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Muscle wasting remains an unmet need for metabolic disease, and new approaches are warranted. The neuropeptide urocortin 2 (UCN2) and its receptor corticotropin releasing factor receptor 2 (CRHR2) are highly expressed in skeletal muscle and play a role in regulating energy balance, glucose metabolism, and muscle mass. The aim of this study was to investigate the effects of modified UCN2 peptides as a pharmaceutical therapy to counteract the loss of skeletal muscle mass associated with obesity and casting immobilization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      High\u2010fat\u2010fed mice (C57Bl\/6J; 26\u00a0weeks old) and ob\/ob mice (11\u00a0weeks old) were injected daily with a PEGylated (Compound A) and non\u2010PEGylated (Compound B) modified human UCN2 at 0.3\u00a0mg\/kg subcutaneously for 14\u00a0days. A separate group of chow\u2010fed C57Bl\/6J mice (12\u00a0weeks old) was subjected to hindlimb cast immobilization and, after 1\u00a0week, received daily injections with Compound A.\n                      <jats:italic>In vivo<\/jats:italic>\n                      functional tests were performed to measure protein synthesis rates and skeletal muscle function.\n                      <jats:italic>Ex vivo<\/jats:italic>\n                      functional and molecular tests were performed to measure contractile force and signal transduction of catabolic and anabolic pathways in skeletal muscle.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Skeletal muscles (\n                      <jats:italic>extensor digitorum longus<\/jats:italic>\n                      ,\n                      <jats:italic>soleus<\/jats:italic>\n                      , and\n                      <jats:italic>tibialis anterior<\/jats:italic>\n                      ) from high\u2010fat\u2010fed mice treated with Compound A were ~14% heavier than muscles from vehicle\u2010treated mice. Chronic treatment with modified UCN2 peptides altered the expression of structural genes and transcription factors in skeletal muscle in high\u2010fat diet\u2010induced obesity including down\u2010regulation of\n                      <jats:italic>Trim63<\/jats:italic>\n                      and up\u2010regulation of\n                      <jats:italic>Nr4a2<\/jats:italic>\n                      and\n                      <jats:italic>Igf1<\/jats:italic>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05 vs. vehicle). Signal transduction via both catabolic and anabolic pathways was increased in\n                      <jats:italic>tibialis anterior<\/jats:italic>\n                      muscle, with increased phosphorylation of ribosomal protein S6 at Ser\n                      <jats:sup>235\/236<\/jats:sup>\n                      , FOXO1 at Ser\n                      <jats:sup>256<\/jats:sup>\n                      , and ULK1 at Ser\n                      <jats:sup>317<\/jats:sup>\n                      , suggesting that UCN2 treatment modulates protein synthesis and degradation pathways (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05 vs. vehicle). Acutely, a single injection of Compound A in drug\u2010na\u00efve mice had no effect on the rate of protein synthesis in skeletal muscle, as measured via the surface sensing of translation method, while the expression of\n                      <jats:italic>Nr4a3<\/jats:italic>\n                      and\n                      <jats:italic>Ppargc1a4<\/jats:italic>\n                      was increased (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.05 vs. vehicle). Compound A treatment prevented the loss of force production from disuse due to casting. Compound B treatment increased time to fatigue during\n                      <jats:italic>ex vivo<\/jats:italic>\n                      contractions of fast\u2010twitch\n                      <jats:italic>extensor digitorum longus<\/jats:italic>\n                      muscle. Compound A and B treatment increased lean mass and rates of skeletal muscle protein synthesis in ob\/ob mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Modified human UCN2 is a pharmacological candidate for the prevention of the loss of skeletal muscle mass associated with obesity and immobilization.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.12746","type":"journal-article","created":{"date-parts":[[2021,8,2]],"date-time":"2021-08-02T22:16:21Z","timestamp":1627942581000},"page":"1232-1248","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Modified UCN2 peptide treatment improves skeletal muscle mass and function in mouse models of obesity\u2010induced insulin resistance"],"prefix":"10.1002","volume":"12","author":[{"given":"Melissa L.","family":"Borg","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Section for Integrative Physiology Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Massart","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Section for Integrative Physiology Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thais","family":"De Castro Barbosa","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Section for Integrative Physiology Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adri\u00e0","family":"Archilla\u2010Ortega","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Section for Integrative Physiology Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathon A.B.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Section for Integrative Physiology Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna T.","family":"Lanner","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Section for Molecular Muscle Physiology and Pathophysiology Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Alsina\u2010Fernandez","sequence":"additional","affiliation":[{"name":"Lilly Research Laboratories Division of Eli Lilly and Company  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Yaden","sequence":"additional","affiliation":[{"name":"Lilly Research Laboratories Division of Eli Lilly and Company  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander E.","family":"Culver","sequence":"additional","affiliation":[{"name":"Lilly Research Laboratories Division of Eli Lilly and Company  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e5kan K.R.","family":"Karlsson","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Section for Integrative Physiology Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph T.","family":"Brozinick","sequence":"additional","affiliation":[{"name":"Lilly Research Laboratories Division of Eli Lilly and Company  Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6891-7497","authenticated-orcid":false,"given":"Juleen R.","family":"Zierath","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Section for Integrative Physiology Karolinska Institutet  Stockholm Sweden"},{"name":"Department of Molecular Medicine and Surgery, Section for Integrative Physiology Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,2]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"Organization WH.Geneva. 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