzalo-Calvo D, et al. Autophagic and proteolytic processes in the Harderian gland are modulated during the estrous cycle. Histochem Cell Biol. 2014;141:519\u201329.","journal-title":"Histochem Cell Biol"},{"key":"6582_CR15","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1111\/j.1600-079X.2011.00922.x","volume":"52","author":"I Vega-Naredo","year":"2012","unstructured":"Vega-Naredo I, Caballero B, Sierra V, Garcia-Macia M, de Gonzalo-Calvo D, Oliveira PJ, et al. Melatonin modulates autophagy through a redox-mediated action in female Syrian hamster Harderian gland controlling cell types and gland activity. J Pineal Res. 2012;52:80\u201392.","journal-title":"J Pineal Res"},{"key":"6582_CR16","doi-asserted-by":"publisher","first-page":"1560","DOI":"10.1038\/cdd.2014.66","volume":"21","author":"I Vega-Naredo","year":"2014","unstructured":"Vega-Naredo I, Loureiro R, Mesquita KA, Barbosa IA, Tavares LC, Branco AF, et al. Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells. Cell Death Differ. 2014;21:1560\u201374.","journal-title":"Cell Death Differ"},{"key":"6582_CR17","doi-asserted-by":"publisher","first-page":"217","DOI":"10.14336\/AD.2018.0430","volume":"10","author":"Y Potes","year":"2019","unstructured":"Potes Y, Perez-Martinez Z, Bermejo-Millo JC, Rubio-Gonzalez A, Fernandez-Fernandez M, Bermudez M, et al. Overweight in the Elderly Induces a Switch in Energy Metabolism that Undermines Muscle Integrity. Aging Dis. 2019;10:217\u201330.","journal-title":"Aging Dis"},{"key":"6582_CR18","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.792825","volume":"9","author":"A Coto-Montes","year":"2021","unstructured":"Coto-Montes A, Gonzalez-Blanco L, Antuna E, Menendez-Valle I, Bermejo-Millo JC, Caballero B, et al. The Interactome in the Evolution From Frailty to Sarcopenic Dependence. Front Cell Dev Biol. 2021;9:792825.","journal-title":"Front Cell Dev Biol"},{"key":"6582_CR19","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.624216","volume":"8","author":"D Ramaccini","year":"2020","unstructured":"Ramaccini D, Montoya-Uribe V, Aan FJ, Modesti L, Potes Y, Wieckowski MR, et al. Mitochondrial Function and Dysfunction in Dilated Cardiomyopathy. Front Cell Dev Biol. 2020;8:624216.","journal-title":"Front Cell Dev Biol"},{"key":"6582_CR20","doi-asserted-by":"publisher","first-page":"5242","DOI":"10.1523\/JNEUROSCI.6366-09.2010","volume":"30","author":"JE Brown","year":"2010","unstructured":"Brown JE, Zeiger SL, Hettinger JC, Brooks JD, Holt B, Morrow JD, et al. Essential role of the redox-sensitive kinase p66shc in determining energetic and oxidative status and cell fate in neuronal preconditioning. J Neurosci. 2010;30:5242\u201352.","journal-title":"J Neurosci"},{"key":"6582_CR21","doi-asserted-by":"publisher","first-page":"304","DOI":"10.4161\/cc.7.3.5360","volume":"7","author":"P Pinton","year":"2008","unstructured":"Pinton P, Rizzuto R. p66Shc, oxidative stress and aging: importing a lifespan determinant into mitochondria. Cell Cycle. 2008;7:304\u20138.","journal-title":"Cell Cycle"},{"key":"6582_CR22","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.abb.2009.03.007","volume":"486","author":"M Lebiedzinska","year":"2009","unstructured":"Lebiedzinska M, Duszynski J, Rizzuto R, Pinton P, Wieckowski MR. Age-related changes in levels of p66Shc and serine 36-phosphorylated p66Shc in organs and mouse tissues. Arch Biochem Biophys. 2009;486:73\u201380.","journal-title":"Arch Biochem Biophys"},{"key":"6582_CR23","doi-asserted-by":"publisher","first-page":"1582","DOI":"10.1038\/nprot.2009.151","volume":"4","author":"MR Wieckowski","year":"2009","unstructured":"Wieckowski MR, Giorgi C, Lebiedzinska M, Duszynski J, Pinton P. Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cells. Nat Protoc. 