{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T10:18:47Z","timestamp":1782209927575,"version":"3.54.5"},"reference-count":80,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,8,31]],"date-time":"2017-08-31T00:00:00Z","timestamp":1504137600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,8,31]],"date-time":"2017-08-31T00:00:00Z","timestamp":1504137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Skeletal muscle wasting is prevalent in many chronic diseases, necessitating inquiries into molecular regulation of muscle mass. Nuclear receptor co-activator peroxisome proliferator-activated receptor co-activator 1 alpha (PGC1\u03b1) and its splice variant PGC1\u03b14 increase skeletal muscle mass. However, the effect of the other PGC1 sub-type, PGC1\u03b2, on muscle size is unclear. In transgenic mice selectively over-expressing PGC1\u03b2 in the skeletal muscle, we have found that PGC1\u03b2 progressively decreases skeletal muscle mass predominantly associated with loss of type 2b fast-twitch myofibers. Paradoxically, PGC1\u03b2 represses the ubiquitin-proteolysis degradation pathway genes resulting in ubiquitinated protein accumulation in muscle. However, PGC1\u03b2 overexpression triggers up-regulation of apoptosis and autophagy genes, resulting in robust activation of these cell degenerative processes, and a concomitant increase in muscle protein oxidation. Concurrently, PGC1\u03b2 up-regulates apoptosis and\/or autophagy transcriptional factors such as E2f1, Atf3, Stat1, and Stat3, which may be facilitating myopathy. Therefore, PGC1\u03b2 activation negatively affects muscle mass over time, particularly fast-twitch muscles, which should be taken into consideration along with its known aerobic effects in the skeletal muscle.<\/jats:p>","DOI":"10.1038\/s41598-017-10238-9","type":"journal-article","created":{"date-parts":[[2017,8,25]],"date-time":"2017-08-25T14:35:58Z","timestamp":1503671758000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Long-term PGC1\u03b2 overexpression leads to apoptosis, autophagy and muscle wasting"],"prefix":"10.1038","volume":"7","author":[{"given":"Danesh H.","family":"Sopariwala","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas","family":"Yadav","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Marie","family":"Badin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neah","family":"Likhite","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megha","family":"Sheth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Lorca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6834-5721","authenticated-orcid":false,"given":"Isabelle K.","family":"Vila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun Ran","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4561-2540","authenticated-orcid":false,"given":"Qingchun","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Sup","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George G.","family":"Rodney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vihang A.","family":"Narkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,8,31]]},"reference":[{"key":"10238_CR1","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/nrd4467","volume":"14","author":"S Cohen","year":"2015","unstructured":"Cohen, S., Nathan, J. A. & Goldberg, A. L. Muscle wasting in disease: molecular mechanisms and promising therapies. Nature reviews. Drug discovery \n                           14, 58\u201374, doi:10.1038\/nrd4467 (2015).","journal-title":"Nature reviews. Drug discovery"},{"key":"10238_CR2","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1164\/rccm.2108013","volume":"166","author":"AG Agusti","year":"2002","unstructured":"Agusti, A. G. et al. Skeletal muscle apoptosis and weight loss in chronic obstructive pulmonary disease. American journal of respiratory and critical care medicine \n                           166, 485\u2013489, doi:10.1164\/rccm.2108013 (2002).","journal-title":"American journal of respiratory and critical care medicine"},{"key":"10238_CR3","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1007\/s13539-012-0074-6","volume":"3","author":"A Fanzani","year":"2012","unstructured":"Fanzani, A., Conraads, V. M., Penna, F. & Martinet, W. Molecular and cellular mechanisms of skeletal muscle atrophy: an update. Journal of cachexia, sarcopenia and muscle \n                           3, 163\u2013179, doi:10.1007\/s13539-012-0074-6 (2012).","journal-title":"Journal of cachexia, sarcopenia and muscle"},{"key":"10238_CR4","doi-asserted-by":"publisher","first-page":"1704","DOI":"10.1126\/science.1065874","volume":"294","author":"SC Bodine","year":"2001","unstructured":"Bodine, S. C. et al. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science \n                           294, 1704\u20131708, doi:10.1126\/science.1065874 (2001).","journal-title":"Science"},{"key":"10238_CR5","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1083\/jcb.200412024","volume":"169","author":"K Nakanishi","year":"2005","unstructured":"Nakanishi, K., Sudo, T. & Morishima, N. Endoplasmic reticulum stress signaling transmitted by ATF6 mediates apoptosis during muscle development. The Journal of cell biology \n                           169, 555\u2013560, doi:10.1083\/jcb.200412024 (2005).","journal-title":"The Journal of cell biology"},{"key":"10238_CR6","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1111\/j.1474-9726.2007.00347.x","volume":"7","author":"B Chabi","year":"2008","unstructured":"Chabi, B. et al. Mitochondrial function and apoptotic susceptibility in aging skeletal muscle. Aging cell \n                           7, 2\u201312, doi:10.1111\/j.1474-9726.2007.00347.x (2008).","journal-title":"Aging cell"},{"key":"10238_CR7","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1242\/dmm.010389","volume":"6","author":"P Bonaldo","year":"2013","unstructured":"Bonaldo, P. & Sandri, M. Cellular and molecular mechanisms of muscle atrophy. Disease models & mechanisms \n                           6, 25\u201339, doi:10.1242\/dmm.010389 (2013).","journal-title":"Disease models & mechanisms"},{"key":"10238_CR8","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1096\/fj.02-0367com","volume":"16","author":"K Baar","year":"2002","unstructured":"Baar, K. et al. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB journal: official publication of the Federation of American Societies for Experimental Biology \n                           16, 1879\u20131886, doi:10.1096\/fj.02-0367com (2002).","journal-title":"FASEB journal: official publication of the Federation of American Societies for Experimental Biology"},{"key":"10238_CR9","doi-asserted-by":"publisher","first-page":"2874","DOI":"10.2337\/diabetes.52.12.2874","volume":"52","author":"AP Russell","year":"2003","unstructured":"Russell, A. P. et al. Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle. Diabetes \n                           52, 2874\u20132881 (2003).","journal-title":"Diabetes"},{"key":"10238_CR10","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1038\/nature00904","volume":"418","author":"J Lin","year":"2002","unstructured":"Lin, J. et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature \n                           418, 797\u2013801, doi:10.1038\/nature00904 (2002).","journal-title":"Nature"},{"key":"10238_CR11","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1038\/nature06613","volume":"451","author":"Z Arany","year":"2008","unstructured":"Arany, Z. et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature \n                           451, 1008\u20131012, doi:10.1038\/nature06613 (2008).","journal-title":"Nature"},{"key":"10238_CR12","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1101\/gad.1525107","volume":"21","author":"C Handschin","year":"2007","unstructured":"Handschin, C. et al. PGC-1alpha regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes & development \n                           21, 770\u2013783, doi:10.1101\/gad.1525107 (2007).","journal-title":"Genes & development"},{"key":"10238_CR13","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1038\/ng1180","volume":"34","author":"VK Mootha","year":"2003","unstructured":"Mootha, V. K. et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature genetics \n                           34, 267\u2013273, doi:10.1038\/ng1180 (2003).","journal-title":"Nature genetics"},{"key":"10238_CR14","doi-asserted-by":"publisher","first-page":"16260","DOI":"10.1073\/pnas.0607795103","volume":"103","author":"M Sandri","year":"2006","unstructured":"Sandri, M. et al. PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proceedings of the National Academy of Sciences of the United States of America \n                           103, 16260\u201316265, doi:10.1073\/pnas.0607795103 (2006).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"10238_CR15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006808","volume":"4","author":"N Sainz","year":"2009","unstructured":"Sainz, N. et al. Leptin administration favors muscle mass accretion by decreasing FoxO3a and increasing PGC-1alpha in ob\/ob mice. PloS one \n                           4, e6808, doi:10.1371\/journal.pone.0006808 (2009).","journal-title":"PloS one"},{"key":"10238_CR16","doi-asserted-by":"publisher","first-page":"1398","DOI":"10.1096\/fj.13-242123","volume":"28","author":"SM Hindi","year":"2014","unstructured":"Hindi, S. M. et al. Regulatory circuitry of TWEAK-Fn14 system and PGC-1alpha in skeletal muscle atrophy program. FASEB journal: official publication of the Federation of American Societies for Experimental Biology \n                           28, 1398\u20131411, doi:10.1096\/fj.13-242123 (2014).","journal-title":"FASEB journal: official publication of the Federation of American Societies for Experimental