{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T23:03:09Z","timestamp":1773874989341,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T00:00:00Z","timestamp":1683763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"REACT-EU","award":["SPACE2-CV-COVID-CM"],"award-info":[{"award-number":["SPACE2-CV-COVID-CM"]}]},{"name":"REACT-EU","award":["PI18\/01016"],"award-info":[{"award-number":["PI18\/01016"]}]},{"name":"REACT-EU","award":["PI20\/00923"],"award-info":[{"award-number":["PI20\/00923"]}]},{"name":"REACT-EU","award":["FEDERRD09\/0076\/00101"],"award-info":[{"award-number":["FEDERRD09\/0076\/00101"]}]},{"name":"REACT-EU","award":["CB07\/08\/2007"],"award-info":[{"award-number":["CB07\/08\/2007"]}]},{"name":"Carlos III","award":["SPACE2-CV-COVID-CM"],"award-info":[{"award-number":["SPACE2-CV-COVID-CM"]}]},{"name":"Carlos III","award":["PI18\/01016"],"award-info":[{"award-number":["PI18\/01016"]}]},{"name":"Carlos III","award":["PI20\/00923"],"award-info":[{"award-number":["PI20\/00923"]}]},{"name":"Carlos III","award":["FEDERRD09\/0076\/00101"],"award-info":[{"award-number":["FEDERRD09\/0076\/00101"]}]},{"name":"Carlos III","award":["CB07\/08\/2007"],"award-info":[{"award-number":["CB07\/08\/2007"]}]},{"name":"Biobank","award":["SPACE2-CV-COVID-CM"],"award-info":[{"award-number":["SPACE2-CV-COVID-CM"]}]},{"name":"Biobank","award":["PI18\/01016"],"award-info":[{"award-number":["PI18\/01016"]}]},{"name":"Biobank","award":["PI20\/00923"],"award-info":[{"award-number":["PI20\/00923"]}]},{"name":"Biobank","award":["FEDERRD09\/0076\/00101"],"award-info":[{"award-number":["FEDERRD09\/0076\/00101"]}]},{"name":"Biobank","award":["CB07\/08\/2007"],"award-info":[{"award-number":["CB07\/08\/2007"]}]},{"DOI":"10.13039\/501100013941","name":"Ciberdem","doi-asserted-by":"publisher","award":["SPACE2-CV-COVID-CM"],"award-info":[{"award-number":["SPACE2-CV-COVID-CM"]}],"id":[{"id":"10.13039\/501100013941","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013941","name":"Ciberdem","doi-asserted-by":"publisher","award":["PI18\/01016"],"award-info":[{"award-number":["PI18\/01016"]}],"id":[{"id":"10.13039\/501100013941","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013941","name":"Ciberdem","doi-asserted-by":"publisher","award":["PI20\/00923"],"award-info":[{"award-number":["PI20\/00923"]}],"id":[{"id":"10.13039\/501100013941","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013941","name":"Ciberdem","doi-asserted-by":"publisher","award":["FEDERRD09\/0076\/00101"],"award-info":[{"award-number":["FEDERRD09\/0076\/00101"]}],"id":[{"id":"10.13039\/501100013941","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013941","name":"Ciberdem","doi-asserted-by":"publisher","award":["CB07\/08\/2007"],"award-info":[{"award-number":["CB07\/08\/2007"]}],"id":[{"id":"10.13039\/501100013941","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Type-2 diabetes (T2DM) and arterial hypertension (HTN) are major risk factors for heart failure. Importantly, these pathologies could induce synergetic alterations in the heart, and the discovery of key common molecular signaling may suggest new targets for therapy. Intraoperative cardiac biopsies were obtained from patients with coronary heart disease and preserved systolic function, with or without HTN and\/or T2DM, who underwent coronary artery bypass grafting (CABG). Control (n = 5), HTN (n = 7), and HTN + T2DM (n = 7) samples were analysed by proteomics and bioinformatics. Additionally, cultured rat cardiomyocytes were used for the analysis (protein level and activation, mRNA expression, and bioenergetic performance) of key molecular mediators under stimulation of main components of HTN and T2DM (high glucose and\/or fatty acids and angiotensin-II). As results, in cardiac biopsies, we found significant alterations of 677 proteins and after filtering for non-cardiac factors, 529 and 41 were changed in HTN-T2DM and in HTN subjects, respectively, against the control. Interestingly, 81% of proteins in HTN-T2DM were distinct from HTN, while 95% from HTN were common with HTN-T2DM. In addition, 78 factors were differentially expressed in HTN-T2DM against HTN, predominantly downregulated proteins of mitochondrial respiration and lipid oxidation. Bioinformatic analyses suggested the implication of mTOR signaling and reduction of AMPK and PPAR\u03b1 activation, and regulation of PGC1\u03b1, fatty acid oxidation, and oxidative phosphorylation. In cultured cardiomyocytes, an excess of the palmitate activated mTORC1 complex and subsequent attenuation of PGC1\u03b1-PPAR\u03b1 transcription of \u03b2-oxidation and mitochondrial electron chain factors affect mitochondrial\/glycolytic ATP synthesis. Silencing of PGC1\u03b1 further reduced total ATP and both mitochondrial and glycolytic ATP. Thus, the coexistence of HTN and T2DM induced higher alterations in cardiac proteins than HTN. HTN-T2DM subjects exhibited a marked downregulation of mitochondrial respiration and lipid metabolism and the mTORC1-PGC1\u03b1-PPAR\u03b1 axis might account as a target for therapeutical strategies.