2009;4:1582\u201390.","journal-title":"Nat Protoc"},{"key":"6582_CR24","doi-asserted-by":"publisher","first-page":"2112","DOI":"10.1073\/pnas.0336359100","volume":"100","author":"C Napoli","year":"2003","unstructured":"Napoli C, Martin-Padura I, de Nigris F, Giorgio M, Mansueto G, Somma P, et al. Deletion of the p66Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet. Proc Natl Acad Sci USA. 2003;100:2112\u20136.","journal-title":"Proc Natl Acad Sci USA"},{"key":"6582_CR25","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1038\/46311","volume":"402","author":"E Migliaccio","year":"1999","unstructured":"Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, et al. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature. 1999;402:309\u201313.","journal-title":"Nature"},{"key":"6582_CR26","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1111\/acel.12060","volume":"12","author":"V Gambino","year":"2013","unstructured":"Gambino V, De Michele G, Venezia O, Migliaccio P, Dall\u2019Olio V, Bernard L, et al. Oxidative stress activates a specific p53 transcriptional response that regulates cellular senescence and aging. Aging Cell. 2013;12:435\u201345.","journal-title":"Aging Cell"},{"key":"6582_CR27","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/S0002-9440(10)63335-4","volume":"165","author":"E Ardite","year":"2004","unstructured":"Ardite E, Barbera JA, Roca J, Fernandez-Checa JC. Glutathione depletion impairs myogenic differentiation of murine skeletal muscle C2C12 cells through sustained NF-kappaB activation. Am J Pathol. 2004;165:719\u201328.","journal-title":"Am J Pathol"},{"key":"6582_CR28","doi-asserted-by":"publisher","first-page":"10555","DOI":"10.1074\/jbc.M511626200","volume":"281","author":"S Nemoto","year":"2006","unstructured":"Nemoto S, Combs CA, French S, Ahn BH, Fergusson MM, Balaban RS, et al. The mammalian longevity-associated gene product p66shc regulates mitochondrial metabolism. J Biol Chem. 2006;281:10555\u201360.","journal-title":"J Biol Chem"},{"key":"6582_CR29","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1515\/BC.2006.176","volume":"387","author":"F Orsini","year":"2006","unstructured":"Orsini F, Moroni M, Contursi C, Yano M, Pelicci P, Giorgio M, et al. Regulatory effects of the mitochondrial energetic status on mitochondrial p66Shc. Biol Chem. 2006;387:1405\u201310.","journal-title":"Biol Chem"},{"key":"6582_CR30","doi-asserted-by":"publisher","first-page":"25689","DOI":"10.1074\/jbc.M401844200","volume":"279","author":"F Orsini","year":"2004","unstructured":"Orsini F, Migliaccio E, Moroni M, Contursi C, Raker VA, Piccini D, et al. The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential. J Biol Chem. 2004;279:25689\u201395.","journal-title":"J Biol Chem"},{"key":"6582_CR31","doi-asserted-by":"publisher","first-page":"948","DOI":"10.4161\/auto.6.7.13007","volume":"6","author":"AM Kleman","year":"2010","unstructured":"Kleman AM, Brown JE, Zeiger SL, Hettinger JC, Brooks JD, Holt B, et al. p66(shc)\u2018s role as an essential mitophagic molecule in controlling neuronal redox and energetic tone. Autophagy. 2010;6:948\u20139.","journal-title":"Autophagy"},{"key":"6582_CR32","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1101\/gad.293266.116","volume":"31","author":"L Latella","year":"2017","unstructured":"Latella L, Dall\u2019Agnese A, Boscolo FS, Nardoni C, Cosentino M, Lahm A, et al. DNA damage signaling mediates the functional antagonism between replicative senescence and terminal muscle differentiation. Genes Dev. 2017;31:648\u201359.","journal-title":"Genes Dev"},{"key":"6582_CR33","doi-asserted-by":"publisher","first-page":"5597","DOI":"10.1242\/jcs.114827","volume":"125","author":"VA Rafalski","year":"2012","unstructured":"Rafalski VA, Mancini E, Brunet A. Energy metabolism and energy-sensing pathways in mammalian embryonic and adult stem cell fate. J Cell Sci. 2012;125:5597\u2013608.","journal-title":"J Cell Sci"},{"key":"6582_CR34","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-35114-y","volume":"8","author":"A Lone","year":"2018","unstructured":"Lone A, Harris RA, Singh O, Betts DH, Cumming RC. p66Shc activation promotes increased oxidative phosphorylation and renders CNS cells more vulnerable to amyloid beta toxicity. Sci Rep. 2018;8:17081.","journal-title":"Sci Rep"},{"key":"6582_CR35","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1002\/mus.25117","volume":"54","author":"Q Yang","year":"2016","unstructured":"Yang Q, Yu J, Yu B, Huang Z, Zhang K, Wu D, et al. PAX3(+) skeletal muscle satellite cells retain long-term self-renewal and proliferation. Muscle Nerve. 