Biology"},{"key":"10238_CR17","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1016\/j.cell.2012.10.050","volume":"151","author":"JL Ruas","year":"2012","unstructured":"Ruas, J. L. et al. A PGC-1alpha isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell \n                           151, 1319\u20131331, doi:10.1016\/j.cell.2012.10.050 (2012).","journal-title":"Cell"},{"key":"10238_CR18","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.cmet.2006.12.003","volume":"5","author":"Z Arany","year":"2007","unstructured":"Arany, Z. et al. The transcriptional coactivator PGC-1beta drives the formation of oxidative type IIX fibers in skeletal muscle. Cell metabolism \n                           5, 35\u201346, doi:10.1016\/j.cmet.2006.12.003 (2007).","journal-title":"Cell metabolism"},{"key":"10238_CR19","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1016\/j.celrep.2014.06.040","volume":"8","author":"V Yadav","year":"2014","unstructured":"Yadav, V., Matsakas, A., Lorca, S. & Narkar, V. A. PGC1beta activates an antiangiogenic program to repress neoangiogenesis in muscle ischemia. Cell reports \n                           8, 783\u2013797, doi:10.1016\/j.celrep.2014.06.040 (2014).","journal-title":"Cell reports"},{"key":"10238_CR20","doi-asserted-by":"publisher","first-page":"19460","DOI":"10.1074\/jbc.M110.113092","volume":"285","author":"JJ Brault","year":"2010","unstructured":"Brault, J. J., Jespersen, J. G. & Goldberg, A. L. Peroxisome proliferator-activated receptor gamma coactivator 1alpha or 1beta overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy. The Journal of biological chemistry \n                           285, 19460\u201319471, doi:10.1074\/jbc.M110.113092 (2010).","journal-title":"The Journal of biological chemistry"},{"key":"10238_CR21","doi-asserted-by":"publisher","first-page":"E533","DOI":"10.1152\/ajpendo.00596.2009","volume":"299","author":"MJ Menconi","year":"2010","unstructured":"Menconi, M. J. et al. Sepsis and glucocorticoids downregulate the expression of the nuclear cofactor PGC-1beta in skeletal muscle. American journal of physiology. Endocrinology and metabolism \n                           299, E533\u2013543, doi:10.1152\/ajpendo.00596.2009 (2010).","journal-title":"American journal of physiology. Endocrinology and metabolism"},{"key":"10238_CR22","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1038\/nm.4093","volume":"22","author":"T Fukawa","year":"2016","unstructured":"Fukawa, T. et al. Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia. Nature medicine \n                           22, 666\u2013671, doi:10.1038\/nm.4093 (2016).","journal-title":"Nature medicine"},{"key":"10238_CR23","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/S0014-5793(02)03270-2","volume":"529","author":"D Ginsberg","year":"2002","unstructured":"Ginsberg, D. E2F1 pathways to apoptosis. FEBS letters \n                           529, 122\u2013125 (2002).","journal-title":"FEBS letters"},{"key":"10238_CR24","doi-asserted-by":"publisher","first-page":"4860","DOI":"10.1038\/onc.2008.117","volume":"27","author":"S Polager","year":"2008","unstructured":"Polager, S., Ofir, M. & Ginsberg, D. E2F1 regulates autophagy and the transcription of autophagy genes. Oncogene \n                           27, 4860\u20134864, doi:10.1038\/onc.2008.117 (2008).","journal-title":"Oncogene"},{"key":"10238_CR25","first-page":"2670","volume":"8","author":"Q Wang","year":"2015","unstructured":"Wang, Q., Shu, C., Su, J. & Li, X. A crosstalk triggered by hypoxia and maintained by MCP-1\/miR-98\/IL-6\/p38 regulatory loop between human aortic smooth muscle cells and macrophages leads to aortic smooth muscle cells apoptosis via Stat1 activation. International journal of clinical and experimental pathology \n                           8, 2670\u20132679 (2015).","journal-title":"International journal of clinical and experimental pathology"},{"key":"10238_CR26","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2007-8-1-r3","volume":"8","author":"P Carmona-Saez","year":"2007","unstructured":"Carmona-Saez, P., Chagoyen, M., Tirado, F., Carazo, J. M. & Pascual-Montano, A. GENECODIS: a web-based tool for finding significant concurrent annotations in gene lists. Genome biology \n                           8, R3, doi:10.1186\/gb-2007-8-1-r3 (2007).","journal-title":"Genome biology"},{"key":"10238_CR27","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/S0163-7258(01)00159-0","volume":"92","author":"KC Zimmermann","year":"2001","unstructured":"Zimmermann, K. C., Bonzon, C. & Green, D. R. The machinery of programmed cell death. Pharmacology & therapeutics \n                           92, 57\u201370 (2001).","journal-title":"Pharmacology & therapeutics"},{"key":"10238_CR28","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1146\/annurev-genet-102808-114910","volume":"43","author":"C