Extracellular heat shock proteins (eHSP70) in exercise: Possible targets outside the immune system and their role for neurodegenerative disorders treatment

SummaryThe intracellular heat shock protein 70 kDa (iHSP70) is a universal marker of stress protein whose expression is induced by different cell stressors, such as heat, metabolite deprivation, redox imbalances and also during physical exercise. The activation of the iHSP70 is sine qua non for the promotion of tissue repair, since the expression of this chaperone confers cytoprotection and also exerts anti-inflammatory effects. On the other hand, exercise also induces the appearance of HSP70 in the extracellular medium (eHSP70) but, so far, the eHSP70 function has been mainly attributed to the activation of the immune system, seeming to perform an opposite function from the iHSP70. Since a moderate intensity exercise bout induces a general anti-inflammatory response even in the presence of an elevated eHSP70, this protein could carry out other functions rather than immune activation. Because exercise generates heat and metabolic challenges (especially on glucose metabolism) we suggests that the motoneurons, a very active (possibly one of the most stressed cells during exercise) and also very sensitive cells to heat and glucose metabolism imbalances, could be the major sites for the eHSP70 function. Due to the importance of the iHSP70 for repair and stress adaptation, this protein must be present in abundance on the site of stress and, because of its intrinsic inability response to stress [low heat shock factor 1 (HSF-1) activation] and the structure of the motoneurons (very long cells), the iHSP70, produced on the very far nucleus, is not appropriately transported through the axon to the axon terminal, were it is required. Then, during the exercise, the released eHSP70 can be internalized by the motoneurons and act as intracellular chaperons, protecting this cell against oxidative damage, protein denaturation and many others. Since a decreased iHSP70 expression capacity is associated with neurodegeneration diseases (such as Parkinson, polyglutamine, Amyotrophic lateral sclerosis, Alzheimer’s, Huntington’s and many others), the understanding of the physiological function of the extracellular HSP70 could be helpful on the treatment of neurodegenerative and other neuronal diseases. Besides that, it could explain some of the beneficial effects of the pharmacological HSP70 activators and also the beneficial effects of the exercise among neuronal cells during neurodegenerative-inducing diseases.