High-intensity training on CREB activation for improving brain health: a narrative review of possible molecular talks

Abstract

Although physical exercise has obvious benefits in brain physiology, the molecular biomarkers induced by exercise protocols are inconclusive. Evidence indicates that exercise interventions are effective in shaping brain physiology. However, the potential mediator for improving brain functions is uncertain. CREB is one of the potential targets of exercise that triggers various molecular cross-talk to improve neurogenesis, long-term potentiation, and synaptogenesis. Therefore, CREB may be situated on the causal path between maintaining brain health and exercising. To support this, studies have shown that exercise-mediated CREB phosphorylation improves cognitive functions and memory. In addition, among the protocols of exercise (types, duration, and frequency), the intensity has been reported to be the most effective in triggering CREB-mediated molecular signaling. For example, HIT increases the synthesis of CREB, which may not only induce brain physiology but also induce brain pathology by higher activation of its downstream targets, such as BDNF. Therefore, this review aims to understand the effects of HIT on CREB function and how HIT can mediate the CREB-induced molecular cross-talk for maintaining brain health.

Keywords: CREB; HIT; brain health; neurons; physical exercise.

Figure 1

High-intensity training (HIT) downregulates the miR-34a for SIRT1 expression, possibly mediated by AMPK and CREB. HIT-induced CREB improves the LDH ratio for lactate metabolism, which can synthesize lactyl-CoA and histone lactylation for neuronal development via stimulating Arg1 gene. This scenario induces NMDAR and Ca2+ flux for CREB expression in a feedback manner. HIT-induced catecholamines can also activate NMDAR for CREB expression. HIT-triggered cAMP-phosphodiesterase 4 (PDE4) activates PAK/CREB for synaptic excitability transmission and plasticity.

Figure 2

Different types of HIT exercise on activating CREB. Swimming exercise activates the CREB binding protein (CBP) and histone acetylation. This can increase the expression of CREB in the neurons. Resistance training activates the CREB through MAPK/ERK/JNK to increase BDNF-mediated benefits in the brain. Cycling training activates the myocyte enhancer factor 2 (MEF2) gene and histone acetyltransferase p300 (EP300) gene for CREB expression. Treadmill training activates the hexokinase and phosphoenolpyruvate carboxykinase (PEPCK) to improve metabolic health in the neurons. However, HIT protocols inhibit the CREB/BDNF functions and cause mitophagy in the aged neurons.