{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T00:32:35Z","timestamp":1777941155150,"version":"3.51.4"},"reference-count":55,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T00:00:00Z","timestamp":1760745600000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01\u2010HL149704"],"award-info":[{"award-number":["R01\u2010HL149704"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01\u2010HL171050"],"award-info":[{"award-number":["R01\u2010HL171050"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["24PRE1191760"],"award-info":[{"award-number":["24PRE1191760"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Physiological Reports"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Peripheral artery disease (PAD) impairs limb perfusion, walking ability, and increases the risk of amputation. Although current therapies reduce cardiovascular events, few interventions improve skeletal muscle function in PAD. Nicotinamide adenine dinucleotide (NAD\n                    <jats:sup>+<\/jats:sup>\n                    ) metabolism is disrupted in PAD. Thus, it was hypothesized that inhibition of nicotinamide N\u2010methyltransferase (NNMT), an enzyme that diverts precursors from the NAD\n                    <jats:sup>+<\/jats:sup>\n                    salvage pathway, would improve ischemic limb function. We analyzed NAD\n                    <jats:sup>+<\/jats:sup>\n                    pathway expression in gastrocnemius muscle from patients with and without PAD using RNA sequencing and proteomics datasets. Single\u2010cell RNA sequencing data were used to assess NNMT expression in muscle stem cells (MuSCs) from BALB\/cJ and C57BL\/6J mice following hindlimb ischemia (HLI). Male BALB\/cJ mice (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200924) were randomized to either placebo or a NNMT inhibitor (NNMTi) delivered 3\u2009h prior to HLI and daily thereafter. Functional assessments included laser Doppler perfusion imaging, muscle contractility, and a 6\u2010min limb function test. Histological analyses were used to assess myofiber area and capillary density. NNMT mRNA and protein levels were significantly elevated in skeletal muscle from patients with PAD and were persistently elevated in MuSCs from BALB\/cJ mice after HLI. NNMTi treatment did not affect limb perfusion recovery or capillary density but trended toward reduced necrosis severity (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.08). Muscle mass and myofiber size were unchanged by treatment; however, NNMTi significantly improved muscle strength (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001), power (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0305), and total work (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0367) in ischemic limbs compared to placebo. Inhibition of NNMT enhanced ischemic muscle strength and performance in a preclinical model of PAD independent of changes in perfusion.\n                  <\/jats:p>","DOI":"10.14814\/phy2.70615","type":"journal-article","created":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T12:52:44Z","timestamp":1760791964000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nicotinamide N\u2010methyltransferase inhibition improves limb function in experimental peripheral artery disease"],"prefix":"10.14814","volume":"13","author":[{"given":"Gengfu","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Applied Physiology and Kinesiology The University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaewon","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Applied Physiology and Kinesiology The University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yufen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Applied Physiology and Kinesiology The University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana C.","family":"Muller","sequence":"additional","affiliation":[{"name":"Department of Applied Physiology and Kinesiology The University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuoxin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Applied Physiology and Kinesiology The University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yangyi E.","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Applied Physiology and Kinesiology The University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0780-029X","authenticated-orcid":false,"given":"Terence E.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Department of Applied Physiology and Kinesiology The University of Florida  Gainesville Florida USA"},{"name":"Center for Exercise Science The University of Florida  Gainesville Florida USA"},{"name":"Myology Institute The University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,18]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.121.318535"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.01.080"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-52107-7"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2025.07.014"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2025.04.002"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00525.2012"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13395-023-00323-1"},{"issue":"12","key":"e_1_2_9_9_1","article-title":"Aerobic and resistance exercise training reverses age\u2010dependent decline in NAD+ salvage capacity in human skeletal muscle","volume":"7","author":"Guia R. M.","year":"2019","journal-title":"Physiological Reports"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-024-66034-9"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.736447"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP278752"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2015.tb00646.x"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.42.5.994"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.avsg.2022.07.009"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.122.322325"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2017.05.011"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.07.005"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13395-018-0154-1"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.121.021917"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1042\/cs0710283"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1113\/EP086905"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00641.2017"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1996.81.2.780"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2022.03.003"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.111656"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvssci.2022.11.003"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.124.325642"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14236"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.024873"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2008.962"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.842328"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.2007.01092.x"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-49092-5"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005768-200112000-00007"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9082575"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2019.02.008"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2024.08.011"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00690.2021"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.123.323161"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0741-5214(03)00602-5"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1067\/mva.2000.106421"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2014.12.004"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/ctm2.658"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.2337\/db16-0387"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.139628"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.123235"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf5504"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2018.01.008"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2016.04.041"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1024\/0301-1526.37.3.199"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-023-01250-y"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000727"},{"key":"e_1_2_9_54_1","first-page":"1208","article-title":"Ultrastructural alterations and mitochondrial dysfunction in skeletal muscle of peripheral artery disease patients: implications for early therapeutic interventions","volume":"23","author":"Wilburn D.","year":"2024","journal-title":"EXCLI Journal"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00043.2011"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf2693"}],"container-title":["Physiological Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.14814\/phy2.70615","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/full-xml\/10.14814\/phy2.70615","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.14814\/phy2.70615","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T06:13:55Z","timestamp":1777702435000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.14814\/phy2.70615"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10]]},"references-count":55,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.14814\/phy2.70615"],"URL":"https:\/\/doi.org\/10.14814\/phy2.70615","archive":["Portico"],"relation":{},"ISSN":["2051-817X","2051-817X"],"issn-type":[{"value":"2051-817X","type":"print"},{"value":"2051-817X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10]]},"assertion":[{"value":"2025-09-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70615"}}