Genomic and epigenomic changes by low force electrically induced exercise of human paralyzed muscle

Abstract

Musculoskeletal deterioration following complete paralysis, such as after a spinal cord injury, results in osteoporotic bone and atrophic, glycolytic, and insulin-resistant skeletal muscle. Decreased bone integrity can be overloaded with very little force; therefore, high force contractions should be avoided in people with long-term spinal cord injury. Together, these changes compromise systemic metabolism for people with SCI and contribute to the development of secondary non-communicable diseases. Electrically induced exercise training offers a unique strategy to ensure full muscle recruitment without high force levels by using high current intensity and a low stimulation frequency (<5Hz) to prevent force summation of stimulus pulses. While acute epigenomic and genomic changes have been found with this low force exercise method; how long-term training affects skeletal muscle and systemic biomarkers of health remains unknown. Purpose: We seek to determine the long-term genomic and epigenomic response of low-force electrically induced exercise in paralyzed skeletal muscle. Methods: 10 males with a complete SCI completed at least 6-months of unilateral electrically induced exercise training using low-force (3Hz) stimulation. Participants completed at least 5 exercise training sessions per week for at least 6-months. A muscle fatigue assessment and fasting venous blood draw were performed before and after training. Percutaneous muscle biopsies were obtained from a trained and untrained vastus lateralis. Gene expression was measured using the Affymetrix HTA 2.0 array and epigenomic expression was measured using Illumina’s MethylEPIC array. Parametric tests were used to compare pre and post training. All participants provided written consent approved by the University of Iowa Institutional Review Board in compliance with the Declaration of Helsinki. Results: Participants maintained a high compliance by completing 119±19% of the training sessions for 7.2±1.2 months. There was a 115±34% change improvement of the fatigue index after training (p=0.002). Serum concentrations of insulin, hsCRP, and myostatin were decreased by 43±8% (p=0.155), 26±8%(p=0.047), 35±9%(p=0.098) after exercise training, respectively. Serum BDNF increased by 68±14%(p=0.093) after exercise training. There was a strong correlation between the primary principal component and the trained limb (R2=0.20, p=0.046). There were 693 and 671 genes to be significantly up or down regulated after exercise training (FDR < 0.05). Of the genes most responsive to exercise training, MYH6, MYH7, and MYL3 were increased in expression and decreased in median methylation. MSTN and ACTN3 were decreased in genomic expression with an increase in median methylation after exercise training. Conclusions: Low-force electrically induced exercise training improved fatigability, a muscle oxidative phenotype transition, and improved serum biomarkers associated with metabolism and inflammation. Together, these data highlight the impact low-force electrically induced exercise can have on paralyzed muscle and is suggestive that this rehabilitation strategy may provide benefits for people living with paralysis. Research Support: This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development: R01HD084645, R01HD082109. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.