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Two avenues for promoting recovery are neuromuscular junction (NMJ)\u2010promoting substrates (e.g., agrin) and endurance exercise. Although mechanical stimulation enhances agrin\u2010induced NMJ formation, the two modalities have yet to be evaluated combinatorially. It is hypothesized that the implantation of human myogenic progenitor\u2010seeded tissue\u2010engineered muscle grafts (hTEMGs) in combination with agrin treatment and\/or exercise will enhance neuromuscular recovery after VML. The hTEMGs alone transplant into VML defects promote significant regeneration with minimal scarring. A sex\u2010appropriate, low\u2010intensity continuous running exercise paradigm increases acetylcholine receptor (AChR) cluster density in male mice twofold relative to hTEMG alone after 7\u00a0weeks of treadmill training (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.05). To further promote neuromuscular recovery, agrin is incorporated into the scaffolds via covalent tethering. In vitro, agrin increases the proliferation of hMPs, and trends toward greater myogenic maturity and AChR clustering. Upon transplantation, both hTEMGs\u00a0+\u00a0agrin and hTEMGs\u00a0+\u00a0exercise induce near 100% recovery of muscle mass and increase twitch and tetanic force output (<jats:italic>p<\/jats:italic>\u00a0&gt;\u00a00.05). However, agrin treatment in combination with exercise produces no additional benefit. These data highlight the unprecedented regenerative potential of using hTEMGs together with either agrin or exercise supplementation to treat VML injuries.<\/jats:p>","DOI":"10.1002\/adhm.202403028","type":"journal-article","created":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T02:33:53Z","timestamp":1731292433000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Neuromuscular Regeneration of Volumetric Muscle Loss Injury in Response to Agrin\u2010Functionalized Tissue Engineered Muscle Grafts and Rehabilitative Exercise"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3760-4532","authenticated-orcid":false,"given":"Eszter","family":"Mihaly","sequence":"first","affiliation":[{"name":"Translational Tissue Engineering Center School of Medicine Johns Hopkins University  Baltimore MD 21231 USA"},{"name":"Department of Biomedical Engineering School of Medicine Johns Hopkins University  Baltimore MD 21205 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neha","family":"Chellu","sequence":"additional","affiliation":[{"name":"Translational Tissue Engineering Center School of Medicine Johns Hopkins University  Baltimore MD 21231 USA"},{"name":"Department of Biomedical Engineering School of Medicine Johns Hopkins University  Baltimore MD 21205 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shama R.","family":"Iyer","sequence":"additional","affiliation":[{"name":"School of Science Mathematics &amp; Engineering Marymount University  Arlington VA 22207 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eileen Y.","family":"Su","sequence":"additional","affiliation":[{"name":"Translational Tissue Engineering Center School of Medicine Johns Hopkins University  Baltimore MD 21231 USA"},{"name":"Department of Biomedical Engineering School of Medicine Johns Hopkins University  Baltimore MD 21205 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dallas E.","family":"Altamirano","sequence":"additional","affiliation":[{"name":"Translational Tissue Engineering Center School of Medicine Johns Hopkins University  Baltimore MD 21231 USA"},{"name":"Department of Biomedical Engineering School of Medicine Johns Hopkins University  Baltimore MD 21205 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaquielle T.","family":"Dias","sequence":"additional","affiliation":[{"name":"Translational Tissue Engineering Center School of Medicine Johns Hopkins University  Baltimore MD 21231 USA"},{"name":"Department of Biomedical Engineering School of Medicine Johns Hopkins University  Baltimore MD 21205 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6099-6469","authenticated-orcid":false,"given":"Warren L.","family":"Grayson","sequence":"additional","affiliation":[{"name":"Translational Tissue Engineering Center School of Medicine Johns Hopkins University  Baltimore MD 21231 USA"},{"name":"Department of Biomedical Engineering School of Medicine Johns Hopkins University  Baltimore MD 21205 USA"},{"name":"Department of Materials Science &amp; Engineering Whiting School of Engineering Johns Hopkins University  Baltimore MD 21218 USA"},{"name":"Department of Chemical &amp; Biomolecular Engineering Whiting School of Engineering Johns Hopkins University  Baltimore MD 21218 USA"},{"name":"Institute for NanoBioTechnology (INBT) Johns Hopkins University School of Engineering  Baltimore MD 21218 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,11,10]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00019.2003"},{"key":"e_1_2_9_2_1","first-page":"32","volume":"94","author":"Bentzinger C. 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