<\/jats:p>","DOI":"10.3390\/ijms24108629","type":"journal-article","created":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T02:36:59Z","timestamp":1683859019000},"page":"8629","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Potential Role of the mTORC1-PGC1\u03b1-PPAR\u03b1 Axis under Type-II Diabetes and Hypertension in the Human Heart"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3670-837X","authenticated-orcid":false,"given":"Tianyu","family":"Hang","sequence":"first","affiliation":[{"name":"Laboratory of Diabetes and Vascular Pathology, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma, 28040 Madrid, Spain"},{"name":"Biomedical Research Network on Diabetes and Associated Metabolic Disorders (CIBERDEM), Carlos III National Health Institute, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3458-0328","authenticated-orcid":false,"given":"Jairo","family":"Lumpuy-Castillo","sequence":"additional","affiliation":[{"name":"Laboratory of Diabetes and Vascular Pathology, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma, 28040 Madrid, Spain"},{"name":"Biomedical Research Network on Diabetes and Associated Metabolic Disorders (CIBERDEM), Carlos III National Health Institute, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4569-028X","authenticated-orcid":false,"given":"Naroa","family":"Goikoetxea-Usandizaga","sequence":"additional","affiliation":[{"name":"Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain"},{"name":"Biomedical Research Network on Liver and Digestive Diseases (CIBERehd), Carlos III National Health Institute, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikel","family":"Azkargorta","sequence":"additional","affiliation":[{"name":"Proteomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6369-448X","authenticated-orcid":false,"given":"Gonzalo","family":"Ald\u00e1miz","sequence":"additional","affiliation":[{"name":"Cardiovascular Surgery Department, Fundaci\u00f3n Jim\u00e9nez D\u00edaz Hospital, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Mart\u00ednez-Milla","sequence":"additional","affiliation":[{"name":"Cardiology Department, Fundaci\u00f3n Jim\u00e9nez D\u00edaz Hospital, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Forteza","sequence":"additional","affiliation":[{"name":"Cardiovascular Surgery Department, Doce de Octubre Hospital, 28041 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 M.","family":"Cortina","sequence":"additional","affiliation":[{"name":"Cardiovascular Surgery Department, Doce de Octubre Hospital, 28041 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jes\u00fas","family":"Egido","sequence":"additional","affiliation":[{"name":"Laboratory of Diabetes and Vascular Pathology, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma, 28040 Madrid, Spain"},{"name":"Biomedical Research Network on Diabetes and Associated Metabolic Disorders (CIBERDEM), Carlos III National Health Institute, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8839-5438","authenticated-orcid":false,"given":"F\u00e9lix","family":"Elortza","sequence":"additional","affiliation":[{"name":"Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6446-9911","authenticated-orcid":false,"given":"Malu","family":"Mart\u00ednez-Chantar","sequence":"additional","affiliation":[{"name":"Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Spain"},{"name":"Biomedical Research Network on Liver and Digestive Diseases (CIBERehd), Carlos III National Health Institute, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1373-0999","authenticated-orcid":false,"given":"Jos\u00e9","family":"Tu\u00f1\u00f3n","sequence":"additional","affiliation":[{"name":"Cardiology Department, Fundaci\u00f3n Jim\u00e9nez D\u00edaz Hospital, 28040 Madrid, Spain"},{"name":"Medicine Department, Universidad Aut\u00f3noma, 28029 Madrid, Spain"},{"name":"Biomedical Research Network on Cardiovascular Diseases (CIBERCV), Carlos III National Health