He","year":"2009","unstructured":"He, C. & Klionsky, D. J. Regulation mechanisms and signaling pathways of autophagy. Annual review of genetics \n                           43, 67\u201393, doi:10.1146\/annurev-genet-102808-114910 (2009).","journal-title":"Annual review of genetics"},{"key":"10238_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/15548627.2015.1100356","volume":"12","author":"DJ Klionsky","year":"2016","unstructured":"Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy \n                           12, 1\u2013222, doi:10.1080\/15548627.2015.1100356 (2016).","journal-title":"Autophagy"},{"key":"10238_CR30","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-016-2664-8","volume":"17","author":"J Zhao","year":"2016","unstructured":"Zhao, J., Li, X., Guo, M., Yu, J. & Yan, C. The common stress responsive transcription factor ATF3 binds genomic sites enriched with p300 and H3K27ac for transcriptional regulation. BMC genomics \n                           17, 335, doi:10.1186\/s12864-016-2664-8 (2016).","journal-title":"BMC genomics"},{"key":"10238_CR31","doi-asserted-by":"publisher","first-page":"11177","DOI":"10.1074\/jbc.M115.641514","volume":"290","author":"KA Silva","year":"2015","unstructured":"Silva, K. A. et al. Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system, leading to preservation of muscle mass in cancer cachexia. The Journal of biological chemistry \n                           290, 11177\u201311187, doi:10.1074\/jbc.M115.641514 (2015).","journal-title":"The Journal of biological chemistry"},{"key":"10238_CR32","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.freeradbiomed.2015.12.032","volume":"93","author":"C Kang","year":"2016","unstructured":"Kang, C. & Ji, L. L. PGC-1alpha overexpression via local transfection attenuates mitophagy pathway in muscle disuse atrophy. Free radical biology & medicine \n                           93, 32\u201340, doi:10.1016\/j.freeradbiomed.2015.12.032 (2016).","journal-title":"Free radical biology & medicine"},{"key":"10238_CR33","doi-asserted-by":"publisher","first-page":"4575","DOI":"10.1113\/jphysiol.2014.275545","volume":"592","author":"J Cannavino","year":"2014","unstructured":"Cannavino, J., Brocca, L., Sandri, M., Bottinelli, R. & Pellegrino, M. A. PGC1-alpha over-expression prevents metabolic alterations and soleus muscle atrophy in hindlimb unloaded mice. The Journal of physiology \n                           592, 4575\u20134589, doi:10.1113\/jphysiol.2014.275545 (2014).","journal-title":"The Journal of physiology"},{"key":"10238_CR34","doi-asserted-by":"publisher","first-page":"20405","DOI":"10.1073\/pnas.0911570106","volume":"106","author":"T Wenz","year":"2009","unstructured":"Wenz, T., Rossi, S. G., Rotundo, R. L., Spiegelman, B. M. & Moraes, C. T. Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proceedings of the National Academy of Sciences of the United States of America \n                           106, 20405\u201320410, doi:10.1073\/pnas.0911570106 (2009).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"10238_CR35","doi-asserted-by":"publisher","first-page":"C710","DOI":"10.1152\/ajpcell.00380.2014","volume":"308","author":"A Vainshtein","year":"2015","unstructured":"Vainshtein, A., Tryon, L. D., Pauly, M. & Hood, D. A. Role of PGC-1alpha during acute exercise-induced autophagy and mitophagy in skeletal muscle. American journal of physiology. Cell physiology \n                           308, C710\u2013719, doi:10.1152\/ajpcell.00380.2014 (2015).","journal-title":"American journal of physiology. Cell physiology"},{"key":"10238_CR36","doi-asserted-by":"publisher","unstructured":"Halling, J. F., Ringholm, S., Nielsen, M. M., Overby, P. & Pilegaard, H. PGC-1alpha promotes exercise-induced autophagy in mouse skeletal muscle. Physiological reports \n                           4, doi:10.14814\/phy2.12698 (2016).","DOI":"10.14814\/phy2.12698"},{"key":"10238_CR37","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.2353\/ajpath.2006.060034","volume":"169","author":"S Miura","year":"2006","unstructured":"Miura, S. et al. Overexpression of peroxisome proliferator-activated receptor gamma co-activator-1alpha leads to muscle atrophy with depletion of ATP. The American journal of pathology \n                           169, 1129\u20131139 (2006).","journal-title":"The American journal of pathology"},{"key":"10238_CR38","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1111\/acel.12399","volume":"14","author":"N Cheema","year":"2015","unstructured":"Cheema, N., Herbst, A., McKenzie, D. & Aiken, J. M. Apoptosis and necrosis mediate skeletal muscle fiber loss in age-induced mitochondrial enzymatic abnormalities. Aging cell \n                           14, 1085\u20131093, doi:10.1111\/acel.12399 (2015).","journal-title":"Aging cell"},{"key":"10238_CR39","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.3892\/ijmm.2014.1675","volume":"33","author":"SY