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Peroxisome proliferator\u2010activated receptor\u2010gamma coactivator\u20101 alpha (PGC1\u03b1), a regulator of mitochondrial biogenesis, is often reduced in cachectic skeletal muscle. Overexpression of PGC1\u03b1 has yielded mixed beneficial results in cancer cachexia, yet investigations using such approach in a chemotherapy setting are limited. Utilizing transgenic mice, we assessed whether overexpression of PGC1\u03b1 could combat the skeletal muscle consequences of cisplatin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Young (2\u00a0month) and old (18\u00a0month) wild\u2010type (WT) and PGC1\u03b1 transgenic male and female mice (Tg) were injected with cisplatin (C; 2.5\u00a0mg\/kg) for 2\u00a0weeks, while control animals received saline (<jats:italic>n<\/jats:italic>\u00a0=\u00a05\u20139\/group). Animals were assessed for muscle mass and force, motor unit connectivity, and expression of mitochondrial proteins.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Young WT\u00a0+\u00a0C mice displayed reduced gastrocnemius mass (male: \u221216%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001; female: \u221211%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), muscle force (\u22126%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05, both sexes), and motor unit number estimation (MUNE; male: \u221253%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01; female: \u221251%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Old WT\u00a0+\u00a0C male and female mice exhibited gastrocnemius wasting (male: \u221222%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05; female: \u221227%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), muscle weakness (male: \u221220%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001; female: \u221217%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), and loss of MUNE (male: \u221282%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01; female: \u221262%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), suggesting exacerbated cachexia compared with younger animals. Overexpression of PGC1\u03b1 had mild protective effects on muscle mass in young Tg\u00a0+\u00a0C male only (gastrocnemius: +10%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05); however, force and MUNE were unchanged in both young Tg\u00a0+\u00a0C male and female, suggesting preservation of neuromuscular function. In older male, protective effects associated with PGC1\u03b1 overexpression were heighted with Tg\u00a0+\u00a0C demonstrating preserved muscle mass (gastrocnemius: +34%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001), muscle force (+13%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01), and MUNE (+3\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Similarly, old female Tg\u00a0+\u00a0C did not exhibit muscle wasting or reductions in MUNE, and had preserved muscle force (+11%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) compared with female WT\u00a0+\u00a0C. Follow\u2010up molecular analysis demonstrated that aged WT animals were more susceptible to cisplatin\u2010induced loss of mitochondrial proteins, including PGC1\u03b1, OPA1, cytochrome\u2010C, and Cox IV.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In our study, the negative effects of cisplatin were heighted in aged animals, whereas overexpression of PGC1\u03b1 was sufficient to combat the neuromuscular dysfunction caused by cisplatin, especially in older animals. Hence, our observations indicate that aged animals may be more susceptible to develop chemotherapy side toxicities and that mitochondria\u2010targeted strategies may serve as a tool to prevent chemotherapy\u2010induced muscle wasting and weakness.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13035","type":"journal-article","created":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T06:42:25Z","timestamp":1659076945000},"page":"2480-2491","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["PGC1\u03b1 overexpression preserves muscle mass and function in cisplatin\u2010induced cachexia"],"prefix":"10.1002","volume":"13","author":[{"given":"Joshua R.","family":"Huot","sequence":"first","affiliation":[{"name":"Department of Surgery Indiana University School of Medicine  Indianapolis IN USA"},{"name":"Department of Anatomy, Cell Biology &amp; Physiology Indiana University School of Medicine  Indianapolis IN 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