Cerebral Benefits Induced by Electrical Muscle Stimulation: Evidence from a Human and Rat Study.

Physical exercise (EX) is well established for its positive impact on brain health. However, conventional EX may not be feasible for certain individuals. In this regard, this study explores electromyostimulation (EMS) as a potential alternative for enhancing cognitive function. Conducted on both human participants and rats, the study involved two sessions of EMS applied to the quadriceps with a duration of 30 min at one-week intervals. The human subjects experienced assessments of cognition and mood, while the rats underwent histological and biochemical analyses on the prefrontal cortex, hippocampus, and quadriceps. Our findings indicated that EMS enhanced executive functions and reduced anxiety in humans. In parallel, our results from the animal studies revealed an elevation in brain-derived neurotrophic factor (BDNF), specifically in the hippocampus. Intriguingly, this increase was not associated with heightened neuronal activity or cerebral hemodynamics; instead, our data point towards a humoral interaction from muscle to brain. While no evidence of increased muscle and circulating BDNF or FNDC5/irisin pathways could be found, our data highlight lactate as a bridging signaling molecule of the muscle-brain crosstalk following EMS. In conclusion, our results suggest that EMS could be an effective alternative to conventional EX for enhancing both brain health and cognitive function.

Impact of Exercise Intensity on Cerebral BDNF Levels: Role of FNDC5/Irisin.

The positive effects of physical exercise (EX) are well known to be mediated by cerebral BDNF (brain-derived neurotrophic factor), a neurotrophin involved in learning and memory, the expression of which could be induced by circulating irisin, a peptide derived from Fibronectin type III domain-containing protein 5 (FNDC5) produced by skeletal muscle contraction. While the influence of EX modalities on cerebral BDNF expression was characterized, their effect on muscle FNDC5/Irisin expression and circulating irisin levels remains to be explored. The present study involved Wistar rats divided into four experimental groups: sedentary (SED), low- (40% of maximal aerobic speed, MAS), intermediate- (50% of MAS) and high- (70% of MAS) intensities of treadmill EX (30 min/day, 7 days). Soleus (SOL) versus gastrocnemius (GAS) FNDC5 and hippocampal BDNF expressions were evaluated by Western blotting. Additionally, muscular FNDC5/Irisin localization and serum/hippocampal irisin levels were studied by immunofluorescence and ELISA, respectively. Our findings revealed that (1) serum irisin and hippocampal BDNF levels vary with EX intensity, showing a threshold intensity at 50% of MAS; (2) hippocampal BDNF levels positively correlate with serum irisin but not with hippocampal FNDC5/Irisin; and (3) GAS, in response to EX intensity, overexpresses FNDC5/Irisin in type II muscle fibers. Altogether, peripheral FNDC5/Irisin levels likely explain EX-dependent hippocampal BDNF expression.

Molecular mechanisms underlying physical exercise-induced brain BDNF overproduction.

Accumulating evidence supports that physical exercise (EX) is the most effective non-pharmacological strategy to improve brain health. EX prevents cognitive decline associated with age and decreases the risk of developing neurodegenerative diseases and psychiatric disorders. These positive effects of EX can be attributed to an increase in neurogenesis and neuroplastic processes, leading to learning and memory improvement. At the molecular level, there is a solid consensus to involve the neurotrophin brain-derived neurotrophic factor (BDNF) as the crucial molecule for positive EX effects on the brain. However, even though EX incontestably leads to beneficial processes through BDNF expression, cellular sources and molecular mechanisms underlying EX-induced cerebral BDNF overproduction are still being elucidated. In this context, the present review offers a summary of the different molecular mechanisms involved in brain's response to EX, with a specific focus on BDNF. It aims to provide a cohesive overview of the three main mechanisms leading to EX-induced brain BDNF production: the neuronal-dependent overexpression, the elevation of cerebral blood flow (hemodynamic hypothesis), and the exerkine signaling emanating from peripheral tissues (humoral response). By shedding light on these intricate pathways, this review seeks to contribute to the ongoing elucidation of the relationship between EX and cerebral BDNF expression, offering valuable insights into the potential therapeutic implications for brain health enhancement.

Region-Dependent Increase of Cerebral Blood Flow During Electrically Induced Contraction of the Hindlimbs in Rats.

Elevation of cerebral blood flow (CBF) may contribute to the cerebral benefits of the regular practice of physical exercise. Surprisingly, while electrically induced contraction of a large muscular mass is a potential substitute for physical exercise to improve cognition, its effect on CBF remains to be investigated. Therefore, the present study investigated CBF in the cortical area representing the hindlimb, the hippocampus and the prefrontal cortex in the same anesthetized rats subjected to either acute (30 min) or chronic (30 min for 7 days) electrically induced bilateral hindlimb contraction. While CBF in the cortical area representing the hindlimb was assessed from both laser doppler flowmetry (LDFCBF) and changes in p-eNOSSer1177 levels (p-eNOSCBF), CBF was evaluated only from changes in p-eNOSSer1177 levels in the hippocampus and the prefrontal cortex. The contribution of increased cardiac output and increased neuronal activity to CBF changes were examined. Stimulation was associated with tachycardia and no change in arterial blood pressure. It increased LDFCBF with a time- and intensity-dependent manner as well as p-eNOSCBF in the area representing the hindlimb. By contrast, p-eNOSCBF was unchanged in the two other regions. The augmentation of LDFCBF was partially reduced by atenolol (a ß1 receptor antagonist) and not reproduced by the administration of dobutamine (a ß1 receptor agonist). Levels of c-fos as a marker of neuronal activation selectively increased in the area representing the hindlimb. In conclusion, electrically induced bilateral hindlimb contraction selectively increased CBF in the cortical area representing the stimulated muscles as a result of neuronal hyperactivity and increased cardiac output. The absence of CBF changes in cognition-related brain regions does not support flow-dependent neuroplasticity in the pro-cognitive effect of electrically induced contraction of a large muscular mass.

Endothelial cells are an important source of BDNF in rat skeletal muscle.

BDNF (brain-derived neurotrophic factor) is present in skeletal muscle, controlling muscular metabolism, strength and regeneration processes. However, there is no consensus on BDNF cellular source. Furthermore, while endothelial tissue expresses BDNF in large amount, whether endothelial cells inside muscle expressed BDNF has never been explored. The aim of the present study was to provide a comprehensive analysis of BDNF localization in rat skeletal muscle. Cellular localization of BDNF and activated Tropomyosin-related kinase B (TrkB) receptors was studied by immunohistochemical analysis on soleus (SOL) and gastrocnemius (GAS). BDNF and activated TrkB levels were also measured in muscle homogenates using Western blot analysis and/or Elisa tests. The results revealed BDNF immunostaining in all cell types examined with a prominent staining in endothelial cells and a stronger staining in type II than type I muscular fibers. Endothelial cells but not other cells displayed easily detectable activated TrkB receptor expression. Levels of BDNF and activated TrkB receptors were higher in SOL than GAS. In conclusion, endothelial cells are an important and still unexplored source of BDNF present in skeletal muscle. Endothelial BDNF expression likely explains why oxidative muscle exhibits higher BDNF levels than glycolytic muscle despite higher the BDNF expression by type II fibers.