Molecular dynamic characteristics of rat gastrocnemius muscle under acute and short-term exercise intervention during the subacute phase of spinal cord injury

Abstract

BACKGROUND: Spinal cord injury triggers a cascade of neuro-muscular system damage, involving central pattern generator dysfunction and peripheral muscle molecular network disruptions. Exercise can regulate key genes and promote the recovery of spinal cord injury. OBJECTIVE: To identify exercise-regulated key genes through bioinformatics analysis and explore the mechanisms by which exercise intervention facilitates the recovery of spinal cord injury. METHODS: The GSE45550 dataset based on the GPL1355 platform was obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes regulated by acute and short-term exercise interventions during the subacute phase of spinal cord injury in rats were identified. Gene Ontology functional enrichment analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and Gene Set Enrichment Analysis were performed on these differentially expressed genes, and a protein-protein interaction network was constructed. RESULTS AND CONCLUSION: (1) After acute exercise intervention in the subacute phase of spinal cord injury, 106 genes were upregulated and 97 genes were downregulated in the gastrocnemius muscle, whereas short-term exercise intervention resulted in 138 upregulated and 105 downregulated genes. (2) Gene Ontology analysis showed that acute exercise mainly enriched genes related to chromosome segregation, while short-term exercise mainly promoted signal transduction processes. (3) KEGG analysis indicated that acute exercise was mainly associated with gastric acid secretion and upregulation of motor protein pathways, whereas short-term exercise mainly involved upregulation of neuroactive ligand-receptor interaction and downregulation of some inflammatory signaling pathways. (4) GSEA analysis revealed that acute exercise mainly upregulated cell cycle and DNA separation, while short-term exercise mainly downregulated interleukin-17 signaling and tumor necrosis factor signaling pathways. (5) Protein-protein interaction network showed that acute and short-term exercise interventions formed 2 and 3 central modules, respectively. In summary, acute exercise intervention significantly activates cell proliferation-related pathways (such as cell cycle and mitosis), upregulating pro-proliferative genes like Top2a and Sele; whereas short-term intervention exerts anti-inflammatory effects by downregulating inflammatory pathways such as interleukin-17 and tumor necrosis factor, and downregulating factors like COMP. These findings provide a reference for the molecular mechanism research of spinal cord injury rehabilitation.

1. Introduction

Spinal cord injury (SCI) can lead to severe motor dysfunction, typically manifested as a significant decrease in the speed and distance of locomotion. The pathological basis of this phenomenon is closely related to central pattern generator (CPG) dysfunction and neurotransmitter-mediated neurochemical pathway disruption. As the core regulatory unit of rhythmic movement, the CPG can generate alternating gait patterns through intrinsic networks even without input from higher centers. Studies on spinal cord transection animal models have shown that even when corticospinal and sensory afferent pathways are interrupted, the preserved CPG network can still drive rhythmic movement, highlighting the key role of the lumbar spinal cord in movement initiation. Specifically, the lumbar spinal cord regulates motor neuron pool discharge and initiates locomotion by integrating descending corticospinal pathways, subcortical pathways, and ascending segmental sensory input, thereby controlling coordinated limb movement. Notably, denervation caused by SCI above the lumbar level leads to reduced motor neuron excitability and dendritic atrophy, disrupting the CPG functional circuit.

After SCI, axonal regeneration capacity is limited, and the safety, efficacy, and scalability of gene modification or drug intervention to promote regeneration across the injury site remain questionable. Exercise training can regulate spinal neural networks, activate and remodel the lumbar CPG to re-establish alternating gait patterns. The mechanisms involve multiple levels of regulation: at the cellular level, exercise training can increase motor neuron excitability and synaptic density, regulate the coordinated expression of neurotrophic factors such as brain-derived neurotrophic factor, synapsin I, growth-associated protein 43, synaptophysin, and postsynaptic density protein 95, and effectively promote synaptic remodeling and adaptive reorganization of neural circuits in the distal region of the injury. At the circuit level, it enhances corticospinal tract function and sensory feedback input to optimize CPG output efficiency, reduce secondary damage, preserve hindlimb motor function, and regulate neurotransmitter release to modulate CPG responses. Furthermore, exercise promotes neural plasticity through two main pathways: axonal sprouting and connection remodeling, and compensatory growth of spared descending tracts and driving nerve fibers.