2016;54:943\u201351.","journal-title":"Muscle Nerve"},{"key":"6582_CR36","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/j.ydbio.2004.08.015","volume":"275","author":"HC Olguin","year":"2004","unstructured":"Olguin HC, Olwin BB. Pax-7 up-regulation inhibits myogenesis and cell cycle progression in satellite cells: a potential mechanism for self-renewal. Dev Biol. 2004;275:375\u201388.","journal-title":"Dev Biol"},{"key":"6582_CR37","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1089\/scd.2011.0526","volume":"21","author":"AT Vessoni","year":"2012","unstructured":"Vessoni AT, Muotri AR, Okamoto OK. Autophagy in stem cell maintenance and differentiation. Stem Cells Dev. 2012;21:513\u201320.","journal-title":"Stem Cells Dev"},{"key":"6582_CR38","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1083\/jcb.151.6.1221","volume":"151","author":"JR Beauchamp","year":"2000","unstructured":"Beauchamp JR, Heslop L, Yu DS, Tajbakhsh S, Kelly RG, Wernig A, et al. Expression of CD34 and Myf5 defines the majority of quiescent adult skeletal muscle satellite cells. J Cell Biol. 2000;151:1221\u201334.","journal-title":"J Cell Biol"},{"key":"6582_CR39","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1083\/jcb.200312007","volume":"166","author":"PS Zammit","year":"2004","unstructured":"Zammit PS, Golding JP, Nagata Y, Hudon V, Partridge TA, Beauchamp JR. Muscle satellite cells adopt divergent fates: a mechanism for self-renewal? J Cell Biol. 2004;166:347\u201357.","journal-title":"J Cell Biol"},{"key":"6582_CR40","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1016\/j.jamda.2014.03.008","volume":"15","author":"TP Ng","year":"2014","unstructured":"Ng TP, Feng L, Nyunt MS, Larbi A, Yap KB. Frailty in older persons: multisystem risk factors and the Frailty Risk Index (FRI). J Am Med Assoc. 2014;15:635\u201342.","journal-title":"J Am Med Assoc"},{"key":"6582_CR41","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/nature11438","volume":"490","author":"JV Chakkalakal","year":"2012","unstructured":"Chakkalakal JV, Jones KM, Basson MA, Brack AS. The aged niche disrupts muscle stem cell quiescence. Nature. 2012;490:355\u201360.","journal-title":"Nature"},{"key":"6582_CR42","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.stem.2017.01.008","volume":"20","author":"J Neves","year":"2017","unstructured":"Neves J, Sousa-Victor P, Jasper H. Rejuvenating Strategies for Stem Cell-Based Therapies in Aging. Cell Stem Cell. 2017;20:161\u201375.","journal-title":"Cell Stem Cell"},{"key":"6582_CR43","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/nm.3465","volume":"20","author":"JD Bernet","year":"2014","unstructured":"Bernet JD, Doles JD, Hall JK, Kelly Tanaka K, Carter TA, Olwin BB. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat Med. 2014;20:265\u201371.","journal-title":"Nat Med"},{"key":"6582_CR44","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1042\/BC20070085","volume":"100","author":"A Bigot","year":"2008","unstructured":"Bigot A, Jacquemin V, Debacq-Chainiaux F, Butler-Browne GS, Toussaint O, Furling D, et al. Replicative aging down-regulates the myogenic regulatory factors in human myoblasts. Biol Cell. 2008;100:189\u201399.","journal-title":"Biol Cell"},{"key":"6582_CR45","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1016\/j.cmet.2020.10.005","volume":"32","author":"MC Ludikhuize","year":"2020","unstructured":"Ludikhuize MC, Meerlo M, Gallego MP, Xanthakis D, Burgaya Julia M, Nguyen NTB, et al. Mitochondria Define Intestinal Stem Cell Differentiation Downstream of a FOXO\/Notch Axis. Cell Metab. 