Institute, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5515-6078","authenticated-orcid":false,"given":"\u00d3scar","family":"Lorenzo","sequence":"additional","affiliation":[{"name":"Laboratory of Diabetes and Vascular Pathology, IIS-Fundaci\u00f3n Jim\u00e9nez D\u00edaz, Universidad Aut\u00f3noma, 28040 Madrid, Spain"},{"name":"Biomedical Research Network on Diabetes and Associated Metabolic Disorders (CIBERDEM), Carlos III National Health Institute, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1056\/NEJMoa052256","article-title":"Trends in prevalence and outcome of heart failure with preserved ejection fraction","volume":"355","author":"Owan","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1185\/03007995.2016.1168291","article-title":"Prevalence and co-prevalence of comorbidities among patients with type 2 diabetes mellitus","volume":"32","author":"Iglay","year":"2016","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.3389\/fphys.2018.01847","article-title":"Clinical Overview of Obesity and Diabetes Mellitus as Risk Factors for Atrial Fibrillation and Sudden Cardiac Death","volume":"9","author":"Homan","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e013114","DOI":"10.1161\/JAHA.119.013114","article-title":"Association of Diabetes Mellitus on Cardiac Remodeling, Quality of Life, and Clinical Outcomes in Heart Failure With Reduced and Preserved Ejection Fraction","volume":"8","author":"Yap","year":"2019","journal-title":"J. Am. Heart Assoc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"d1072","DOI":"10.2741\/1137","article-title":"Regulation of GLUT4 traffic and function by insulin and contraction in skeletal muscle","volume":"8","author":"Tremblay","year":"2003","journal-title":"Front. Biosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1161\/01.RES.0000207406.94146.c2","article-title":"Diabetic cardiomyopathy: The search for a unifying hypothesis","volume":"98","author":"Poornima","year":"2006","journal-title":"Circ. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1161\/CIRCRESAHA.113.302095","article-title":"Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes","volume":"113","author":"Kolwicz","year":"2013","journal-title":"Circ. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1161\/CIRCRESAHA.121.318241","article-title":"Cardiac Energy Metabolism in Heart Failure","volume":"128","author":"Lopaschuk","year":"2021","journal-title":"Circ. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"461967","DOI":"10.1155\/2013\/461967","article-title":"Alteration of energy substrates and ROS production in diabetic cardiomyopathy","volume":"2013","author":"Lorenzo","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1016\/j.jacc.2009.07.031","article-title":"Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart","volume":"54","author":"Anderson","year":"2009","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"H118","DOI":"10.1152\/ajpheart.00932.2010","article-title":"Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways","volume":"300","author":"Anderson","year":"2011","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"391762","DOI":"10.4061\/2011\/391762","article-title":"Insulin resistance, obesity, hypertension, and renal sodium transport","volume":"2011","author":"Horita","year":"2011","journal-title":"Int. J. Hypertens."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.maturitas.2018.03.013","article-title":"Hypertension in patients with type 2 diabetes mellitus: Targets and management","volume":"112","author":"Pavlou","year":"2018","journal-title":"Maturitas"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.echo.2014.10.003","article-title":"Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging","volume":"28","author":"Lang","year":"2015","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.1093\/eurheartj\/ehy339","article-title":"2018 ESC\/ESH Guidelines for the management of arterial hypertension","volume":"39","author":"Williams","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/eurheartj\/ehz486","article-title":"2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD","volume":"41","author":"Cosentino","year":"2020","journal-title":"Eur. Heart J."},{"key":"ref_17","first-page":"e918972","article-title":"Echocardiographic Changes in Newly Diagnosed Type 2 Diabetes Mellitus Patients with and without Hypertension","volume":"26","author":"Zhao","year":"2020","journal-title":"Med. Sci. Monit."