{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T14:41:10Z","timestamp":1783953670890,"version":"3.55.0"},"reference-count":44,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL160820"],"award-info":[{"award-number":["R01HL160820"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Theodore F. Hubbard Foundation and NIH","award":["R01HL153175"],"award-info":[{"award-number":["R01HL153175"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Background: Aging elevates reactive oxygen species (ROS) and weakens antioxidant defenses, contributing to cardiac dysfunction. The objective of this study was to determine whether sustained activation of skeletal muscle (SkM) Nrf2 preserves cardiac function during aging and to explore the underlying mechanisms, focusing on myocardial antioxidant pathways. Methods: Tamoxifen-induced SkM-specific Keap1 knockout male mice (iMS-Keap1flox\/flox; SkM-Nrf2 overexpression) were divided into young wild-type (Y-WT), aged wild-type (A-WT), and aged knockout (A-KO) groups. Cardiac performance was evaluated by echocardiography and invasive hemodynamics. Myocardial proteomics identified differentially expressed proteins (DEPs) and enriched biological pathways. Results: Compared with Y-WT, A-WT mice showed impaired left ventricular function, including reduced ejection fraction, prolonged isovolumic relaxation time, blunted inotropic response to dobutamine, and elevated Tau index. These age-related deficits were partially reversed in A-KO mice. Proteomic analysis revealed 561 DEPs between A-WT and Y-WT, and 741 DEPs between A-KO and A-WT, enriched in calcium signaling, Nrf2-mediated oxidative stress response, oxidative phosphorylation, ROS detoxification, and cardiac-specific processes, such as hypertrophy, conduction, and dilated cardiomyopathy. Conclusions: Lifelong SkM-Nrf2 activation strengthens myocardial antioxidant capacity and alleviates age-related cardiac dysfunction. These data support an antioxidant crosstalk between skeletal muscle and the heart, highlighting a potential therapeutic target for aging-associated heart failure.<\/jats:p>","DOI":"10.3390\/antiox14121491","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T09:37:48Z","timestamp":1765532268000},"page":"1491","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Lifetime Deletion of Skeletal Muscle Keap1 Attenuates Aging-Induced Cardiac Dysfunction via an Nrf2\u2013Antioxidant Mechanism"],"prefix":"10.3390","volume":"14","author":[{"given":"Kanika","family":"Sharma","sequence":"first","affiliation":[{"name":"Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri Campus, Kollam 690525, Kerala, India"},{"name":"Multiomics Mass Spectrometry and Proteomics Core Facility, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4528-4836","authenticated-orcid":false,"given":"Sarah","family":"Pribil Pardun","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0853-5758","authenticated-orcid":false,"given":"Neha","family":"Dhyani","sequence":"additional","affiliation":[{"name":"Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3636-7720","authenticated-orcid":false,"given":"Irving H.","family":"Zucker","sequence":"additional","affiliation":[{"name":"Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bipin G.","family":"Nair","sequence":"additional","affiliation":[{"name":"Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri Campus, Kollam 690525, Kerala, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudarslal Sadasivan","family":"Nair","sequence":"additional","affiliation":[{"name":"Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri Campus, Kollam 690525, Kerala, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biotechnology, UMass Chan Medical School, Shrewsbury, MA 01545, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7880-7213","authenticated-orcid":false,"given":"Lie","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1161\/CIRCRESAHA.119.315889","article-title":"Targeting Age-Related Pathways in Heart Failure","volume":"126","author":"Li","year":"2020","journal-title":"Circ. 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