{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T03:07:52Z","timestamp":1789614472489,"version":"build-2803163510"},"reference-count":42,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,10,25]],"date-time":"2023-10-25T00:00:00Z","timestamp":1698192000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AR078903"],"award-info":[{"award-number":["R01 AR078903"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>This study was designed to develop an understanding of the pathophysiology of traumatic muscle injury in the context of Western diet (WD; high fat and high sugar) and obesity. The objective was to interrogate the combination of WD and injury on skeletal muscle mass and contractile and metabolic function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Male and female C57BL\/6J mice were randomized into four groups based on a two\u2010factor study design: (1) injury (uninjured vs. volumetric muscle loss [VML]) and (2) diet (WD vs. normal chow [NC]). Electrophysiology was used to test muscle strength and metabolic function in cohorts of uninjured\u00a0+\u00a0NC, uninjured\u00a0+\u00a0WD, VML\u00a0+\u00a0NC and VML\u00a0+\u00a0WD at 8\u00a0weeks of intervention.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      VML\u2010injured male and female mice both exhibited decrements in muscle mass (\u221217%,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.001) and muscle strength (\u221228%,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.001); however, VML\u00a0+\u00a0WD females had a 28% greater muscle mass compared to VML\u00a0+\u00a0NC females (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.034), a compensatory response not detected in males. VML\u2010injured male and female mice both had lower carbohydrate\u2010 and fat\u2010supported muscle mitochondrial respiration (\n                      <jats:italic>J<\/jats:italic>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      ) and less electron conductance through the electron transport system (ETS); however, male VML\u2013WD had 48% lower carbohydrate\u2010supported\n                      <jats:italic>J<\/jats:italic>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.014) and 47% less carbohydrate\u2010supported electron conductance (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.026) compared to male VML\u00a0+\u00a0NC, and this diet\u2013injury phenotype was not present in females. ETS electron conductance starts with complex I and complex II dehydrogenase enzymes at the inner mitochondrial membrane, and male VML\u00a0+\u00a0WD had 31% less complex I activity (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.004) and 43% less complex II activity (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.005) compared to male VML\u00a0+\u00a0NC. This was a diet\u2013injury phenotype not present in females. Pyruvate dehydrogenase (PDH), \u03b2\u2010hydroxyacyl\u2010CoA dehydrogenase, citrate synthase, \u03b1\u2010ketoglutarate dehydrogenase and malate dehydrogenase metabolic enzyme activities were evaluated as potential drivers of impaired\n                      <jats:italic>J<\/jats:italic>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      in the context of diet and injury. There were notable male and female differential effects in the enzyme activity and post\u2010translational regulation of PDH. PDH enzyme activity was 24% less in VML\u2010injured males, independent of diet (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&lt;\u00a00.001), but PDH enzyme activity was not influenced by injury in females. PDH enzyme activity is inhibited by phosphorylation at serine\u2010293 by PDH kinase 4 (PDK4). In males, there was greater total PDH, phospho\u2010PDH\n                      <jats:sup>ser293<\/jats:sup>\n                      and phospho\u2010PDH\u2010to\u2010total PDH ratio in WD mice compared to NC, independent of injury (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0\u2264\u00a00.041). In females, PDK4 was 51% greater in WD compared to NC, independent of injury (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.025), and was complemented by greater phospho\u2010PDH\n                      <jats:sup>ser293<\/jats:sup>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Males are more susceptible to muscle metabolic dysfunction in the context of combined WD and traumatic injury compared to females, and this may be due to impaired metabolic enzyme functions.<\/jats:p>\n                  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