Long‐Term Electrically‐Induced Muscle Exercise Duration Modulates Distinct Gene Signaling Pathways in People with Spinal Cord Injury

Abstract

Exercise as a form of medicine attenuates the development of chronic non‐communicable diseases (NCDs) in people with intact nervous systems as they age. However, there is a knowledge gap regarding the influence of electrically induced skeletal muscle exercise on NCDs in people with spinal cord injury (SCI). Gene signaling pathway analysis offers an opportunity to understand the long‐term effects of electrically induced exercise on people with chronic and complete paralysis from SCI; providing a basis for interventions to be studied in future clinical trials.PurposeTo determine if long term electrically induced skeletal muscle exercise regulates complex network signaling pathways associated with improved metabolic health in people with SCI.MethodsWe analyzed 17 paired muscle samples from 11 males with complete SCI who completed at least 3 months of a unilateral exercise training program using electrical stimulation. During their exercise training, participants underwent routine physiological assessments. At the end of their exercise training, muscle samples were obtained from the exercised and non‐exercised limb. Extracted RNA was hybridized to Affymetrix Human Exon microarrays. Probe intensities were normalized using a robust multi‐array average. Gene expression values were analyzed using an a priori list of gene sets defined by the Reactome Pathways Knowledgebase and genes related to metabolic and hypertrophy pathways in skeletal muscle using the gene set enrichment algorithm and a fold‐change signature. Muscle biopsy samples were grouped together as a single cohort, and subdivided into 2 groups based on the training duration and muscle physiologic properties (<6 and >6 months of training). All participants provided written consent approved by the University of Iowa Institutional Review Board in compliance with the Declaration of Helsinki.ResultsWe analyzed over 17,000 genes and 1,900 genesets curated from the Reactome Pathways Knowledgebase. When we subdivided the muscle samples into 2 phenotypes based on training duration, we found 19 pathways associated with metabolism and mitochondrial function to be significantly up regulated (FDR < 0.25) in the trained phenotype compared to the untrained phenotype. A subset of representative genes that were up regulated included the mitochondria protein carrier genes (MPC1 and MPC2), the citric acid cycle genes (SDHA, SDHB), the oxidative phosphorylation genes (NDUFA2 and NDUFB1), and mitochondrial biogenesis genes (PGC1α).ConclusionsOverall health is dependent, in part, on skeletal muscle size and metabolic capacity. 6 months of chronic electrically induced exercise was sufficient to reverse the expression of important metabolic gene pathways needed to recreate an oxidative phenotype in chronically paralyzed skeletal muscles. Future studies are underway to ascertain if electrically induced exercise attenuates the development of NCDs in people with SCI.Support or Funding InformationResearch Support: This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development: R01HD084645, R01HD082109This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.