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Exercise is among the most effective interventions to mitigate muscle dysfunction in aging and reverse deficits. However, low attrition and an impaired capacity to exercise may limit its utility in improving muscle function in aged persons. Therefore, it is crucial to advance our mechanistic understanding of the molecular transducers of exercise to identify new and innovative drug targets to improve muscle health. Transcriptomic profiling of the human response to exercise has revealed that the nuclear receptor NR4A3 (NOR\u20101) is among the most responsive genes to acute exercise. Previously, we observed that in\u00a0vitro knockdown of NOR\u20101 alters metabolic signaling in C2C12 myotubes. Specifically, we found that expression of PERM1, CKMT2, myoglobin, and mTORC1 signaling were perturbed during the knockdown of NOR\u20101. Herein, we extend these findings and observe that a NOR\u20101\u2010PERM1\u2010myoglobin axis regulates myoglobin expression in\u00a0vitro. Furthermore, we found that aging is associated with reduced skeletal muscle NOR\u20101 expression. Although it is well known that exercise improves aged muscle function, whether overexpression of the exercise\u2010responsive gene NOR\u20101 can confer benefits and improve muscle function in an aged context has not been evaluated. We found that the overexpression of NOR\u20101 in aged muscle results in enhanced muscle endurance, mitochondrial respiration, and elevated expression of NOR\u20101 responsive genes that we previously identified in loss of function studies. However, we also observed that overexpression of NOR\u20101 did not improve maximal muscle torque production and resulted in a small but significant loss of muscle wet weight that was concomitant with elevated autophagy signaling. Our data suggest that NOR\u20101 expression may reduce muscle fatigability and that NOR\u20101 drives myoglobin expression in a PERM1\u2010dependent manner.<\/jats:p>","DOI":"10.1096\/fj.202500375r","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T03:04:07Z","timestamp":1744772647000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp>NOR<\/scp>\n                    \u20101 Overexpression Elevates Myoglobin Expression via\n                    <scp>PERM1<\/scp>\n                    and Enhances Mitochondrial Function and Endurance in Skeletal Muscles of Aged Mice"],"prefix":"10.1096","volume":"39","author":[{"given":"Hector G.","family":"Paez","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Medicine University of Tennessee Health Science Center  Memphis Tennessee USA"},{"name":"Integrated Biomedical Sciences Graduate Program, College of Graduate Health Sciences University of Tennessee Health Science Center  Memphis Tennessee USA"},{"name":"Laboratory of Muscle Biology and Sarcopenia, Department of Physical Therapy, College of Health Professions University of Tennessee Health Science Center  Memphis Tennessee USA"},{"name":"Division of Rehabilitation Sciences, Center for Muscle, Metabolism and Neuropathology, College of Health Professions University of Tennessee Health Science Center  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher R.","family":"Pitzer","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine University of Tennessee Health Science Center  Memphis Tennessee USA"},{"name":"Integrated Biomedical Sciences Graduate Program, College of Graduate Health Sciences University of Tennessee Health Science Center  Memphis Tennessee USA"},{"name":"Laboratory of Muscle Biology and Sarcopenia, Department of Physical Therapy, College of 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Physiology, College of Medicine University of Tennessee Health Science Center  Memphis Tennessee USA"},{"name":"Integrated Biomedical Sciences Graduate Program, College of Graduate Health Sciences University of Tennessee Health Science Center  Memphis Tennessee USA"},{"name":"Laboratory of Muscle Biology and Sarcopenia, Department of Physical Therapy, College of Health Professions University of Tennessee Health Science Center  Memphis Tennessee USA"},{"name":"Division of Rehabilitation Sciences, Center for Muscle, Metabolism and Neuropathology, College of Health Professions University of Tennessee Health Science Center  Memphis Tennessee 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