Park","year":"2014","unstructured":"Park, S. Y. et al. Differential expression of apoptosis-related factors induces the age-related apoptosis of the gracilis muscle in humans. International journal of molecular medicine \n                           33, 1110\u20131116, doi:10.3892\/ijmm.2014.1675 (2014).","journal-title":"International journal of molecular medicine"},{"key":"10238_CR40","doi-asserted-by":"publisher","first-page":"2583","DOI":"10.1007\/s00018-016-2132-2","volume":"73","author":"LA Cea","year":"2016","unstructured":"Cea, L. A. et al. Fast skeletal myofibers of mdx mouse, model of Duchenne muscular dystrophy, express connexin hemichannels that lead to apoptosis. Cellular and molecular life sciences: CMLS \n                           73, 2583\u20132599, doi:10.1007\/s00018-016-2132-2 (2016).","journal-title":"Cellular and molecular life sciences: CMLS"},{"key":"10238_CR41","doi-asserted-by":"publisher","first-page":"4306","DOI":"10.1093\/hmg\/ddt280","volume":"22","author":"J Yamauchi","year":"2013","unstructured":"Yamauchi, J., Kumar, A., Duarte, L., Mehuron, T. & Girgenrath, M. Triggering regeneration and tackling apoptosis: a combinatorial approach to treating congenital muscular dystrophy type 1 A. Human molecular genetics \n                           22, 4306\u20134317, doi:10.1093\/hmg\/ddt280 (2013).","journal-title":"Human molecular genetics"},{"key":"10238_CR42","doi-asserted-by":"publisher","first-page":"7344","DOI":"10.1158\/0008-5472.CAN-14-0057","volume":"74","author":"YS Gallot","year":"2014","unstructured":"Gallot, Y. S. et al. Myostatin gene inactivation prevents skeletal muscle wasting in cancer. Cancer research \n                           74, 7344\u20137356, doi:10.1158\/0008-5472.CAN-14-0057 (2014).","journal-title":"Cancer research"},{"key":"10238_CR43","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1152\/japplphysiol.01017.2010","volume":"111","author":"E Barreiro","year":"2011","unstructured":"Barreiro, E. et al. Inflammatory cells and apoptosis in respiratory and limb muscles of patients with COPD. Journal of applied physiology \n                           111, 808\u2013817, doi:10.1152\/japplphysiol.01017.2010 (2011).","journal-title":"Journal of applied physiology"},{"key":"10238_CR44","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1080\/01926230701320337","volume":"35","author":"S Elmore","year":"2007","unstructured":"Elmore, S. Apoptosis: a review of programmed cell death. Toxicologic pathology \n                           35, 495\u2013516, doi:10.1080\/01926230701320337 (2007).","journal-title":"Toxicologic pathology"},{"key":"10238_CR45","doi-asserted-by":"publisher","first-page":"1674","DOI":"10.1016\/j.biocel.2008.02.001","volume":"40","author":"JM Argiles","year":"2008","unstructured":"Argiles, J. M., Lopez-Soriano, F. J. & Busquets, S. Apoptosis signalling is essential and precedes protein degradation in wasting skeletal muscle during catabolic conditions. The international journal of biochemistry & cell biology \n                           40, 1674\u20131678, doi:10.1016\/j.biocel.2008.02.001 (2008).","journal-title":"The international journal of biochemistry & cell biology"},{"key":"10238_CR46","doi-asserted-by":"publisher","first-page":"7987","DOI":"10.1074\/jbc.274.12.7987","volume":"274","author":"O Micheau","year":"1999","unstructured":"Micheau, O., Solary, E., Hammann, A. & Dimanche-Boitrel, M. T. Fas ligand-independent, FADD-mediated activation of the Fas death pathway by anticancer drugs. The Journal of biological chemistry \n                           274, 7987\u20137992 (1999).","journal-title":"The Journal of biological chemistry"},{"key":"10238_CR47","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.bbrc.2004.05.145","volume":"320","author":"R Gniadecki","year":"2004","unstructured":"Gniadecki, R. Depletion of membrane cholesterol causes ligand-independent activation of Fas and apoptosis. Biochemical and biophysical research communications \n                           320, 165\u2013169, doi:10.1016\/j.bbrc.2004.05.145 (2004).","journal-title":"Biochemical and biophysical research communications"},{"key":"10238_CR48","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/nature16187","volume":"529","author":"L Garcia-Prat","year":"2016","unstructured":"Garcia-Prat, L. et al. Autophagy maintains stemness by preventing senescence. Nature \n                           529, 37\u201342, doi:10.1038\/nature16187 (2016).","journal-title":"Nature"},{"key":"10238_CR49","doi-asserted-by":"publisher","first-page":"1509","DOI":"10.1016\/j.celrep.2014.07.061","volume":"8","author":"S Carnio","year":"2014","unstructured":"Carnio, S. et al. Autophagy impairment in muscle induces neuromuscular junction degeneration and precocious aging. Cell reports \n                           8, 1509\u20131521, doi:10.1016\/j.celrep.2014.07.061 (2014).","journal-title":"Cell reports"},{"key":"10238_CR50","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.4161\/auto.21691","volume":"8","author":"AC Nascimbeni","year":"2012","unstructured":"Nascimbeni, A. C., Fanin, M., Masiero, E., Angelini, C. & Sandri, M. Impaired autophagy contributes to muscle atrophy in glycogen storage disease type II patients. Autophagy \n                           8, 1697\u20131700, doi:10.4161\/auto.21691 (2012).","journal-title":"Autophagy"},{"key":"10238_CR51","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1038\/nature10758","volume":"481","author":"C He","year":"2012","unstructured":"He, C. et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature \n                           481, 511\u2013515, doi:10.1038\/nature10758 (2012).","journal-title":"Nature"},{"key":"10238_CR52","doi-asserted-by":"publisher","first-page":"4184","DOI":"10.1096\/fj.13-228486","volume":"27","author":"VA Lira","year":"2013","unstructured":"Lira, V. A. et al. Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance. FASEB journal: official publication of the Federation of American Societies for Experimental Biology \n                           27, 4184\u20134193, doi:10.1096\/fj.13-228486 (2013).","journal-title":"FASEB journal: official publication of the Federation of American Societies for Experimental Biology"},{"key":"10238_CR53","doi-asserted-by":"publisher","DOI":"10.1038\/srep30340","volume":"6","author":"Z Aversa","year":"2016","unstructured":"Aversa, Z. et al. Autophagy is induced in the skeletal muscle of cachectic cancer patients. Scientific reports \n                           6, 30340, doi:10.1038\/srep30340 (2016).","journal-title":"Scientific reports"},{"key":"10238_CR54","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1016\/j.cmet.2007.11.004","volume":"6","author":"J Zhao","year":"2007","unstructured":"Zhao, J. et al. FoxO3 coordinately activates protein degradation by the autophagic\/lysosomal and proteasomal pathways in atrophying muscle cells. Cell metabolism \n                           6, 472\u2013483, doi:10.1016\/j.cmet.2007.11.004 (2007).","journal-title":"Cell metabolism"},{"key":"10238_CR55","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1016\/j.cmet.2007.11.001","volume":"6","author":"C Mammucari","year":"2007","unstructured":"Mammucari, C. et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell metabolism \n                           6, 458\u2013471, doi:10.1016\/j.cmet.2007.11.001 (2007).","journal-title":"Cell metabolism"},{"key":"10238_CR56","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.abb.2016.04.015","volume":"600","author":"Y Guo","year":"2016","unstructured":"Guo, Y. et al. AMP-activated kinase alpha2 deficiency protects mice from denervation-induced skeletal muscle atrophy. Archives of biochemistry and biophysics \n                           600, 56\u201360, doi:10.1016\/j.abb.2016.04.015 (2016).","journal-title":"Archives of biochemistry and biophysics"},{"key":"10238_CR57","doi-asserted-by":"publisher","first-page":"1914","DOI":"10.1172\/JCI72327","volume":"124","author":"D Sala","year":"2014","unstructured":"Sala, D. et al. Autophagy-regulating TP53INP2 mediates muscle wasting and is repressed in diabetes. The Journal of clinical investigation \n                           124, 1914\u20131927, doi:10.1172\/JCI72327 (2014).","journal-title":"The Journal of clinical investigation"},{"key":"10238_CR58","doi-asserted-by":"publisher","first-page":"113","DOI":"10.4161\/15548627.2014.994402","volume":"11","author":"CN Young","year":"2015","unstructured":"Young, C. N. et al. A novel mechanism of autophagic cell death in dystrophic muscle regulated by P2RX7 receptor large-pore formation and HSP90. Autophagy \n                           11, 113\u2013130, doi:10.4161\/15548627.2014.994402 (2015).","journal-title":"Autophagy"},{"key":"10238_CR59","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1016\/j.celrep.2012.03.014","volume":"1","author":"E Yamada","year":"2012","unstructured":"Yamada, E. et al. Mouse skeletal muscle fiber-type-specific macroautophagy and muscle wasting are regulated by a Fyn\/STAT3\/Vps34 signaling pathway. Cell reports \n                           1, 557\u2013569, doi:10.1016\/j.celrep.2012.03.014 (2012).","journal-title":"Cell reports"},{"key":"10238_CR60","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1096\/fj.10-164152","volume":"25","author":"A Doyle","year":"2011","unstructured":"Doyle, A., Zhang, G., Abdel Fattah, E. A., Eissa, N. T. & Li, Y. P. Toll-like receptor 4 mediates lipopolysaccharide-induced muscle catabolism via coordinate activation of ubiquitin-proteasome and autophagy-lysosome pathways. FASEB journal: official publication of the Federation of American Societies for Experimental Biology \n                           25, 99\u2013110, doi:10.1096\/fj.10-164152 (2011).","journal-title":"FASEB