Testosterone and long pulse width stimulation (TLPS) for denervated muscles after spinal cord injury: a study protocol of randomised clinical trial

Ashraf S Gorgey, Refka E Khalil, Malak Alrubaye, Ranjodh Gill, Jeannie Rivers, Lance L Goetz, David X Cifu, Teodoro Castillo, Deborah Caruso, Timothy D Lavis, Edward J Lesnefsky, Christopher C Cardozo, Robert A Adler, Ashraf S Gorgey, Refka E Khalil, Malak Alrubaye, Ranjodh Gill, Jeannie Rivers, Lance L Goetz, David X Cifu, Teodoro Castillo, Deborah Caruso, Timothy D Lavis, Edward J Lesnefsky, Christopher C Cardozo, Robert A Adler

Abstract

Introduction: Long pulse width stimulation (LPWS; 120-150 ms) has the potential to stimulate denervated muscles and to restore muscle size in denervated people with spinal cord injury (SCI). We will determine if testosterone treatment (TT)+LPWS would increase skeletal muscle size, leg lean mass and improve overall metabolic health in persons with SCI with denervation. We hypothesise that the 1-year TT+LPWS will upregulate protein synthesis pathways, downregulate protein degradation pathways and increase overall mitochondrial health.

Methods and analysis: Twenty-four male participants (aged 18-70 years with chronic SCI) with denervation of both knee extensor muscles and tolerance to the LPWS paradigm will be randomised into either TT+neuromuscular electrical stimulation via telehealth or TT+LPWS. The training sessions will be twice weekly for 1 year. Measurements will be conducted 1 week prior training (baseline; week 0), 6 months following training (postintervention 1) and 1 week after the end of 1 year of training (postintervention 2). Measurements will include body composition assessment using anthropometry, dual X-ray absorptiometry and MRI to measure size of different muscle groups. Metabolic profile will include measuring of basal metabolic rate, followed by blood drawn to measure fasting biomarkers similar to hemoglobin A1c, lipid panels, C reactive protein, interleukin-6 and free fatty acids and then intravenous glucose tolerance test to test for insulin sensitivity and glucose effectiveness. Finally, muscle biopsy will be captured to measure protein expression and intracellular signalling; and mitochondrial electron transport chain function. The participants will fill out 3 days dietary record to monitor their energy intake on a weekly basis.

Ethics and dissemination: The study was approved by Institutional Review Board of the McGuire Research Institute (ID # 02189). Dissemination plans will include the Veteran Health Administration and its practitioners, the national SCI/D services office, the general healthcare community and the veteran population, as well as the entire SCI community via submitting quarterly letters or peer-review articles.

Trial registration number: NCT03345576.

Keywords: neurobiology; neuromuscular disease; neurophysiology.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
The study timeline (table 4) and procedure are highlighted. After screening and consent, participants will be randomised into one of two testing groups. Each participant will undergo baseline testing before beginning TT+LPWS or control TT+NMES. Each group will be tested for metabolic, body and muscle composition (P1) after a 6-month period. Each group will then complete another 6 months of electrical stimulation exercise training followed by another testing (P2). BMR, basal metabolic rate; DXA, dual-energy X-ray absorptiometry; IVGTT, intravenous glucose tolerance test; LPWS, long pulse width stimulation; NMES, neuromuscular electrical stimulation; TT, testosterone treatment.

