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The maintenance of skeletal muscle mass is essential for health, yet the molecular and signaling mechanisms that control skeletal muscle mass remain poorly understood. Transforming growth factor\u2010\u03b2\u2010activated kinase 1 (TAK1) is a key signaling protein that regulates multiple intracellular pathways. Recent studies have demonstrated that TAK1 is a critical regulator of skeletal muscle mass. However, the mechanisms by which TAK1 regulates muscle mass and whether its role is sex\u2010dependent remain incompletely understood. In this study, we show that targeted inactivation of TAK1 induces muscle atrophy more rapidly in male than in female mice. Loss of TAK1 activity also abolished mechanical overload\u2010induced phosphorylation of p70S6K and rpS6, and the induction of myofiber hypertrophy in both sexes. RNA\u2010Seq analysis further revealed that TAK1 inactivation in skeletal muscle disrupts the gene expression of various molecules involved in catabolic processes, calcium signaling, muscle structure development, and aerobic respiration. Moreover, TAK1 inactivation impairs fatty acid oxidation and promotes lipid accumulation in skeletal muscle of adult mice in a sex\u2010independent manner. Collectively, our findings demonstrate that TAK1 regulates skeletal muscle mass and growth by coordinating distinct intracellular pathways in both male and female mice.<\/jats:p>","DOI":"10.1096\/fj.202601212r","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T14:29:37Z","timestamp":1778596177000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>TAK1<\/scp>\n                    Regulates Skeletal Muscle Mass, Hypertrophic Signaling, and Metabolic Homeostasis in Male and Female Mice"],"prefix":"10.1096","volume":"40","author":[{"given":"Meiricris","family":"Tomaz da Silva","sequence":"first","affiliation":[{"name":"Institute of Muscle Biology and Cachexia University of Houston  Houston Texas USA"},{"name":"Department of Pharmacological and Pharmaceutical Sciences University of Houston College of Pharmacy  Houston Texas 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