2020;32:889\u2013900.e7.","journal-title":"Cell Metab"},{"key":"6582_CR46","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1016\/j.cell.2012.09.010","volume":"151","author":"A Fedorenko","year":"2012","unstructured":"Fedorenko A, Lishko PV, Kirichok Y. Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell. 2012;151:400\u201313.","journal-title":"Cell"},{"key":"6582_CR47","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-55296-3","volume":"9","author":"R Shiratori","year":"2019","unstructured":"Shiratori R, Furuichi K, Yamaguchi M, Miyazaki N, Aoki H, Chibana H, et al. Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner. Sci Rep. 2019;9:18699.","journal-title":"Sci Rep"},{"key":"6582_CR48","doi-asserted-by":"publisher","first-page":"13106","DOI":"10.1096\/fj.202000767R","volume":"34","author":"P Marchetti","year":"2020","unstructured":"Marchetti P, Fovez Q, Germain N, Khamari R, Kluza J. Mitochondrial spare respiratory capacity: Mechanisms, regulation, and significance in non-transformed and cancer cells. FASEB J. 2020;34:13106\u201324.","journal-title":"FASEB J"},{"key":"6582_CR49","doi-asserted-by":"publisher","first-page":"175","DOI":"10.3858\/emm.2010.42.3.018","volume":"42","author":"AR Ji","year":"2010","unstructured":"Ji AR, Ku SY, Cho MS, Kim YY, Kim YJ, Oh SK, et al. Reactive oxygen species enhance differentiation of human embryonic stem cells into mesendodermal lineage. Exp Mol Med. 2010;42:175\u201386.","journal-title":"Exp Mol Med"},{"key":"6582_CR50","doi-asserted-by":"publisher","first-page":"4223","DOI":"10.18632\/oncotarget.23786","volume":"9","author":"Q Hu","year":"2018","unstructured":"Hu Q, Khanna P, Ee Wong BS, Lin Heng ZS, Subhramanyam CS, Thanga LZ, et al. Oxidative stress promotes exit from the stem cell state and spontaneous neuronal differentiation. Oncotarget. 2018;9:4223\u201338.","journal-title":"Oncotarget"},{"key":"6582_CR51","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1042\/BJ20081386","volume":"417","author":"MP Murphy","year":"2009","unstructured":"Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417:1\u201313.","journal-title":"Biochem J"},{"key":"6582_CR52","doi-asserted-by":"publisher","first-page":"31453","DOI":"10.1074\/jbc.M702511200","volume":"282","author":"G Zaccagnini","year":"2007","unstructured":"Zaccagnini G, Martelli F, Magenta A, Cencioni C, Fasanaro P, Nicoletti C, et al. p66(ShcA) and oxidative stress modulate myogenic differentiation and skeletal muscle regeneration after hind limb ischemia. J Biol Chem. 2007;282:31453\u20139.","journal-title":"J Biol Chem"},{"key":"6582_CR53","doi-asserted-by":"publisher","first-page":"43900","DOI":"10.1074\/jbc.M403936200","volume":"279","author":"A Natalicchio","year":"2004","unstructured":"Natalicchio A, Laviola L, De Tullio C, Renna LA, Montrone C, Perrini S, et al. Role of the p66Shc isoform in insulin-like growth factor I receptor signaling through MEK\/Erk and regulation of actin cytoskeleton in rat myoblasts. J Biol Chem. 2004;279:43900\u20139.","journal-title":"J Biol Chem"},{"key":"6582_CR54","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-06363-0","volume":"7","author":"V Granatiero","year":"2017","unstructured":"Granatiero V, Gherardi G, Vianello M, Salerno E, Zecchini E, Toniolo L, et al. Role of p66shc in skeletal muscle function. Sci Rep. 2017;7:6283.","journal-title":"Sci Rep"},{"key":"6582_CR55","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1016\/j.nut.2015.02.014","volume":"31","author":"VS Pereira Panza","year":"2015","unstructured":"Pereira Panza VS, Diefenthaeler F, da Silva EL. Benefits of dietary phytochemical supplementation on eccentric exercise-induced muscle damage: Is including antioxidants enough? Nutrition. 