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"a025924","DOI":"10.1101\/cshperspect.a025924","article-title":"Inhibition of the Mechanistic Target of Rapamycin (mTOR)-Rapamycin and Beyond","volume":"6","author":"Lamming","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1016\/j.bbadis.2012.07.008","article-title":"The role of AMPK\/mTOR\/S6K1 signaling axis in mediating the physiological process of exercise-induced insulin sensitization in skeletal muscle of C57BL\/6 mice","volume":"1822","author":"Liu","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.molcel.2008.03.003","article-title":"AMPK phosphorylation of raptor mediates a metabolic checkpoint","volume":"30","author":"Gwinn","year":"2008","journal-title":"Mol. Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/j.mehy.2015.08.019","article-title":"Inflammasome, mTORC1 activation, and metabolic derangement contribute to the susceptibility of diabetics to infections","volume":"85","author":"Krakauer","year":"2015","journal-title":"Med. Hypotheses"},{"key":"ref_22","first-page":"1452696","article-title":"PGC-1alpha, Inflammation, and Oxidative Stress: An Integrative View in Metabolism","volume":"2020","author":"Millan","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Botta, A., Laher, I., Beam, J., Decoffe, D., Brown, K., Halder, S., Devlin, A., Gibson, D.L., and Ghosh, S. (2013). Short term exercise induces PGC-1alpha, ameliorates inflammation and increases mitochondrial membrane proteins but fails to increase respiratory enzymes in aging diabetic hearts. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070248"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"29","DOI":"10.21775\/cimb.028.029","article-title":"PGC-1: The Energetic Regulator in Cardiac Metabolism","volume":"28","author":"Di","year":"2018","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1128\/MCB.20.5.1868-1876.2000","article-title":"The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes","volume":"20","author":"Vega","year":"2000","journal-title":"Mol. Cell. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"Mootha","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"753","DOI":"10.3389\/fendo.2018.00753","article-title":"Metformin-Induced Mitochondrial Complex I Inhibition: Facts, Uncertainties, and Consequences","volume":"9","author":"Fontaine","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/s41440-017-0008-y","article-title":"Hypertension with diabetes mellitus complications","volume":"41","author":"Yamazaki","year":"2018","journal-title":"Hypertens. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1161\/HYPERTENSIONAHA.121.17981","article-title":"Hypertension in Diabetes: An Update of Basic Mechanisms and Clinical Disease","volume":"78","author":"Jia","year":"2021","journal-title":"Hypertension"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1161\/HYPERTENSIONAHA.110.162446","article-title":"Cardiovascular outcomes in framingham participants with diabetes: The importance of blood pressure","volume":"57","author":"Chen","year":"2011","journal-title":"Hypertension"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.phrs.2017.05.013","article-title":"Obesity and hypertension","volume":"122","author":"Seravalle","year":"2017","journal-title":"Pharm. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1161\/CIRCRESAHA.119.315714","article-title":"PKG1alpha Cysteine-42 Redox State Controls mTORC1 Activation in Pathological Cardiac Hypertrophy","volume":"127","author":"Oeing","year":"2020","journal-title":"Circ. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1161\/CIRCRESAHA.120.317710","article-title":"MTORC1-Regulated Metabolism Controlled by TSC2 Limits Cardiac Reperfusion Injury","volume":"128","author":"Oeing","year":"2021","journal-title":"Circ. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.jbior.2019.03.003","article-title":"Diverse signaling mechanisms of mTOR complexes: mTORC1 and mTORC2 in forming a formidable relationship","volume":"72","author":"Wainwright","year":"2019","journal-title":"Adv. Biol. Regul."