{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:04:31Z","timestamp":1787508271733,"version":"build-2736575974"},"reference-count":41,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T00:00:00Z","timestamp":1721088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Rappaport Family Institute for Research in the Medical Sciences"},{"name":"the Groupe de Bibliographie Endocrinienne"},{"name":"Y. Rabinovitch Fellowship on Juvenile Diabetes"},{"name":"Rambam Medical Center Research Grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Excessive calorie intake leads to mitochondrial overload and triggers metabolic inflexibility and insulin resistance. In this study, we examined how attenuated p38\u03b1 activity affects glucose and fat metabolism in the skeletal muscles of mice on a high-fat diet (HFD). Mice exhibiting diminished p38\u03b1 activity (referred to as p38\u03b1AF) gained more weight and displayed elevated serum insulin levels, as well as a compromised response in the insulin tolerance test, compared to the control mice. Additionally, their skeletal muscle tissue manifested impaired insulin signaling, leading to resistance in insulin-mediated glucose uptake. Examination of muscle metabolites in p38\u03b1AF mice revealed lower levels of glycolytic intermediates and decreased levels of acyl-carnitine metabolites, suggesting reduced glycolysis and \u03b2-oxidation compared to the controls. Additionally, muscles of p38\u03b1AF mice exhibited severe abnormalities in their mitochondria. Analysis of myotubes derived from p38\u03b1AF mice revealed reduced mitochondrial respiratory capacity relative to the myotubes of the control mice. Furthermore, these myotubes showed decreased expression of Acetyl CoA Carboxylase 2 (ACC2), leading to increased fatty acid oxidation and diminished inhibitory phosphorylation of pyruvate dehydrogenase (PDH), which resulted in elevated mitochondrial pyruvate oxidation. The expected consequence of reduced mitochondrial respiratory function and uncontrolled nutrient oxidation observed in p38\u03b1AF myotubes mitochondrial overload and metabolic inflexibility. This scenario explains the increased likelihood of insulin resistance development in the muscles of p38\u03b1AF mice compared to the control mice on a high-fat diet. In summary, within skeletal muscles, p38\u03b1 assumes a crucial role in orchestrating the mitochondrial adaptation to caloric surplus by promoting mitochondrial biogenesis and regulating the selective oxidation of nutrients, thereby preventing mitochondrial overload, metabolic inflexibility, and insulin resistance.<\/jats:p>","DOI":"10.3390\/ijms25147789","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T16:35:58Z","timestamp":1721234158000},"page":"7789","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["P38\u03b1 MAPK Coordinates Mitochondrial Adaptation to Caloric Surplus in Skeletal Muscle"],"prefix":"10.3390","volume":"25","author":[{"given":"Liron","family":"Waingerten-Kedem","sequence":"first","affiliation":[{"name":"Department of Biochemistry, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, P.O. Box 9649, Bat Galim, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Aviram","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, P.O. Box 9649, Bat Galim, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achinoam","family":"Blau","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, P.O. Box 9649, Bat Galim, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony","family":"Hayek","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, P.O. Box 9649, Bat Galim, Haifa 31096, Israel"},{"name":"Department of Internal Medicine E, Rambam Health Care Campus, P.O. Box 9602, Bat Galim, Haifa 31096, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eyal","family":"Bengal","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, P.O. 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Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"50230","DOI":"10.1074\/jbc.M200958200","article-title":"Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)\u2014Associated phosphatidylinositol 3-kinase activity in muscle","volume":"277","author":"Yu","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/S0140-6736(63)91500-9","article-title":"The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus","volume":"1","author":"Randle","year":"1963","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.cmet.2007.10.013","article-title":"Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance","volume":"7","author":"Koves","year":"2008","journal-title":"Cell Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.cmet.2012.04.010","article-title":"Lipid-induced mitochondrial stress and insulin action in muscle","volume":"15","author":"Muoio","year":"2012","journal-title":"Cell Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"22840","DOI":"10.1074\/jbc.M109.032888","article-title":"Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control","volume":"284","author":"Noland","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1053\/meta.2000.6250","article-title":"Acetyl-L-carnitine infusion increases glucose disposal in type 2 diabetic patients","volume":"49","author":"Giancaterini","year":"2000","journal-title":"Metabolism"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1016\/S0140-6736(10)60408-4","article-title":"Lipid-induced insulin resistance: Unravelling the mechanism","volume":"375","author":"Samuel","year":"2010","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.2337\/db06-0783","article-title":"Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients","volume":"56","author":"Befroy","year":"2007","journal-title":"Diabetes"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3587","DOI":"10.1172\/JCI25151","article-title":"Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents","volume":"115","author":"Morino","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1056\/NEJMoa031314","article-title":"Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes","volume":"350","author":"Petersen","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sanz-Ezquerro, J.J., and Cuenda, A. (2021). p38 Signalling Pathway. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031003"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Bengal, E., Aviram, S., and Hayek, T. (2020). p38 MAPK in Glucose Metabolism of Skeletal Muscle: Beneficial or Harmful?. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186480"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1038\/nature00904","article-title":"Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres","volume":"418","author":"Lin","year":"2002","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.cmet.2011.03.008","article-title":"PGC-1 coactivators and the regulation of skeletal muscle fiber-type determination","volume":"13","author":"Handschin","year":"2011","journal-title":"Cell Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1016\/j.freeradbiomed.2009.08.014","article-title":"Oxidant stress-induced loss of IRS-1 and IRS-2 proteins in rat skeletal muscle: Role of p38 MAPK","volume":"47","author":"Archuleta","year":"2009","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"17070","DOI":"10.1074\/jbc.M312021200","article-title":"Tumor necrosis factor alpha produces insulin resistance in skeletal muscle by activation of inhibitor kappaB kinase in a p38 MAPK-dependent manner","volume":"279","author":"Teruel","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/embor.2010.160","article-title":"MAPK signalling in cellular metabolism: Stress or wellness?","volume":"11","author":"Gehart","year":"2010","journal-title":"EMBO Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1007\/s00125-003-1196-3","article-title":"Aberrant p38 mitogen-activated protein kinase signalling in skeletal muscle from Type 2 diabetic patients","volume":"46","author":"Koistinen","year":"2003","journal-title":"Diabetologia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"624","DOI":"10.2337\/db17-0826","article-title":"Skeletal Muscle-Specific Deletion of MKP-1 Reveals a p38 MAPK\/JNK\/Akt Signaling Node That Regulates Obesity-Induced Insulin Resistance","volume":"67","author":"Lawan","year":"2018","journal-title":"Diabetes"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3817","DOI":"10.1172\/JCI39054","article-title":"MAPK phosphatase-1 facilitates the loss of oxidative myofibers associated with obesity in mice","volume":"119","author":"Roth","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.cmet.2006.05.010","article-title":"Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity","volume":"4","author":"Wu","year":"2006","journal-title":"Cell Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.devcel.2009.05.009","article-title":"p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age","volume":"17","author":"Wong","year":"2009","journal-title":"Dev. Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1042\/bst0311274","article-title":"Regulation of PDH activity and isoform expression: Diet and exercise","volume":"31","author":"Peters","year":"2003","journal-title":"Biochem. Soc. Trans."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chandel, N.S. (2021). Amino Acid Metabolism. Cold Spring Harb. Perspect. Biol., 13.","DOI":"10.1101\/cshperspect.a040584"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"116539","DOI":"10.1016\/j.bone.2022.116539","article-title":"Lipid metabolism in sarcopenia","volume":"164","author":"Debruin","year":"2022","journal-title":"Bone"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/nrd2589","article-title":"Fatty acid-binding proteins: Role in metabolic diseases and potential as drug targets","volume":"7","author":"Furuhashi","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_30","first-page":"E1","article-title":"Malonyl-CoA, fuel sensing, and insulin resistance","volume":"276","author":"Ruderman","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jcb.240550002","article-title":"Glucose fatty acid interactions and the regulation of glucose disposal","volume":"55","author":"Randle","year":"1994","journal-title":"J. Cell Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1042\/BJ20082055","article-title":"AMPK and the biochemistry of exercise: Implications for human health and disease","volume":"418","author":"Richter","year":"2009","journal-title":"Biochem. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/febs.15070","article-title":"P38alpha MAPK coordinates the activities of several metabolic pathways that together induce atrophy of denervated muscles","volume":"287","author":"Odeh","year":"2020","journal-title":"FEBS J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"718","DOI":"10.18632\/aging.100802","article-title":"Attenuation of p38alpha MAPK stress response signaling delays the in vivo aging of skeletal muscle myofibers and progenitor cells","volume":"7","author":"Papaconstantinou","year":"2015","journal-title":"Aging"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/oby.2007.104","article-title":"Retinoic acid treatment increases lipid oxidation capacity in skeletal muscle of mice","volume":"16","author":"Amengual","year":"2008","journal-title":"Obesity"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/emm.2003.4","article-title":"Acetyl-CoA carboxylase beta expression mediated by MyoD and muscle regulatory factor 4 is differentially affected by retinoic acid receptor and retinoid X receptor","volume":"35","author":"Kim","year":"2003","journal-title":"Exp. Mol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1002\/jcb.20944","article-title":"Expression of genes regulating malonyl-CoA in human skeletal muscle","volume":"99","author":"Pender","year":"2006","journal-title":"J. Cell Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1007\/s11302-017-9577-0","article-title":"Colonic motor dysfunctions in a mouse model of high-fat diet-induced obesity: An involvement of A(2B) adenosine receptors","volume":"13","author":"Antonioli","year":"2017","journal-title":"Purinergic Signal."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/bs.mie.2015.05.016","article-title":"Analysis of Cell Metabolism Using LC-MS and Isotope Tracers","volume":"561","author":"Mackay","year":"2015","journal-title":"Methods Enzym."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/978-1-61779-343-1_2","article-title":"Skeletal muscle satellite cells: Background and methods for isolation and analysis in a primary culture system","volume":"798","author":"Danoviz","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Sivandzade, F., Bhalerao, A., and Cucullo, L. (2019). Analysis of the Mitochondrial Membrane Potential Using the Cationic JC-1 Dye as a Sensitive Fluorescent Probe. Bio. Protoc, 9.","DOI":"10.21769\/BioProtoc.3128"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/14\/7789\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:17:50Z","timestamp":1760109470000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/14\/7789"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,16]]},"references-count":41,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["ijms25147789"],"URL":"https:\/\/doi.org\/10.3390\/ijms25147789","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,16]]}}}