References

    1. Gater DR. Obesity after spinal cord injury. Phys Med Rehabil Clin N Am 2007;18:333–51. 10.1016/j.pmr.2007.03.004
    1. Gater D. Pathophysiology of obesity after spinal cord injury. Top Spinal Cord Inj Rehabil 2007;12:20–34. 10.1310/sci1204-20
    1. Weaver FM, Collins EG, Kurichi J, et al. . Prevalence of obesity and high blood pressure in veterans with spinal cord injuries and disorders: a retrospective review. Am J Phys Med Rehabil 2007;86:22–9. 10.1097/phm.0b013e31802b8937
    1. Bauman WA, Spungen AM. Disorders of carbohydrate and lipid metabolism in veterans with paraplegia or quadriplegia: a model of premature aging. Metabolism 1994;43:749–56. 10.1016/0026-0495(94)90126-0
    1. Lavela SL, Weaver FM, Goldstein B, et al. . Diabetes mellitus in individuals with spinal cord injury or disorder. J Spinal Cord Med 2006;29:387–95. 10.1080/10790268.2006.11753887
    1. DeVivo MJ, Go BK, Jackson AB. Overview of the national spinal cord injury statistical center database. J Spinal Cord Med 2002;25:335–8. 10.1080/10790268.2002.11753637
    1. Strauss DJ, Devivo MJ, Paculdo DR, et al. . Trends in life expectancy after spinal cord injury. Arch Phys Med Rehabil 2006;87:1079–85. 10.1016/j.apmr.2006.04.022
    1. DeVivo MJ. Causes and costs of spinal cord injury in the United States. Spinal Cord 1997;35:809–13. 10.1038/sj.sc.3100501
    1. Dudley GA, Castro MJ, Rogers S, et al. . A simple means of increasing muscle size after spinal cord injury: a pilot study. Eur J Appl Physiol Occup Physiol 1999;80:394–6. 10.1007/s004210050609
    1. Mahoney ET, Bickel CS, Elder C, et al. . Changes in skeletal muscle size and glucose tolerance with electrically stimulated resistance training in subjects with chronic spinal cord injury. Arch Phys Med Rehabil 2005;86:1502–4. 10.1016/j.apmr.2004.12.021
    1. Ryan TE, Brizendine JT, Backus D, et al. . Electrically induced resistance training in individuals with motor complete spinal cord injury. Arch Phys Med Rehabil 2013;94:2166–73. 10.1016/j.apmr.2013.06.016
    1. Gorgey AS, Mather KJ, Cupp HR, et al. . Effects of resistance training on adiposity and metabolism after spinal cord injury. Med Sci Sports Exerc 2012;44:165–74. 10.1249/MSS.0b013e31822672aa
    1. Kanzleiter T, Rath M, Görgens SW, et al. . The myokine decorin is regulated by contraction and involved in muscle hypertrophy. Biochem Biophys Res Commun 2014;450:1089–94. 10.1016/j.bbrc.2014.06.123
    1. Pedersen BK, Febbraio MA, Muscles FMA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 2012;8:457–65. 10.1038/nrendo.2012.49
    1. Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 2008;88:1379–406. 10.1152/physrev.90100.2007
    1. Boncompagni S. Severe muscle atrophy due to spinal cord injury can be reversed in complete absence of peripheral nerves. Eur J Transl Myol 2012;22:161–200. 10.4081/bam.2012.4.161
    1. Carraro U, Boncompagni S, Gobbo V, et al. . Persistent muscle fiber regeneration in long term denervation. past, present, future. Eur J Transl Myol 2015;25:77. 10.4081/bam.2015.2.77
    1. Kurz A, Volk GF, Arnold D, et al. . Selective electrical surface stimulation to support functional recovery in the early phase after unilateral acute facial nerve or vocal fold paralysis. Front Neurol 2022;13:869900. 10.3389/fneur.2022.869900
    1. Arnold D, Thielker J, Klingner CM, et al. . Selective surface electrostimulation of the denervated zygomaticus muscle. Diagnostics 2021;11:188. 10.3390/diagnostics11020188
    1. Kern H, Carraro U. Home-based functional electrical stimulation of human permanent denervated muscles: a narrative review on diagnostics, managements, results and Byproducts revisited 2020. Diagnostics 2020;10:529. 10.3390/diagnostics10080529
