Transcriptomic Response to Neuromuscular Electrical Stimulation in Muscle, Brain, and Plasma EVs in WT and Klotho-Deficient Mice

Neuromuscular electrical stimulation (NMES) has been shown to improve motor activities and daily living. Prior studies indicated extracellular vesicles (EVs) play a role in cellular communication. Here, we evaluated transcriptomic profiles of tibialis muscle, brain, and plasma-derived EVs following NMES in wild type (WT) and <i>Klotho</i> heterozygous (Kl^HET) mice. Muscle RNA-seq data demonstrated that, in both genotypes, the most upregulated functional categories were related to glucose metabolism and response to insulin, with pathways uniquely affected in each genotype. There was a similarity of the non-coding RNA transcriptome of plasma EVs, with functional patterns suggesting response to oxygen and insulin and long-term synaptic potentiation. The brain transcriptome showed little functional overlap between WT and Kl^HET mice. In WT, brain upregulation of genes was related to blood flow and cell adhesion processes, while Kl^HET showed upregulation of immune function. The results indicate that similar metabolic function is impacted in the location of stimulation, but the distal impact of stimulation on the brain is associated with Klotho deficiency.