{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T20:44:24Z","timestamp":1792183464142,"version":"4.4.0"},"reference-count":99,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Peripheral artery disease (PAD), caused by atherosclerosis, leads to limb ischemia, muscle damage, and impaired mobility in the lower extremities. Recent studies suggest that circadian rhythm disruptions can hinder vascular repair during ischemia, but the specific tissues involved and the impact on muscle health remain unclear. This study investigates the role of the skeletal muscle circadian clock in muscle adaptation to ischemic stress using a surgical mouse model of hindlimb ischemia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We performed secondary analysis of publicly available RNA-sequencing data sets derived from patients with PAD to identify the differential expression of circadian-related genes in endothelial cells and ischemic limb skeletal muscles. We used mice with specific genetic loss of the circadian clock activator, BMAL1 (brain and muscle ARNT-like 1), in adult skeletal muscle tissues (\n                      <jats:italic toggle=\"yes\">Bmal1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">muscle<\/jats:italic>\n                      <\/jats:sup>\n                      ).\n                      <jats:italic toggle=\"yes\">Bmal1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">muscle<\/jats:italic>\n                      <\/jats:sup>\n                      mice and controls underwent femoral artery ligation surgery to induce hindlimb ischemia. Laser Doppler imaging was used to assess limb perfusion at various time points after the surgery. Muscle tissues were analyzed with RNA sequencing and histological examination to investigate PAD-related muscle pathologies. Additionally, we studied the role of BMAL1 in muscle fiber adaptation to hypoxia using RNA and assay for transposase-accessible chromatin with sequencing analyses in primary myotube culture model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Disrupted expression of circadian rhythm\u2013related genes was observed in existing RNA-sequencing data sets from endothelial cells and ischemic limb skeletal muscles derived from patients with PAD. Genetic loss of\n                      <jats:italic toggle=\"yes\">Bmal1<\/jats:italic>\n                      specifically in adult mouse skeletal muscle tissues delayed reperfusion recovery following induction of hindlimb ischemia. Histological examination of muscle tissues showed reduced regenerated myofiber number and a decreased proportion of type IIB fast-twitch myofibers in\n                      <jats:italic toggle=\"yes\">Bmal1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">muscle<\/jats:italic>\n                      <\/jats:sup>\n                      mouse muscles in the ischemic limbs but not in their contralateral nonischemic limbs. Transcriptomic analysis revealed abrogated metabolic, angiogenic, and myogenic pathways relevant to hypoxia adaptation in\n                      <jats:italic toggle=\"yes\">Bmal1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">muscle<\/jats:italic>\n                      <\/jats:sup>\n                      mouse muscles. These changes were corroborated in\n                      <jats:italic toggle=\"yes\">Bmal1<\/jats:italic>\n                      -deficient cultured primary myotubes cultured under hypoxic conditions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Circadian clock in skeletal muscle is crucial for the muscle\u2019s response to hypoxia during hindlimb ischemia. Targeting the muscle circadian clock may have therapeutic potential for enhancing muscle response to reduced blood flow and promoting recovery in conditions such as PAD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.124.321772","type":"journal-article","created":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T05:00:41Z","timestamp":1733374841000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":6,"title":["Circadian Dysfunction in the Skeletal Muscle Impairs Limb Perfusion and Muscle Regeneration in Peripheral Artery Disease"],"prefix":"10.1161","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0321-9636","authenticated-orcid":true,"given":"Pei","family":"Zhu (\u6731\u57f9)","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics (P.Z., A.W.T.S., N.X.H., E.M.P., C.B.P.), Northwestern University Feinberg School of Medicine, Chicago, IL."},{"name":"Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine (P.Z., A.W.T.S., N.X.H., E.M.P., C.B.P.), Northwestern University Feinberg School of Medicine, Chicago, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calvin L.","family":"Chao","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Vascular Surgery (C.L.C., C.D., B.J.), Northwestern University Feinberg School of Medicine, Chicago, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5660-9371","authenticated-orcid":true,"given":"Adam W.T.","family":"Steffeck","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics (P.Z., A.W.T.S., N.X.H., E.M.P., C.B.P.), Northwestern University Feinberg School of Medicine, Chicago, IL."},{"name":"Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine (P.Z., A.W.T.S., N.X.H., E.M.P., C.B.P.), Northwestern University Feinberg School of Medicine, Chicago, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0555-0509","authenticated-orcid":true,"given":"Caitlyn","family":"Dang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Vascular Surgery (C.L.C., C.D., B.J.), Northwestern University Feinberg School of Medicine, Chicago, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4318-8675","authenticated-orcid":true,"given":"Noah X.","family":"Hamlish","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics (P.Z., A.W.T.S., N.X.H., E.M.P., C.B.P.), Northwestern University Feinberg School of Medicine, Chicago, IL."},{"name":"Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine (P.Z., A.W.T.S., N.X.H., E.M.P., C.B.P.), Northwestern University Feinberg School of Medicine, Chicago, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M.","family":"Pfrender","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics (P.Z., A.W.T.S., N.X.H., E.M.P., C.B.P.), Northwestern University Feinberg School of Medicine, Chicago, IL."},{"name":"Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine (P.Z., A.W.T.S., N.X.H., E.M.P., C.B.P.), Northwestern University Feinberg School of Medicine, Chicago, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2390-4312","authenticated-orcid":true,"given":"Bin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Vascular Surgery (C.L.C., C.D., B.J.), Northwestern University Feinberg School of Medicine, Chicago, IL."},{"name":"Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Chicago, IL (B.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0873-0879","authenticated-orcid":true,"given":"Clara B.","family":"Peek","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics (P.Z., A.W.T.S., N.X.H., E.M.P., C.B.P.), Northwestern University Feinberg School of Medicine, Chicago, IL."