journal: official publication of the Federation of American Societies for Experimental Biology"},{"key":"10238_CR61","doi-asserted-by":"publisher","DOI":"10.1186\/2044-5040-1-4","volume":"1","author":"S Schiaffino","year":"2011","unstructured":"Schiaffino, S. & Mammucari, C. Regulation of skeletal muscle growth by the IGF1-Akt\/PKB pathway: insights from genetic models. Skeletal muscle \n                           1, 4, doi:10.1186\/2044-5040-1-4 (2011).","journal-title":"Skeletal muscle"},{"key":"10238_CR62","doi-asserted-by":"publisher","first-page":"2389","DOI":"10.1016\/j.biocel.2009.06.004","volume":"41","author":"Z Wu","year":"2009","unstructured":"Wu, Z., Zheng, S. & Yu, Q. The E2F family and the role of E2F1 in apoptosis. The international journal of biochemistry & cell biology \n                           41, 2389\u20132397, doi:10.1016\/j.biocel.2009.06.004 (2009).","journal-title":"The international journal of biochemistry & cell biology"},{"key":"10238_CR63","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1126\/science.1069861","volume":"296","author":"H Ogawa","year":"2002","unstructured":"Ogawa, H., Ishiguro, K., Gaubatz, S., Livingston, D. M. & Nakatani, Y. A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science \n                           296, 1132\u20131136, doi:10.1126\/science.1069861 (2002).","journal-title":"Science"},{"key":"10238_CR64","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1038\/8991","volume":"1","author":"JD Weber","year":"1999","unstructured":"Weber, J. D., Taylor, L. J., Roussel, M. F., Sherr, C. J. & Bar-Sagi, D. Nucleolar Arf sequesters Mdm2 and activates p53. Nature cell biology \n                           1, 20\u201326, doi:10.1038\/8991 (1999).","journal-title":"Nature cell biology"},{"key":"10238_CR65","doi-asserted-by":"publisher","first-page":"2425","DOI":"10.1038\/sj.emboj.7600712","volume":"24","author":"C Yan","year":"2005","unstructured":"Yan, C., Lu, D., Hai, T. & Boyd, D. D. Activating transcription factor 3, a stress sensor, activates p53 by blocking its ubiquitination. The EMBO journal \n                           24, 2425\u20132435, doi:10.1038\/sj.emboj.7600712 (2005).","journal-title":"The EMBO journal"},{"key":"10238_CR66","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1083\/jcb.201001136","volume":"191","author":"A Raffaello","year":"2010","unstructured":"Raffaello, A. et al. JunB transcription factor maintains skeletal muscle mass and promotes hypertrophy. The Journal of cell biology \n                           191, 101\u2013113, doi:10.1083\/jcb.201001136 (2010).","journal-title":"The Journal of cell biology"},{"key":"10238_CR67","doi-asserted-by":"publisher","first-page":"E410","DOI":"10.1152\/ajpendo.00039.2012","volume":"303","author":"A Bonetto","year":"2012","unstructured":"Bonetto, A. et al. JAK\/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia. American journal of physiology. Endocrinology and metabolism \n                           303, E410\u2013421, doi:10.1152\/ajpendo.00039.2012 (2012).","journal-title":"American journal of physiology. Endocrinology and metabolism"},{"key":"10238_CR68","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1146\/annurev.pharmtox.47.120505.105122","volume":"47","author":"S Orrenius","year":"2007","unstructured":"Orrenius, S., Gogvadze, V. & Zhivotovsky, B. Mitochondrial oxidative stress: implications for cell death. Annual review of pharmacology and toxicology \n                           47, 143\u2013183, doi:10.1146\/annurev.pharmtox.47.120505.105122 (2007).","journal-title":"Annual review of pharmacology and toxicology"},{"key":"10238_CR69","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1016\/j.devcel.2007.03.016","volume":"12","author":"Z Liu","year":"2007","unstructured":"Liu, Z. & Lenardo, M. J. Reactive oxygen species regulate autophagy through redox-sensitive proteases. Developmental cell \n                           12, 484\u2013485, doi:10.1016\/j.devcel.2007.03.016 (2007).","journal-title":"Developmental cell"},{"key":"10238_CR70","doi-asserted-by":"publisher","first-page":"C413","DOI":"10.1152\/ajpcell.00362.2007","volume":"294","author":"C Ricci","year":"2008","unstructured":"Ricci, C. et al. Mitochondrial DNA damage triggers mitochondrial-superoxide generation and apoptosis. American journal of physiology. Cell physiology \n                           294, C413\u2013422, doi:10.1152\/ajpcell.00362.2007 (2008).","journal-title":"American journal of physiology. Cell physiology"},{"key":"10238_CR71","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10210","volume":"6","author":"T Gali Ramamoorthy","year":"2015","unstructured":"Gali Ramamoorthy, T. et al. The transcriptional coregulator PGC-1beta controls mitochondrial function and anti-oxidant defence in skeletal muscles. Nature communications \n                           6, 