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To identify early molecular changes in nerves that may drive sarcopenia initiation, we performed a longitudinal transcriptomic analysis of the sciatic nerve, which governs lower limb muscles, in aging mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Sciatic nerve and gastrocnemius muscle were obtained from female C57BL\/6JN mice aged 5, 18, 21 and 24\u00a0months old (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a06 per age group). Sciatic nerve RNA was extracted and underwent RNA sequencing (RNA\u2010seq). Differentially expressed genes (DEGs) were validated using quantitative reverse transcription PCR (qRT\u2010PCR). Functional enrichment analysis of clusters of genes associated with patterns of gene expression across age groups (adjusted\n                      <jats:italic>P<\/jats:italic>\n                      \u2010value\u00a0&lt;\u00a00.05, likelihood ratio test [LRT]) was performed. Pathological skeletal muscle aging was confirmed between 21 and 24\u00a0months by a combination of molecular and pathological biomarkers. Myofiber denervation was confirmed with qRT\u2010PCR of\n                      <jats:italic>Chrnd<\/jats:italic>\n                      ,\n                      <jats:italic>Chrng<\/jats:italic>\n                      ,\n                      <jats:italic>Myog<\/jats:italic>\n                      ,\n                      <jats:italic>Runx1<\/jats:italic>\n                      and\n                      <jats:italic>Gadd45\u0251<\/jats:italic>\n                      in gastrocnemius muscle. Changes in muscle mass, cross\u2010sectional myofiber size and percentage of fibres with centralized nuclei were analysed in a separate cohort of mice from the same colony (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a04\u20136 per age group).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We detected 51 significant DEGs in sciatic nerve of 18\u2010month\u2010old mice compared with 5\u2010month\u2010old mice (absolute value of fold change\u00a0&gt;\u00a02; false discovery rate [FDR]\u00a0&lt;\u00a00.05). Up\u2010regulated DEGs included\n                      <jats:italic>Dbp<\/jats:italic>\n                      (log\n                      <jats:sub>2<\/jats:sub>\n                      fold change [LFC]\u00a0=\u00a02.63, FDR\u00a0&lt;\u00a00.001) and\n                      <jats:italic>Lmod2<\/jats:italic>\n                      (LFC\u00a0=\u00a07.52, FDR\u00a0=\u00a00.001). Down\u2010regulated DEGs included\n                      <jats:italic>Cdh6<\/jats:italic>\n                      (LFC\u00a0=\u00a0\u221221.38, FDR\u00a0&lt;\u00a00.001) and\n                      <jats:italic>Gbp1<\/jats:italic>\n                      (LFC\u00a0=\u00a0\u221221.78, FDR\u00a0&lt;\u00a00.001). We validated RNA\u2010seq findings with qRT\u2010PCR of various up\u2010 and down\u2010regulated genes including\n                      <jats:italic>Dbp<\/jats:italic>\n                      and\n                      <jats:italic>Cdh6<\/jats:italic>\n                      . Up\u2010regulated genes (FDR\u00a0&lt;\u00a00.1) were associated with the AMP\u2010activated protein kinase signalling pathway (FDR\u00a0=\u00a00.02) and circadian rhythm (FDR\u00a0=\u00a00.02), whereas down\u2010regulated DEGs were associated with biosynthesis and metabolic pathways (FDR\u00a0&lt;\u00a00.05). We identified seven significant clusters of genes (FDR\u00a0&lt;\u00a00.05, LRT) with similar expression patterns across groups. Functional enrichment analysis of these clusters revealed biological processes that may be implicated in age\u2010related changes in skeletal muscles and\/or sarcopenia initiation including extracellular matrix organization and an immune response (FDR\u00a0&lt;\u00a00.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Gene expression changes in mouse peripheral nerve were detected prior to disturbances in myofiber innervation and sarcopenia onset. These early molecular changes we report shed a new light on biological processes that may be implicated in sarcopenia initiation and pathogenesis. Future studies are warranted to confirm the disease modifying and\/or biomarker potential of the key changes we report here.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13204","type":"journal-article","created":{"date-parts":[[2023,3,11]],"date-time":"2023-03-11T01:40:13Z","timestamp":1678498813000},"page":"1322-1336","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Longitudinal transcriptomic analysis of mouse sciatic nerve reveals pathways associated with age\u2010related muscle pathology"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6827-3043","authenticated-orcid":false,"given":"Nicole","family":"Comfort","sequence":"first","affiliation":[{"name":"Department of Environmental Health Sciences, Mailman School of Public Health Columbia University  New York NY 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Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Parodi","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences, Mailman School of Public Health Columbia University  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Marcinczyk","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences, Mailman School of Public Health Columbia University  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea","family":"Jean\u2010Francois","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences, Mailman School of Public Health Columbia University  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessa R.","family":"Bloomquist","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences, Mailman School of Public 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