{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T03:23:34Z","timestamp":1768706614404,"version":"3.49.0"},"reference-count":40,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T00:00:00Z","timestamp":1648598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["R01HL136566"],"award-info":[{"award-number":["R01HL136566"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Introduction: We previously showed that caspase-1 and -11, which are activated by inflammasomes, mediate recovery from muscle ischemia in mice. We hypothesized that similar to murine models, inflammatory caspases modulate myogenicity and inflammation in ischemic muscle disease. Methods: Caspase activity was measured in ischemic and perfused human myoblasts in response to the NLRP3 and AIM2 inflammasome agonists (nigericin and poly(dA:dT), respectively) with and without specific caspase-1 or pan-caspase inhibition. mRNA levels of myogenic markers and caspase-1 were assessed, and protein levels of caspases-1, -4, -5, and -3 were measured by Western blot. Results: When compared to perfused cells, ischemic myoblasts demonstrated attenuated MyoD and myogenin and elevated caspase-1 mRNA. Ischemic myoblasts also had significantly higher enzymatic caspase activity with poly(dA:dT) (p &lt; 0.001), but not nigericin stimulation. Inhibition of caspase activity including caspase-4\/-5, but not caspase-1, blocked activation effects of poly(dA:dT). Ischemic myoblasts had elevated cleaved caspase-5. Inhibition of caspase activity deterred differentiation in ischemic but not perfused myoblasts and reduced the release of HMGB1 from both groups. Conclusion: Inflammatory caspases can be activated in ischemic myoblasts by AIM2 and influence ischemic myoblast differentiation and release of pro-angiogenic HMGB1. AIM2 inflammasome involvement suggests a role as a DNA damage sensor, and our data suggest that caspase-5 rather than caspase-1 may mediate the downstream mediator of this pathway.<\/jats:p>","DOI":"10.3390\/cells11071163","type":"journal-article","created":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T21:22:14Z","timestamp":1648675334000},"page":"1163","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Inflammatory Caspase Activity Mediates HMGB1 Release and Differentiation in Myoblasts Affected by Peripheral Arterial Disease"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2161-109X","authenticated-orcid":false,"given":"Ricardo","family":"Ferrari","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4150-6131","authenticated-orcid":false,"given":"Bowen","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edwyn","family":"Assaf","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristin","family":"Morder","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6864-5970","authenticated-orcid":false,"given":"Melanie","family":"Scott","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Calderon","sequence":"additional","affiliation":[{"name":"University of Pittsburgh Center for Biologic Imaging, Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Ross","sequence":"additional","affiliation":[{"name":"University of Pittsburgh Center for Biologic Imaging, Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Loughran","sequence":"additional","affiliation":[{"name":"University of Pittsburgh Center for Biologic Imaging, Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon C.","family":"Watkins","sequence":"additional","affiliation":[{"name":"University of Pittsburgh Center for Biologic Imaging, Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iraklis","family":"Pipinos","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Nebraska, Omaha, NE 68198, USA"},{"name":"Department of Surgery, Veterans Affairs Hospital, Pittsburgh, PA 15240, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Casale","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Nebraska, Omaha, NE 68198, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edith","family":"Tzeng","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"},{"name":"Department of Surgery, Veterans Affairs Hospital, Pittsburgh, PA 15240, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3040-0366","authenticated-orcid":false,"given":"Ryan","family":"McEnaney","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"},{"name":"Department of Surgery, Veterans Affairs Hospital, Pittsburgh, PA 15240, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4648-0735","authenticated-orcid":false,"given":"Ulka","family":"Sachdev","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1161\/01.CIR.0000137913.26087.F0","article-title":"Prevalence of and Risk Factors for Peripheral Arterial Disease in the United States: Results from the National Health and Nutrition Examination Survey, 1999\u20132000","volume":"110","author":"Selvin","year":"2004","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1369\/0022155415569348","article-title":"Abnormal Accumulation of Desmin in Gastrocnemius Myofibers of Patients with Peripheral Artery Disease: Associations with Altered Myofiber Morphology and Density, Mitochondrial Dysfunction and Impaired Limb Function","volume":"63","author":"Koutakis","year":"2015","journal-title":"J. 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