    1. Kern H, Hofer C, Strohhofer M, et al. . Standing up with denervated muscles in humans using functional electrical stimulation. Artif Organs 1999;23:447–52. 10.1046/j.1525-1594.1999.06376.x
    1. Carraro U, Rossini K, Zanin ME. Induced myogenesis in long-term permanent denervation: perspective role in functional electrical stimulation of denervated legs in humans. BAM-PADOVA 2002;12:53–64.
    1. Hofer C, Mayr W, Stöhr H, et al. . A stimulator for functional activation of denervated muscles. Artif Organs 2002;26:276–9. 10.1046/j.1525-1594.2002.06951.x
    1. Kern H, Hofer C, Mödlin M, et al. . Denervated muscles in humans: limitations and problems of currently used functional electrical stimulation training protocols. Artif Organs 2002;26:216–8. 10.1046/j.1525-1594.2002.06933.x
    1. Chandrasekaran S, Davis J, Bersch I, et al. . Electrical stimulation and denervated muscles after spinal cord injury. Neural Regen Res 2020;15:1397–407. 10.4103/1673-5374.274326
    1. Gorgey AS, Khalil RE, Gill R, et al. . Low-dose testosterone and evoked resistance exercise after spinal cord injury on cardio-metabolic risk factors: an open-label randomized clinical trial. J Neurotrauma 2019;36:2631–45. 10.1089/neu.2018.6136
    1. Gorgey AS, Graham ZA, Chen Q, et al. . Sixteen weeks of testosterone with or without evoked resistance training on protein expression, fiber hypertrophy and mitochondrial health after spinal cord injury. J Appl Physiol 2020;128:1487–96. 10.1152/japplphysiol.00865.2019
    1. Bauman WA, Cirnigliaro CM, La Fountaine MF, et al. . A small-scale clinical trial to determine the safety and efficacy of testosterone replacement therapy in hypogonadal men with spinal cord injury. Horm Metab Res 2011;43:574–9. 10.1055/s-0031-1280797
    1. Kostovski E, Iversen PO, Birkeland K, et al. . Decreased levels of testosterone and gonadotrophins in men with long-standing tetraplegia. Spinal Cord 2008;46:559–64. 10.1038/sc.2008.3
    1. Wu Y, Zhao J, Zhao W, et al. . Nandrolone normalizes determinants of muscle mass and fiber type after spinal cord injury. J Neurotrauma 2012;29:1663–75. 10.1089/neu.2011.2203
    1. Sinha-Hikim I, Taylor WE, Gonzalez-Cadavid NF, et al. . Androgen receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by androgen treatment. J Clin Endocrinol Metab 2004;89:5245–55. 10.1210/jc.2004-0084
    1. Gorgey AS, Lai RE, Khalil RE, et al. . Neuromuscular electrical stimulation resistance training enhances oxygen uptake and ventilatory efficiency independent of mitochondrial complexes after spinal cord injury: a randomized clinical trial. J Appl Physiol 2021;131:265–76. 10.1152/japplphysiol.01029.2020
    1. Gorgey AS, Lester RM, Wade RC, et al. . A feasibility pilot using telehealth videoconference monitoring of home-based NMES resistance training in persons with spinal cord injury. Spinal Cord Ser Cases 2017;3:17039. 10.1038/scsandc.2017.39
    1. Gorgey AS, Mather KJ, Poarch HJ, et al. . Influence of motor complete spinal cord injury on visceral and subcutaneous adipose tissue measured by multi-axial magnetic resonance imaging. J Spinal Cord Med 2011;34:99–109. 10.1179/107902610X12911165975106
    1. Gorgey AS, Gater DR. Regional and relative adiposity patterns in relation to carbohydrate and lipid metabolism in men with spinal cord injury. Appl Physiol Nutr Metab 2011;36:107–14. 10.1139/H10-091
    1. Lester RM, Ghatas MP, Khan RM, et al. . Prediction of thigh skeletal muscle mass using dual energy X-ray absorptiometry compared to magnetic resonance imaging after spinal cord injury. J Spinal Cord Med 2019;42:622–30. 10.1080/10790268.2019.1570438
    1. Ogawa M, Lester R, Akima H, et al. . Quantification of intermuscular and intramuscular adipose tissue using magnetic resonance imaging after neurodegenerative disorders. Neural Regen Res 2017;12:2100–5. 10.4103/1673-5374.221170
