{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T21:21:01Z","timestamp":1789852861708,"version":"4.0.1"},"reference-count":58,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Veterans for America","award":["1 I01 RX002649-01A;"],"award-info":[{"award-number":["1 I01 RX002649-01A;"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Long pulse width stimulation (LPWS; 120\u2013150 ms) has the potential to stimulate denervated muscles in persons with spinal cord injury (SCI). We examined whether testosterone treatment (TT) + LPWS would increase skeletal muscle size, leg lean mass and improve overall metabolic health in SCI persons with denervation. We hypothesized that one year of combined TT + LPWS would downregulate gene expression of muscle atrophy and upregulate gene expression of muscle hypertrophy and increase mitochondrial health in SCI persons with lower motor neuron (LMN) injury. Methods: Ten SCI participants with chronic LMN injury were randomized into either 12 months, twice weekly, of TT + LPWS (n = 5) or a TT+ standard neuromuscular electrical stimulation (NMES; n = 5). Measurements were conducted at baseline (week 0), 6 months following training (post-intervention 1), and one week following 12 months of training (post-intervention 2). Measurements included body composition assessment using magnetic resonance imaging (MRI) and dual x-ray absorptiometry (DXA). Metabolic profile assessment encompassed measurements of resting metabolic rate, carbohydrate and lipid profiles. Finally, muscle biopsy was captured to measure RNA signaling pathways and mitochondrial oxidative phosphorylation. Results: Compliance and adherence were greater in the TT + NMES compared to the TT + LPWS group. There was a 25% increase in the RF muscle CSA following P1 measurement in the TT + LPWS group. There was a recognizable non-significant decrease in intramuscular fat in both groups. There was a trend (p = 0.07) of decrease in trunk fat mass following TT + LPWS, with an interaction (p = 0.037) in android lean mass between groups. There was a trend (p = 0.08) in mean differences in DXA-visceral adipose tissue (VAT) between groups at P1 measurements. For genes targeting muscle atrophy, TT + LPWS showed a trending decline in MURF1 and FOXO3 genes returning to similar levels as TT + NMES before 12 months. Conclusions: These pilot data demonstrated the safety of applying LPWS in persons with SCI. Six months of TT + LPWS demonstrated increases in rectus femoris muscle CSA. The effects on muscle size were modest between groups. Signaling pathway analysis suggested downregulation of genes involved in muscle atrophy pathways. Future clinical trials may consider a home-based approach with more frequent applications of LPWS.<\/jats:p>","DOI":"10.3390\/cells14241974","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T15:43:43Z","timestamp":1765467823000},"page":"1974","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Testosterone and Long-Pulse-Width Stimulation (TLPS) on Denervated Muscles and Cardio-Metabolic Risk Factors After Spinal Cord Injury: A Pilot Randomized Trial"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9157-6034","authenticated-orcid":false,"given":"Ashraf S.","family":"Gorgey","sequence":"first","affiliation":[{"name":"Spinal Cord Injury and Disorders, Central Virginia VA Medical Center, Richmond, VA 23249, USA"},{"name":"Department of Physical Medicine & Rehabilitation, Virginia Commonwealth University, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Refka E.","family":"Khalil","sequence":"additional","affiliation":[{"name":"Spinal Cord Injury and Disorders, Central Virginia VA Medical Center, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Alazzam","sequence":"additional","affiliation":[{"name":"Spinal Cord Injury and Disorders, Central Virginia VA Medical Center, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjodh","family":"Gill","sequence":"additional","affiliation":[{"name":"Endocrinology Service, Central Virginia VA Medical Center, Richmond, VA 23249, USA"},{"name":"Endocrine Division, School of Medicine Virginia Commonwealth University, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8553-8648","authenticated-orcid":false,"given":"Jeannie","family":"Rivers","sequence":"additional","affiliation":[{"name":"Surgery Service, Central Virginia VA Medical Center, Richmond, VA 23249, USA"},{"name":"Department of Surgery, Virginia Commonwealth University, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Caruso","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine & Rehabilitation, Central Virginia VA Medical Center, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8939-6093","authenticated-orcid":false,"given":"Ryan","family":"Garten","sequence":"additional","affiliation":[{"name":"Kinesiology and Health Sciences, Virginia Commonwealth University, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James T.","family":"Redden","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5428-5270","authenticated-orcid":false,"given":"Michael J.","family":"McClure","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teodoro","family":"Castillo","sequence":"additional","affiliation":[{"name":"Spinal Cord Injury and Disorders, Central Virginia VA Medical Center, Richmond, VA 23249, USA"},{"name":"Department of Physical Medicine & Rehabilitation, Virginia Commonwealth University, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4250-551X","authenticated-orcid":false,"given":"Lance","family":"Goetz","sequence":"additional","affiliation":[{"name":"Spinal Cord Injury and Disorders, Central Virginia VA Medical Center, Richmond, VA 23249, USA"},{"name":"Department of Physical Medicine & Rehabilitation, Virginia Commonwealth University, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5683-7844","authenticated-orcid":false,"given":"Qun","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Pauley Heart Center Virginia Commonwealth University, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward J.","family":"Lesnefsky","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Pauley Heart Center Virginia Commonwealth University, Richmond, VA 23249, USA"},{"name":"Cardiology Service, Central Virginia VA Medical Center, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2019-0417","authenticated-orcid":false,"given":"Robert A.","family":"Adler","sequence":"additional","affiliation":[{"name":"Endocrinology Service, Central Virginia VA Medical Center, Richmond, VA 23249, USA"},{"name":"Endocrine Division, School of Medicine Virginia Commonwealth University, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1046\/j.1525-1594.2002.06933.x","article-title":"Denervated muscles in humans: Limitations and problems of currently used functional electrical stimulation training 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