{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:03:26Z","timestamp":1784887406357,"version":"3.55.0"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DK119202"],"award-info":[{"award-number":["R01DK119202"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DK128823"],"award-info":[{"award-number":["R01DK128823"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH\u201016\u20100464"],"award-info":[{"award-number":["W81XWH\u201016\u20100464"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["19CDA34760244"],"award-info":[{"award-number":["19CDA34760244"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["898725"],"award-info":[{"award-number":["898725"]}],"id":[{"id":"10.13039\/100000968","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":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Heme oxygenases, HO\u20101 (\n                      <jats:italic>Hmox1<\/jats:italic>\n                      ) and HO\u20102 (\n                      <jats:italic>Hmox2<\/jats:italic>\n                      ), regulate skeletal muscle homeostasis by degrading heme and generating carbon monoxide (CO), a bioactive signalling molecule. Although HO\u20101 is known to influence muscle fibre composition and mitochondrial function, the role of HO\u20102 in activity\u2010dependent neuromuscular plasticity remains poorly understood. This study aimed to define the distinct contributions of each isoform and test whether CO could restore muscle function in HO\u2010deficient states.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We generated Hmox1\/2 double\u2010knockout mice (\n                      <jats:italic>Hmox1\/2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      ) and compared their skeletal muscle phenotype with that of single HO\u20101 or HO\u20102 knockouts and wild\u2010type (WT) controls under sedentary and exercised conditions. We evaluated endurance capacity using treadmill running (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20098\u201312 per group), assessed fibre\u2010type distribution and neuromuscular junction (NMJ) morphology via immunohistochemistry and measured mitochondrial function using high\u2010resolution respirometry. Primary neuronal cultures were analysed using multielectrode array recordings to assess firing dynamics. Inhaled CO was administered to test its capacity to rescue muscle phenotype and performance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      HO\u20101 deficiency led to a significant reduction in oxidative fibres (Type I and IIa), decreased mitochondrial respiratory capacity (reduced by ~30%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01) and diminished treadmill endurance (\u221240% running time vs. WT,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Hmox2 deficiency was associated with NMJ remodelling, increased acetylcholine receptor expression, reduced Sox2 transcription and heightened burst firing. The double deletion of HO\u20101\/HO\u20102 produced an additive phenotype characterized by severe mitochondrial dysfunction, increased glycolytic fibre content and NMJ remodelling. We identify CO, a by\u2010product of HO\u20101, as a crucial modulator of skeletal muscle adaptation, capable of compensating for HO deficiency. Treatment with CO in\n                      <jats:italic>Hmox1\/2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2212\/\u2212<\/jats:italic>\n                      <\/jats:sup>\n                      mice restored fibre\u2010type distribution toward oxidative fibres (increased by 25%,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), improved mitochondrial respiratory parameters and doubled endurance performance (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). CO also normalized mitochondrial protein expression and modulated key metabolic pathways, including nucleotide metabolism, the TCA cycle and redox balance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>HO\u20101 and HO\u20102 have distinct roles in regulating muscle phenotype and metabolic adaptation. HO\u20101 modulates mitochondrial content and muscle plasticity, whereas Hmox2 regulates, in part, activity\u2010dependent neuromuscular plasticity and responsiveness to exercise. Exogenous CO effectively restores mitochondrial and functional deficits in HO\u2010deficient muscle, mimicking endurance exercise adaptations. These findings support the therapeutic potential of CO in conditions of muscle disuse, aging or disease where exercise is limited or not feasible.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70309","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T05:55:30Z","timestamp":1778824530000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Heme Metabolism\u2010Derived Carbon Monoxide Regulates Skeletal Muscle Function"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4401-9048","authenticated-orcid":false,"given":"Rodrigo W.","family":"Alves de Souza","sequence":"first","affiliation":[{"name":"Department of Surgery, Beth Israel Deaconess Medical Center Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyo","family":"In Kim","sequence":"additional","affiliation":[{"name":"Department of Surgery, Beth Israel Deaconess Medical Center Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula Ketilly Nascimento","family":"Alves","sequence":"additional","affiliation":[{"name":"Department of Surgery, Beth Israel Deaconess Medical Center Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ailma Oliveira","family":"da Paix\u00e3o","sequence":"additional","affiliation":[{"name":"Department of Surgery, Beth Israel Deaconess Medical Center Harvard Medical School  Boston Massachusetts USA"},{"name":"School of Physical Education and Sport University of S\u00e3o Paulo  SP Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashlee","family":"Rasmussen","sequence":"additional","affiliation":[{"name":"Department of Surgery, Beth Israel Deaconess Medical Center Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidharth","family":"Shankar","sequence":"additional","affiliation":[{"name":"Department of Surgery, Beth Israel Deaconess Medical Center Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Harbison","sequence":"additional","affiliation":[{"name":"Department of Surgery, Beth Israel Deaconess Medical Center Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa Azevedo","family":"Voltarelli","sequence":"additional","affiliation":[{"name":"Department of Surgery, Beth Israel Deaconess Medical Center Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7900-0825","authenticated-orcid":false,"given":"Leo E.","family":"Otterbein","sequence":"additional","affiliation":[{"name":"Department of Surgery, Beth Israel Deaconess Medical Center Harvard Medical School  Boston Massachusetts USA"},{"name":"Department of Pharmacology, College of Korean Medicine Kyung Hee University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3228"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2021.102183"},{"key":"e_1_2_8_4_1","unstructured":"S.Wilbur M.Williams R.Williams F.Scinicariello J. M.Klotzbach andG. L.Diamond \u201cToxicological Profile for Carbon Monoxide US Agency for Toxic Substances and Disease Registry \u201d (2012): 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