2015;31:1072\u201382.","journal-title":"Nutrition"},{"key":"6582_CR56","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1634\/stemcells.2006-0442","volume":"25","author":"P Sansone","year":"2007","unstructured":"Sansone P, Storci G, Giovannini C, Pandolfi S, Pianetti S, Taffurelli M, et al. p66Shc\/Notch-3 interplay controls self-renewal and hypoxia survival in human stem\/progenitor cells of the mammary gland expanded in vitro as mammospheres. Stem Cells. 2007;25:807\u201315.","journal-title":"Stem Cells"},{"key":"6582_CR57","doi-asserted-by":"publisher","first-page":"2116","DOI":"10.1091\/mbc.e13-11-0666","volume":"25","author":"M Miyazawa","year":"2014","unstructured":"Miyazawa M, Tsuji Y. Evidence for a novel antioxidant function and isoform-specific regulation of the human p66Shc gene. Mol Biol Cell. 2014;25:2116\u201327.","journal-title":"Mol Biol Cell"},{"key":"6582_CR58","doi-asserted-by":"publisher","first-page":"1881","DOI":"10.1089\/ars.2012.4963","volume":"20","author":"P Chaudhari","year":"2014","unstructured":"Chaudhari P, Ye Z, Jang YY. Roles of reactive oxygen species in the fate of stem cells. Antioxid Redox Sig. 2014;20:1881\u201390.","journal-title":"Antioxid Redox Sig"},{"key":"6582_CR59","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1091\/mbc.e08-03-0274","volume":"20","author":"KL Urish","year":"2009","unstructured":"Urish KL, Vella JB, Okada M, Deasy BM, Tobita K, Keller BB, et al. Antioxidant levels represent a major determinant in the regenerative capacity of muscle stem cells. Mol Biol Cell. 2009;20:509\u201320.","journal-title":"Mol Biol Cell"},{"key":"6582_CR60","doi-asserted-by":"publisher","first-page":"11719","DOI":"10.1074\/jbc.270.20.11719","volume":"270","author":"JA Epstein","year":"1995","unstructured":"Epstein JA, Lam P, Jepeal L, Maas RL, Shapiro DN. Pax3 inhibits myogenic differentiation of cultured myoblast cells. J Biol Chem. 1995;270:11719\u201322.","journal-title":"J Biol Chem"},{"key":"6582_CR61","doi-asserted-by":"publisher","DOI":"10.1038\/srep02498","volume":"3","author":"Q Li","year":"2013","unstructured":"Li Q, Le May M, Lacroix N, Chen J. Induction of Pax3 gene expression impedes cardiac differentiation. Scientific Rep. 2013;3:2498.","journal-title":"Scientific Rep"},{"key":"6582_CR62","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1016\/j.cell.2017.07.049","volume":"170","author":"RI Martinez-Zamudio","year":"2017","unstructured":"Martinez-Zamudio RI, Robinson L, Roux PF, Bischof O. SnapShot: Cellular Senescence Pathways. Cell. 2017;170:816\u2013816.e1.","journal-title":"Cell"},{"key":"6582_CR63","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/j.stem.2012.10.005","volume":"11","author":"J Zhang","year":"2012","unstructured":"Zhang J, Nuebel E, Daley GQ, Koehler CM, Teitell MA. Metabolic regulation in pluripotent stem cells during reprogramming and self-renewal. Cell Stem Cell. 2012;11:589\u201395.","journal-title":"Cell Stem Cell"},{"key":"6582_CR64","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1080\/15548627.2019.1607694","volume":"16","author":"S Magalhaes-Novais","year":"2020","unstructured":"Magalhaes-Novais S, Bermejo-Millo JC, Loureiro R, Mesquita KA, Domingues MR, Maciel E, et al. Cell quality control mechanisms maintain stemness and differentiation potential of P19 embryonic carcinoma cells. Autophagy. 2020;16:313\u201333.","journal-title":"Autophagy"},{"key":"6582_CR65","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1007\/s00441-018-2829-7","volume":"374","author":"A Sotthibundhu","year":"2018","unstructured":"Sotthibundhu A, Promjuntuek W, Liu M, Shen S, Noisa P. Roles of autophagy in controlling stem cell identity: a perspective of self-renewal and differentiation. Cell Tissue Res. 2018;374:205\u201316.","journal-title":"Cell Tissue Res"},{"key":"6582_CR66","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1080\/15548627.2017.1362525","volume":"14","author":"T Riffelmacher","year":"2018","unstructured":"Riffelmacher T, Richter FC, Simon AK. Autophagy dictates metabolism and differentiation of inflammatory immune cells. Autophagy. 