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2132","DOI":"10.1161\/CIRCULATIONAHA.113.003638","article-title":"Mechanistic target of rapamycin complex 2 protects the heart from ischemic damage","volume":"128","author":"Volkers","year":"2013","journal-title":"Circulation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/emmm.201303183","article-title":"PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity","volume":"6","author":"Volkers","year":"2014","journal-title":"EMBO Mol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.cmet.2014.03.018","article-title":"Grb10 promotes lipolysis and thermogenesis by phosphorylation-dependent feedback inhibition of mTORC1","volume":"19","author":"Liu","year":"2014","journal-title":"Cell Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6618","DOI":"10.1038\/s41598-017-07011-3","article-title":"Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1alpha and mTORC1: Role of protein farnesylation","volume":"7","author":"Nakazawa","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2728","DOI":"10.1002\/art.39791","article-title":"Mitochondrial Dysfunction in the Liver and Antiphospholipid Antibody Production Precede Disease Onset and Respond to Rapamycin in Lupus-Prone Mice","volume":"68","author":"Oaks","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e13086","DOI":"10.1111\/acel.13086","article-title":"Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment","volume":"19","author":"Quarles","year":"2020","journal-title":"Aging Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/s41598-018-36265-8","article-title":"Mechanistic Target of Rapamycin Complex 1 Promotes the Expression of Genes Encoding Electron Transport Chain Proteins and Stimulates Oxidative Phosphorylation in Primary Human Trophoblast Cells by Regulating Mitochondrial Biogenesis","volume":"9","author":"Rosario","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.biochi.2015.09.006","article-title":"Palmitate activates mTOR\/p70S6K through AMPK inhibition and hypophosphorylation of raptor in skeletal muscle cells: Reversal by oleate is similar to metformin","volume":"118","author":"Kwon","year":"2015","journal-title":"Biochimie"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3389\/fcvm.2018.00068","article-title":"Loss of Metabolic Flexibility in the Failing Heart","volume":"5","author":"Karwi","year":"2018","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1161\/CIRCULATIONAHA.122.061846","article-title":"Myocardial Metabolomics of Human Heart Failure With Preserved Ejection Fraction","volume":"147","author":"Hahn","year":"2023","journal-title":"Circulation"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nmeth.1322","article-title":"Universal sample preparation method for proteome analysis","volume":"6","author":"Wisniewski","year":"2009","journal-title":"Nat. Methods"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/nmeth.3901","article-title":"The Perseus computational platform for comprehensive analysis of (prote)omics data","volume":"13","author":"Tyanova","year":"2016","journal-title":"Nat. Methods"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s12933-017-0643-2","article-title":"Sitagliptin improved glucose assimilation in detriment of fatty-acid utilization in experimental type-II diabetes: Role of GLP-1 isoforms in Glut4 receptor trafficking","volume":"17","author":"Ramirez","year":"2018","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.cell.2017.03.001","article-title":"Selective Chemical Inhibition of PGC-1alpha Gluconeogenic Activity Ameliorates Type 2 Diabetes","volume":"169","author":"Sharabi","year":"2017","journal-title":"Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1007\/s10753-020-01255-4","article-title":"Overexpression of Peroxisome Proliferator-Activated Receptor gamma Coactivator 1-alpha Protects Cardiomyocytes from Lipopolysaccharide-Induced Mitochondrial Damage and Apoptosis","volume":"43","author":"Zhang","year":"2020","journal-title":"Inflammation"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1186\/1475-2840-12-172","article-title":"Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes","volume":"12","author":"Ramirez","year":"2013","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"112847","DOI":"10.1016\/j.biopha.2022.112847","article-title":"The enhanced mitochondrial dysfunction by cantleyoside confines inflammatory response and promotes apoptosis of human HFLS-RA cell line via AMPK\/Sirt 1\/NF-kappaB pathway activation","volume":"149","author":"Bai","year":"2022","journal-title":"Biomed. Pharm."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8629\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:33:18Z","timestamp":1760124798000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8629"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,11]]},"references-count":51,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24108629"],"URL":"https:\/\/doi.org\/10.3390\/ijms24108629","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,11]]}}}