    1. Gorgey A, Gater D. Insulin growth factor-1 may explain the variability in skeletal muscle size in spastic individuals with spinal cord injury. J Rehabil Res Dev 2012;49:373–80. 10.1682/jrrd.2011.04.0076
    1. Edmunds KJ, Gíslason MK, Arnadottir ID, et al. . Quantitative computed tomography and image analysis for advanced muscle assessment. Eur J Transl Myol 2016;26:6015. 10.4081/ejtm.2016.6015
    1. Ghatas MP, Lester RM, Khan MR, et al. . Semi-automated segmentation of magnetic resonance images for thigh skeletal muscle and fat using threshold technique after spinal cord injury. Neural Regen Res 2018;13:1787–95. 10.4103/1673-5374.238623
    1. Abilmona SM, Sumrell RM, Gill RS, et al. . Serum testosterone levels may influence body composition and cardiometabolic health in men with spinal cord injury. Spinal Cord 2019;57:229–39. 10.1038/s41393-018-0207-7
    1. Gorgey AS, Cirnigliaro CM, Bauman WA, et al. . Estimates of the precision of regional and whole body composition by dual-energy X-ray absorptiometry in persons with chronic spinal cord injury. Spinal Cord 2018;56:987–95. 10.1038/s41393-018-0079-x
    1. Graham ZA, Collier L, Peng Y, et al. . A soluble activin receptor IIb fails to prevent muscle atrophy in a mouse model of spinal cord injury. J Neurotrauma 2016;33:1128–35. 10.1089/neu.2015.4058
    1. O'Brien LC, Wade RC, Segal L, et al. . Mitochondrial mass and activity as a function of body composition in individuals with spinal cord injury. Physiol Rep 2017;5:e13080. 10.14814/phy2.13080
    1. Bhasin S, Cunningham GR, Hayes FJ, et al. . Testosterone therapy in men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2010;95:2536–59. 10.1210/jc.2009-2354
    1. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999;84:3666–72. 10.1210/jcem.84.10.6079
    1. Manns PJ, McCubbin JA, Williams DP. Fitness, inflammation, and the metabolic syndrome in men with paraplegia. Arch Phys Med Rehabil 2005;86:1176–81. 10.1016/j.apmr.2004.11.020
    1. Bergman RN. Lilly lecture 1989. Toward physiological understanding of glucose tolerance. Minimal-model approach. Diabetes 1989;38:1512–27. 10.2337/diab.38.12.1512
    1. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 1999;22:1462–70. 10.2337/diacare.22.9.1462
    1. Matthews DR, Hosker JP, Rudenski AS, et al. . Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–9. 10.1007/BF00280883
    1. Brass EP, Hiatt WR, Gardner AW, et al. . Decreased NADH dehydrogenase and ubiquinol-cytochrome c oxidoreductase in peripheral arterial disease. Am J Physiol Heart Circ Physiol 2001;280:H603–9. 10.1152/ajpheart.2001.280.2.H603
    1. Scarpulla RC. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 2011;1813:1269–78. 10.1016/j.bbamcr.2010.09.019
    1. Groll A, Tutz G. Variable selection for generalized linear mixed models by L 1-penalized estimation. Stat Comput 2014;24:137–54. 10.1007/s11222-012-9359-z
    1. Gill S, Sumrell RM, Sima A, et al. . Waist circumference cutoff identifying risks of obesity, metabolic syndrome, and cardiovascular disease in men with spinal cord injury. PLoS One 2020;15:e0236752. 10.1371/journal.pone.0236752
    1. Sessa C, Cortes J, Conte P, et al. . The impact of COVID-19 on cancer care and oncology clinical research: an experts' perspective. ESMO Open 2022;7:100339. 10.1016/j.esmoop.2021.100339
    1. Elaraby A, Shahein M, Bekhet AH, et al. . The COVID-19 pandemic impacts all domains of quality of life in Egyptians with spinal cord injury: a retrospective longitudinal study. Spinal Cord 2022;60:757–62. 10.1038/s41393-022-00775-0
    1. Mitsikostas D-D, Moka E, Orrillo E, et al. . Neuropathic pain in neurologic disorders: a narrative review. Cureus 2022;14:e22419. 10.7759/cureus.22419

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