Genomic and Epigenomic Evaluation of Electrically Induced Exercise in People With Spinal Cord Injury: Application to Precision Rehabilitation.

OBJECTIVE: Physical therapists develop patient-centered exercise prescriptions to help overcome the physical, emotional, psychosocial, and environmental stressors that undermine a person's health. Optimally prescribing muscle activity for people with disability, such as a spinal cord injury, is challenging because of their loss of volitional movement control and the deterioration of their underlying skeletal systems. This report summarizes spinal cord injury-specific factors that should be considered in patient-centered, precision prescription of muscle activity for people with spinal cord injury. This report also presents a muscle genomic and epigenomic analysis to examine the regulation of the proliferator-activated receptor γ coactivator 1α (PGC-1α) (oxidative) and myostatin (hypertrophy) signaling pathways in skeletal muscle during low-frequency (lower-force) electrically induced exercise versus higher-frequency (higher-force) electrically induced exercise under constant muscle recruitment (intensity). METHODS: Seventeen people with spinal cord injury participated in 1 or more unilateral electrically induced exercise sessions using a lower-force (1-, 3-, or 5-Hz) or higher-force (20-Hz) protocol. Three hours after the exercise session, percutaneous muscle biopsies were performed on exercised and nonexercised muscles for genomic and epigenomic analysis. RESULTS: We found that low-frequency (low-force) electrically induced exercise significantly increased the expression of PGC-1α and decreased the expression of myostatin, consistent with the expression changes observed with high-frequency (higher-force) electrically induced exercise. Further, we found that low-frequency (lower-force) electrically induced exercise significantly demethylated, or epigenetically promoted, the PGC-1α signaling pathway. A global epigenetic analysis showed that >70 pathways were regulated with low-frequency (lower-force) electrically induced exercise. CONCLUSION: These novel results support the notion that low-frequency (low-force) electrically induced exercise may offer a more precise rehabilitation strategy for people with chronic paralysis and severe osteoporosis. Future clinical trials are warranted to explore whether low-frequency (lower-force) electrically induced exercise training affects the overall health of people with chronic spinal cord injury.

A minimal dose of electrically induced muscle activity regulates distinct gene signaling pathways in humans with spinal cord injury.

Paralysis after a spinal cord injury (SCI) induces physiological adaptations that compromise the musculoskeletal and metabolic systems. Unlike non-SCI individuals, people with spinal cord injury experience minimal muscle activity which compromises optimal glucose utilization and metabolic control. Acute or chronic muscle activity, induced through electrical stimulation, may regulate key genes that enhance oxidative metabolism in paralyzed muscle. We investigated the short and long term effects of electrically induced exercise on mRNA expression of human paralyzed muscle. We developed an exercise dose that activated the muscle for only 0.6% of the day. The short term effects were assessed 3 hours after a single dose of exercise, while the long term effects were assessed after training 5 days per week for at least one year (adherence 81%). We found a single dose of exercise regulated 117 biological pathways as compared to 35 pathways after one year of training. A single dose of electrical stimulation increased the mRNA expression of transcriptional, translational, and enzyme regulators of metabolism important to shift muscle toward an oxidative phenotype (PGC-1α, NR4A3, IFRD1, ABRA, PDK4). However, chronic training increased the mRNA expression of specific metabolic pathway genes (BRP44, BRP44L, SDHB, ACADVL), mitochondrial fission and fusion genes (MFF, MFN1, MFN2), and slow muscle fiber genes (MYH6, MYH7, MYL3, MYL2). These findings support that a dose of electrical stimulation (∼10 minutes/day) regulates metabolic gene signaling pathways in human paralyzed muscle. Regulating these pathways early after SCI may contribute to reducing diabetes in people with longstanding paralysis from SCI.