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

Neuromuscular electrical stimulation (NMES) was 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 anterior muscle, brain, and plasma-derived EVs following NMES of WT and Klotho heterozygous (Kl ^HET ). 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 non-coding RNA transcriptome of plasma EVs with functional patterns suggesting response to oxygen and insulin, and long-term synaptic potentiation. Brain transcriptome showed little functional overlap between WT and Kl ^HET mice. In WT, brain upregulation of genes were related to blood flow and cell adhesion processes while Kl ^HET shows upregulation of immune function. 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.