Abstract
This study investigates whether electrical stimulation (ES) could mimic traditional exercise in enhancing brain-derived neurotrophic factor (BDNF)-dependent neuroplasticity via muscle-brain communication, specifically through the fibronectin type III domain-containing protein 5 (FNDC5)/Irisin pathway. Male Wistar rats received transcutaneous ES targeting the lumbar nerve roots to induce hindlimb muscle contractions for 30 min daily over seven consecutive days. Blood and tissue samples were collected for biochemical, histological, and molecular analyses 1 day after the final session. Our findings reveal that ES disrupted BDNF signaling in the hippocampus, reducing synaptic protein expression. At the muscular level, ES caused significant damage, particularly in the soleus muscle, accompanied by muscle satellite cell (MuSC) activation, proliferation, and differentiation. Notably, ES increased FNDC5 expression in injured muscles, but this was associated with MuSC activation rather than humoral communication between muscle and brain. Moreover, a positive correlation was observed between the pro-inflammatory state of the injured muscles and hippocampal glucocorticoid receptor activation, as an indicator of stress, which was linked to impaired BDNF signaling. These results suggest two key conclusions: (1) Increased FNDC5 expression in damaged muscle fibers primarily reflects local repair mechanisms rather than a beneficial humoral dialogue, and (2) ES protocols that induce muscle injury can negatively impact BDNF-dependent plasticity by triggering maladaptive muscle-brain interactions. These findings highlight the importance of optimizing muscle stimulation protocols to minimize muscle damage, particularly when applied to individuals unable to engage in conventional physical activity or suffering from muscle weakness.