2018;14:199\u2013206.","journal-title":"Autophagy"},{"key":"6582_CR67","doi-asserted-by":"publisher","first-page":"1688","DOI":"10.15252\/embj.201695916","volume":"36","author":"L Esteban-Martinez","year":"2017","unstructured":"Esteban-Martinez L, Sierra-Filardi E, McGreal RS, Salazar-Roa M, Marino G, Seco E, et al. Programmed mitophagy is essential for the glycolytic switch during cell differentiation. EMBO J. 2017;36:1688\u2013706.","journal-title":"EMBO J"},{"key":"6582_CR68","doi-asserted-by":"publisher","first-page":"C190","DOI":"10.1152\/ajpcell.00066.2016","volume":"311","author":"AS Nichenko","year":"2016","unstructured":"Nichenko AS, Southern WM, Atuan M, Luan J, Peissig KB, Foltz SJ, et al. Mitochondrial maintenance via autophagy contributes to functional skeletal muscle regeneration and remodeling. Am J Physiol Cell Physiol. 2016;311:C190\u2013200.","journal-title":"Am J Physiol Cell Physiol"},{"key":"6582_CR69","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/nature16187","volume":"529","author":"L Garcia-Prat","year":"2016","unstructured":"Garcia-Prat L, Martinez-Vicente M, Perdiguero E, Ortet L, Rodriguez-Ubreva J, Rebollo E, et al. Autophagy maintains stemness by preventing senescence. Nature. 2016;529:37\u201342.","journal-title":"Nature"},{"key":"6582_CR70","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1182\/blood-2018-02-833475","volume":"133","author":"TD Nguyen","year":"2019","unstructured":"Nguyen TD, Shaid S, Vakhrusheva O, et al. Loss of the selective autophagy receptor p62 impairs murine myeloid leukemia progression and mitophagy. Blood. 2019;133:168\u201379.","journal-title":"Blood"},{"key":"6582_CR71","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1016\/j.stemcr.2019.01.023","volume":"12","author":"J Calvo-Garrido","year":"2019","unstructured":"Calvo-Garrido J, Maffezzini C, Schober FA, Clemente P, Uhlin E, Kele M, et al. SQSTM1\/p62-Directed Metabolic Reprogramming Is Essential for Normal Neurodifferentiation. Stem Cell Rep. 2019;12:696\u2013711.","journal-title":"Stem Cell Rep"},{"key":"6582_CR72","doi-asserted-by":"publisher","first-page":"9626","DOI":"10.1007\/s11357-014-9626-3","volume":"36","author":"A Bitto","year":"2014","unstructured":"Bitto A, Lerner CA, Nacarelli T, Crowe E, Torres C, Sell C. P62\/SQSTM1 at the interface of aging, autophagy, and disease. Age (Dordr). 2014;36:9626.","journal-title":"Age (Dordr)"},{"key":"6582_CR73","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.ceb.2009.12.005","volume":"22","author":"AR Young","year":"2010","unstructured":"Young AR, Narita M. Connecting autophagy to senescence in pathophysiology. Curr Opin Cell Biol. 2010;22:234\u201340.","journal-title":"Curr Opin Cell Biol"},{"key":"6582_CR74","doi-asserted-by":"publisher","first-page":"3003","DOI":"10.3892\/mmr.2014.2624","volume":"10","author":"Y Zheng","year":"2014","unstructured":"Zheng Y, Hu CJ, Zhuo RH, Lei YS, Han NN, He L. Inhibition of autophagy alleviates the senescent state of rat mesenchymal stem cells during long-term culture. Mol Med Rep. 2014;10:3003\u20138.","journal-title":"Mol Med Rep"},{"key":"6582_CR75","doi-asserted-by":"publisher","first-page":"3099","DOI":"10.1002\/jcp.30079","volume":"236","author":"D Bloemberg","year":"2021","unstructured":"Bloemberg D, Quadrilatero J. Autophagy displays divergent roles during intermittent amino acid starvation and toxic stress-induced senescence in cultured skeletal muscle cells. J Cell Physiol. 2021;236:3099\u2013113.","journal-title":"J Cell Physiol"},{"key":"6582_CR76","doi-asserted-by":"publisher","DOI":"10.1186\/s13395-015-0061-7","volume":"5","author":"A Filareto","year":"2015","unstructured":"Filareto A, Rinaldi F, Arpke RW, Darabi R, Belanto JJ, Toso EA, et al. Pax3-induced expansion enables the genetic correction of dystrophic satellite cells. Skelet Muscle. 