10210, doi:10.1038\/ncomms10210 (2015).","journal-title":"Nature communications"},{"key":"10238_CR72","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-03475-5","volume":"7","author":"HJ Lee","year":"2017","unstructured":"Lee, H. J. et al. Dysregulation of nuclear receptor COUP-TFII impairs skeletal muscle development. Scientific reports \n                           7, 3136, doi:10.1038\/s41598-017-03475-5 (2017).","journal-title":"Scientific reports"},{"key":"10238_CR73","doi-asserted-by":"publisher","first-page":"3929","DOI":"10.1172\/JCI87414","volume":"126","author":"X Xie","year":"2016","unstructured":"Xie, X., Tsai, S. Y. & Tsai, M. J. COUP-TFII regulates satellite cell function and muscular dystrophy. The Journal of clinical investigation \n                           126, 3929\u20133941, doi:10.1172\/JCI87414 (2016).","journal-title":"The Journal of clinical investigation"},{"key":"10238_CR74","doi-asserted-by":"publisher","first-page":"C447","DOI":"10.1152\/ajpcell.00451.2011","volume":"303","author":"MF O\u2019Leary","year":"2012","unstructured":"O\u2019Leary, M. F., Vainshtein, A., Carter, H. N., Zhang, Y. & Hood, D. A. Denervation-induced mitochondrial dysfunction and autophagy in skeletal muscle of apoptosis-deficient animals. American journal of physiology. Cell physiology \n                           303, C447\u2013454, doi:10.1152\/ajpcell.00451.2011 (2012).","journal-title":"American journal of physiology. Cell physiology"},{"key":"10238_CR75","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1242\/dmm.018127","volume":"8","author":"A Bargiela","year":"2015","unstructured":"Bargiela, A. et al. Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model. Disease models & mechanisms \n                           8, 679\u2013690, doi:10.1242\/dmm.018127 (2015).","journal-title":"Disease models & mechanisms"},{"key":"10238_CR76","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1038\/cdd.2010.33","volume":"17","author":"E Loro","year":"2010","unstructured":"Loro, E. et al. Normal myogenesis and increased apoptosis in myotonic dystrophy type-1 muscle cells. Cell death and differentiation \n                           17, 1315\u20131324, doi:10.1038\/cdd.2010.33 (2010).","journal-title":"Cell death and differentiation"},{"key":"10238_CR77","doi-asserted-by":"publisher","first-page":"4891","DOI":"10.1093\/hmg\/ddr427","volume":"20","author":"V Carmignac","year":"2011","unstructured":"Carmignac, V. et al. Autophagy is increased in laminin alpha2 chain-deficient muscle and its inhibition improves muscle morphology in a mouse model of MDC1A. Human molecular genetics \n                           20, 4891\u20134902, doi:10.1093\/hmg\/ddr427 (2011).","journal-title":"Human molecular genetics"},{"key":"10238_CR78","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1161\/CIRCRESAHA.112.266478","volume":"110","author":"A Matsakas","year":"2012","unstructured":"Matsakas, A., Yadav, V., Lorca, S., Evans, R. M. & Narkar, V. A. Revascularization of ischemic skeletal muscle by estrogen-related receptor-gamma. Circulation research \n                           110, 1087\u20131096, doi:10.1161\/CIRCRESAHA.112.266478 (2012).","journal-title":"Circulation research"},{"key":"10238_CR79","doi-asserted-by":"publisher","DOI":"10.1038\/srep26442","volume":"6","author":"PM Badin","year":"2016","unstructured":"Badin, P. M. et al. Exercise-like effects by Estrogen-related receptor-gamma in muscle do not prevent insulin resistance in db\/db mice. Scientific reports \n                           6, 26442, doi:10.1038\/srep26442 (2016).","journal-title":"Scientific reports"},{"key":"10238_CR80","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5425","volume":"5","author":"R Pal","year":"2014","unstructured":"Pal, R. et al. Src-dependent impairment of autophagy by oxidative stress in a mouse model of Duchenne muscular dystrophy. Nature communications \n                           5, 4425, doi:10.1038\/ncomms5425 (2014).","journal-title":"Nature communications"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-10238-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-10238-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-10238-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T05:00:57Z","timestamp":1671771657000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-10238-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,31]]},"references-count":80,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["10238"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-10238-9","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.730367869.793541594","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,31]]},"assertion":[{"value":"22 March 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 August 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 August 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"10237"}}