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This narrative review aimed to synthesize current evidence regarding the intracellular signaling pathways, metabolic alterations, and endocrine interactions involved in obesity-induced skeletal muscle dysfunction independent of overt sarcopenia. Relevant literature from experimental, clinical, and review studies was identified through searches of PubMed, Scopus, and Web of Science databases, focusing on obesity-associated alterations in skeletal muscle metabolism, ectopic lipid accumulation, inflammatory signaling, mitochondrial dysfunction, and adipose\u2013muscle crosstalk. Current evidence indicates that obesity per se promotes skeletal muscle dysfunction through ectopic lipid deposition, lipotoxicity, mitochondrial impairment, and chronic low-grade inflammation mediated by dysregulated intracellular signaling pathways. Altered adipomyokine signaling, including interleukin-6 and tumor necrosis factor-\u03b1, further contributes to impaired insulin signaling, reduced metabolic flexibility, oxidative stress, and compromised muscle integrity. These molecular and cellular alterations reinforce skeletal muscle as both a target and an active regulator of obesity-associated metabolic inflammation. Collectively, these findings support the concept that obesity intrinsically disrupts skeletal muscle metabolic and endocrine homeostasis independently of sarcopenic obesity and highlight the importance of targeted strategies aimed at preserving skeletal muscle metabolic function and overall metabolic health.<\/jats:p>","DOI":"10.1007\/s11033-026-12146-6","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T12:10:01Z","timestamp":1782216601000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cellular and molecular pathways linking obesity to skeletal muscle dysfunction"],"prefix":"10.1007","volume":"53","author":[{"given":"Diego","family":"Pinheiro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anabelle Silva","family":"Cornachione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"12146_CR1","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/S0140-6736(25)00397-6","volume":"405","author":"GBD 2021 Obesity Collaborators","year":"2025","unstructured":"GBD 2021 Obesity Collaborators (2025) Global, regional, and national prevalence of adult overweight and obesity, 1990\u20132021, with forecasts to 2050. 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