2015;5:36.","journal-title":"Skelet Muscle"},{"key":"6582_CR77","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1016\/S0308-8146(00)00324-1","volume":"73","author":"MB Arnao","year":"2001","unstructured":"Arnao MB, Antonio C, Manuel A. The hydrophilic and lipophilic contribution to total antioxidant activity. Food Chem. 2001;73:239\u201344.","journal-title":"Food Chem"},{"key":"6582_CR78","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1016\/j.freeradbiomed.2010.05.019","volume":"49","author":"D de Gonzalo-Calvo","year":"2010","unstructured":"de Gonzalo-Calvo D, Neitzert K, Fernandez M, Vega-Naredo I, Caballero B, Garcia-Macia M, et al. Differential inflammatory responses in aging and disease: TNF-alpha and IL-6 as possible biomarkers. Free Radic Biol Med. 2010;49:733\u20137.","journal-title":"Free Radic Biol Med"},{"key":"6582_CR79","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/0003-9861(87)90400-0","volume":"255","author":"JP Martin Jr","year":"1987","unstructured":"Martin JP Jr, Dailey M, Sugarman E. Negative and positive assays of superoxide dismutase based on hematoxylin autoxidation. Arch Biochem Biophys. 1987;255:329\u201336.","journal-title":"Arch Biochem Biophys"},{"key":"6582_CR80","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1093\/genetics\/91.4.723","volume":"91","author":"S Lubinsky","year":"1979","unstructured":"Lubinsky S, Bewley GC. Genetics of Catalase in drosophila melanogaster: Rates of Synthesis and Degradation of the Enzyme in Flies Aneuploid and Euploid for the Structural Gene. Genetics. 1979;91:723\u201342.","journal-title":"Genetics"},{"key":"6582_CR81","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1021\/tx9701790","volume":"11","author":"D Gerard-Monnier","year":"1998","unstructured":"Gerard-Monnier D, Erdelmeier I, Regnard K, Moze-Henry N, Yadan JC, Chaudiere J. Reactions of 1-methyl-2-phenylindole with malondialdehyde and 4-hydroxyalkenals. Analytical applications to a colorimetric assay of lipid peroxidation. Chem Res Toxicol. 1998;11:1176\u201383.","journal-title":"Chem Res Toxicol"},{"key":"6582_CR82","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1016\/0076-6879(90)86141-H","volume":"186","author":"RL Levine","year":"1990","unstructured":"Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG, et al. Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol. 1990;186:464\u201378.","journal-title":"Methods Enzymol"},{"key":"6582_CR83","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1111\/j.1600-079X.1999.tb00610.x","volume":"27","author":"A Coto-Montes","year":"1999","unstructured":"Coto-Montes A, Hardeland R. Antioxidative effects of melatonin in Drosophila melanogaster: antagonization of damage induced by the inhibition of catalase. J Pineal Res. 1999;27:154\u20138.","journal-title":"J Pineal Res"},{"key":"6582_CR84","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","volume":"72","author":"MM Bradford","year":"1976","unstructured":"Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248\u201354.","journal-title":"Anal Biochem"},{"key":"6582_CR85","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1038\/nprot.2006.179","volume":"1","author":"V Vichai","year":"2006","unstructured":"Vichai V, Kirtikara K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc. 2006;1:1112\u20136.","journal-title":"Nat Protoc"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-024-06582-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-024-06582-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-024-06582-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T16:02:03Z","timestamp":1709913723000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-024-06582-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,8]]},"references-count":85,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["6582"],"URL":"https:\/\/doi.org\/10.1038\/s41419-024-06582-0","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,8]]},"assertion":[{"value":"2 August 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 February 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 March 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 March 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"200"}}