Distinct Genomic Expression Signatures after Low-Force Electrically Induced Exercises in Persons with Spinal Cord Injury

Abstract

People with a spinal cord injury are at an increased risk of metabolic dysfunction due to skeletal muscle atrophy and the transition of paralyzed muscle to a glycolytic, insulin-resistant phenotype. Providing doses of exercise through electrical muscle stimulation may provide a therapeutic intervention to help restore metabolic function for people with a spinal cord injury, but high-frequency and high-force electrically induced muscle contractions increase fracture risk for the underlying osteoporotic skeletal system. Therefore, we investigated the acute molecular responses after a session of either a 3 Hz or 1 Hz electrically induced exercise program. Ten people with a complete spinal cord injury completed a 1 h (3 Hz) or 3 h (1 Hz) unilateral electrically induced exercise session prior to a skeletal muscle biopsy of the vastus lateralis. The number of pulses was held constant. Tissue samples were analyzed for genomic and epigenomic expression profiles. There was a strong acute response after the 3 Hz exercise leading to the upregulation of early response genes (NR4A3, PGC-1α, ABRA, IRS2, EGR1, ANKRD1, and MYC), which have prominent roles in regulating molecular pathways that control mitochondrial biogenesis, contractile protein synthesis, and metabolism. Additionally, these genes, and others, contributed to the enrichment of pathways associated with signal transduction, cellular response to stimuli, gene expression, and metabolism. While there were similar trends observed after the 1 Hz exercise, the magnitude of gene expression changes did not reach our significance thresholds, despite a constant number of stimuli delivered. There were also no robust acute changes in muscle methylation after either form of exercise. Taken together, this study supports that a dose of low-force electrically induced exercise for 1 h using a 3 Hz stimulation frequency is suitable to trigger an acute genomic response in people with chronic paralysis, consistent with an expression signature thought to improve the metabolic and contractile phenotype of paralyzed muscle, if performed on a regular basis.