},{"name":"Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine (P.Z., A.W.T.S., N.X.H., E.M.P., C.B.P.), Northwestern University Feinberg School of Medicine, Chicago, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001005"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.120.313831"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aah4965"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.932596"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.5665\/sleep.4892"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2012.02.003"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12514"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1177\/0748730414561638"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13395-016-0107-5"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.211706"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvad057"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.349066.121"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ctdb.2024.01.017"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.09.010"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.2310\/6670.2006.00056"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.153346"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/btm2.10592"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.123235"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1180"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1177\/0962280212460441"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1421708111"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-00886-3"},{"key":"e_1_3_3_25_2","first-page":"291","article-title":"Quantification of histochemical staining by color deconvolution.","volume":"23","author":"Ruifrok AC","year":"2001","unstructured":"Ruifrok AC, Johnston DA. Quantification of histochemical staining by color deconvolution. Anal Quant Cytol Histol. 2001;23:291\u2013299.","journal-title":"Anal Quant Cytol Histol"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-323"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.7563.2"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw377"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.05.004"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1923"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13072-020-00342-y"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw257"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1106148"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.712903"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.121.020896"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.2007.01092.x"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1067\/mva.2000.106421"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.3791\/1035"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2015.02.011"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.87.2.413"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2005.01.037"},{"key":"e_1_3_3_46_2","first-page":"658","article-title":"Histochemical changes in striated muscle in patients with intermittent claudication.","volume":"101","author":"Makitie J","year":"1977","unstructured":"Makitie J, Teravainen H. Histochemical changes in striated muscle in patients with intermittent claudication. Arch Pathol Lab Med. 1977;101:658\u2013663.","journal-title":"Arch Pathol Lab Med"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9082575"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2021.166278"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.120.314824"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-016-1030-6"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21113923"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111982"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1177\/1947601911423031"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.785712"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.01.021"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2017.11.010"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0925-4773(96)00631-4"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.2001.281.6.E1128"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1014523107"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abi9654"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.3791\/59582"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2017.11.024"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-15-6082-8_5"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-232629"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/hr.2016.9"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.120.314318"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201601030R"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23010504"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-018-0122-1"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22922-6"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsmc.2015.08.002"},{"key":"e_1_3_3_72_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11853"},{"key":"e_1_3_3_73_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI82719"},{"key":"e_1_3_3_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2018.05.046"},{"key":"e_1_3_3_75_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.653303"},{"key":"e_1_3_3_76_2","doi-asserted-by":"publisher","DOI":"10.3400\/avd.ra.18-00074"},{"key":"e_1_3_3_77_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2020.02.008"},{"key":"e_1_3_3_78_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40256-016-0210-3"},{"key":"e_1_3_3_79_2","doi-asserted-by":"publisher","DOI":"10.1177\/1753944718786926"},{"key":"e_1_3_3_80_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000093398.16124.29"},{"key":"e_1_3_3_81_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005768-200112000-00007"},{"key":"e_1_3_3_82_2","doi-asserted-by":"publisher","DOI":"10.1177\/1358863X07084858"},{"key":"e_1_3_3_83_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2014.07.002"},{"key":"e_1_3_3_84_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0604893104"},{"key":"e_1_3_3_85_2","first-page":"56","article-title":"Myostatin (GDF-8) as a key factor linking muscle mass and bone structure.","volume":"10","author":"Elkasrawy MN","year":"2010","unstructured":"Elkasrawy MN, Hamrick MW. Myostatin (GDF-8) as a key factor linking muscle mass and bone structure. J Musculoskelet Neuronal Interact. 2010;10:56\u201363.","journal-title":"J Musculoskelet Neuronal Interact"},{"key":"e_1_3_3_86_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP271436"},{"key":"e_1_3_3_87_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00259.2007"},{"key":"e_1_3_3_88_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40104-019-0338-5"},{"key":"e_1_3_3_89_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2015.00077"},{"key":"e_1_3_3_90_2","doi-asserted-by":"publisher","DOI":"10.1160\/TH14-05-0453"},{"key":"e_1_3_3_91_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0049-3848(98)00127-3"},{"key":"e_1_3_3_92_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.smrv.2014.07.001"},{"key":"e_1_3_3_93_2","doi-asserted-by":"publisher","DOI":"10.1111\/cen.12942"},{"key":"e_1_3_3_94_2","doi-asserted-by":"publisher","DOI":"10.2147\/DMSO.S23904"},{"key":"e_1_3_3_95_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2016-1083"},{"key":"e_1_3_3_96_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-018-0150-x"},{"key":"e_1_3_3_97_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcin.2019.02.018"},{"key":"e_1_3_3_98_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000727"},{"key":"e_1_3_3_99_2","doi-asserted-by":"publisher","DOI":"10.1093\/bjs\/znad437"},{"key":"e_1_3_3_100_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-020-00109-w"}],"container-title":["Arteriosclerosis, Thrombosis, and Vascular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/ATVBAHA.124.321772","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T16:03:46Z","timestamp":1764864226000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/ATVBAHA.124.321772"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2]]},"references-count":99,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["10.1161\/ATVBAHA.124.321772"],"URL":"https:\/\/doi.org\/10.1161\/atvbaha.124.321772","relation":{},"ISSN":["1079-5642","1524-4636"],"issn-type":[{"value":"1079-5642","type":"print"},{"value":"1524-4636","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2]]},"assertion":[{"value":"2024-08-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}