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We focused on L\u2010citrulline, a precursor of L\u2010arginine, required for NO production in muscle, which is reduced in dystrophic\n                      <jats:italic>mdx<\/jats:italic>\n                      muscle.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      L\u2010Citrulline was administered (2\u00a0mg\u2009g\n                      <jats:sup>\u22121<\/jats:sup>\n                      \u2009die\n                      <jats:sup>\u22121<\/jats:sup>\n                      ), through diet, in comparison and\/or in combination with prednisolone (1\u00a0mg\u2009kg\n                      <jats:sup>\u22121<\/jats:sup>\n                      , 5\u00a0days per week subcutaneously) to 4\u2010 to 5\u2010week\u2010old\n                      <jats:italic>mdx<\/jats:italic>\n                      mice for 8\u00a0weeks.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      L\u2010Citrulline increased the levels of L\u2010arginine, L\u2010citrulline and L\u2010ornithine in plasma and quadriceps of\n                      <jats:italic>mdx<\/jats:italic>\n                      mice. L\u2010citrulline, alone or plus prednisolone, significantly improved maximal forelimb force in vivo, while ameliorating diaphragm movement amplitude and reducing diaphragm echodensity. In parallel, ex vivo, we detected a significant improvement of diaphragm force and contraction kinetics in mice treated with L\u2010citrulline alone or in combination with prednisolone. L\u2010citrulline also restored the expression of genes involved in Ca\n                      <jats:sup>2+<\/jats:sup>\n                      handling during contraction (\n                      <jats:italic>RyR1<\/jats:italic>\n                      ,\n                      <jats:italic>RyR3<\/jats:italic>\n                      and\n                      <jats:italic>SERCA<\/jats:italic>\n                      ), while reducing the markers of inflammation and fibrosis (\n                      <jats:italic>CD68<\/jats:italic>\n                      and\n                      <jats:italic>TGF\u03b21<\/jats:italic>\n                      ) and ameliorating mitochondrial biogenesis\u2010associated genes (\n                      <jats:italic>PGC1\u2010\u03b1<\/jats:italic>\n                      and\n                      <jats:italic>MEF2C<\/jats:italic>\n                      ). No effect was observed on S\u2010nitrosylation levels of HDAC2 and on diaphragm and gastrocnemius nNOS gene expression, suggesting a NO\u2010independent mechanism underlying the positive outcome observed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our results revealed the ability of L\u2010citrulline supplementation to ameliorate in vivo and ex vivo function of diaphragm muscle, highlighting novel metabolic and calcium\u2010related mechanisms of potential clinical interest.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70437","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:30:44Z","timestamp":1776904244000},"page":"3866-3884","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Diaphragm\u2010specific effects of L\u2010citrulline in\n                    <i>mdx<\/i>\n                    mice highlight its potential as adjuvant of standard therapy in Duchenne muscular dystrophy"],"prefix":"10.1111","volume":"183","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2177-6152","authenticated-orcid":false,"given":"Lisamaura","family":"Tulimiero","sequence":"first","affiliation":[{"name":"Section of Pharmacology, Department of Pharmacy\u2014Drug Sciences University of Bari \u201cAldo Moro\u201d  Bari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1078-8490","authenticated-orcid":false,"given":"Brigida","family":"Boccanegra","sequence":"additional","affiliation":[{"name":"Section of Pharmacology, Department of Pharmacy\u2014Drug Sciences University of Bari \u201cAldo Moro\u201d  Bari 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