Figure 2.

Signaling pathways through which physical exercise and skeletal muscle metabolites impact the brain. Irisin and cathepsin B are capable of increasing BDNF synthesis in the CNS. BDNF interacts with the TrkB receptor and triggers the activation of different downstream pathways, including the PLCγ/IP3/Ca²⁺/CaMKII/CREB, PLCγ/DAG/PKC/ERK/CREB and PLCγ/PI3K/Akt/mTOR pathways, leading to pro-neurogenic effects. Physical exercise can also increase other growth factors, including IGF-1 and VEGF, which further contribute to neurogenesis. Lactate can reach the brain through MCT and increase SIRT1 activity, which in turn induces the FNDC5/irisin pathway, further increasing BDNF gene expression. In addition, lactate activates the GPR81/HCAR1 receptor, which stimulates the expression of synaptic-plasticity-related genes, such as Arc, c-Fos and Zif268, through a mechanism involving NMDA receptor activity and its downstream signaling cascade ERK1/2. The activation of GPR81 by lactate also inhibits the NLRP3 inflammasome complex by activating β-Arrestin 2. Finally, physical exercise has a hormetic effect leading to the activation of cellular protective systems, such as the transcription factor Nrf2, resulting in the expression of antioxidant proteins. Abbreviations: 4EBP: initiation factor 4E-binding protein; Akt: protein kinase B; Arc: cytoskeleton associated protein; ARE: antioxidant response elements; ATP: adenosine triphosphate; BDNF: brain-derived neurotrophic factor; Ca²⁺: calcium; CaMKII: calcium/calmodulin-dependent protein kinase II; cAMP: cyclic adenosine monophosphate; c-Fos: fos proto-oncogene, AP-1 transcription factor subunit; CREB: cAMP response element-binding protein; P-CREB: phosphor-CREB; DAG: diacylglycerol; ERK 1/2: extracellular-signal-regulated kinase 1/2; Fndc5: fibronectin type III domain-containing 5; GPR81/HCAR1: G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1; IGF-1: insulin-like growth factor-1; IGF-1R: insulin-like growth factor-1 receptor; IP3: inositol trisphosphate 3; Keap1: Kelch-like ECH-associated protein 1; LDH1: lactate dehydrogenase 1; MCT: monocarboxylate transporter; mTOR: mechanistic target of rapamycin; NAD⁺: nicotinamide adenine dinucleotide; NADH: nicotinamide adenine dinucleotide reduced; Nrf2: nuclear factor erythroid-derived related factor-2; NLRP3: NOD-like receptor pyrin domain-containing-3; NMDAR: N-methyl D-aspartate receptor; p70S6K: 70-kDa ribosomal protein S6 kinase; PGC-1α: proliferator-activated receptoFndc5r gamma coactivator-1α; PI3K: phosphatidylinositol-3-kinase; PIP2: phosphatidylinositol 4,5-bisphosphate; PKA: protein kinase A; PKC: protein kinase C; PLC: phospholipase C; Shc: Src-homologous and collagen-like protein; Sirt-1: sirtuin 1; TrkB: tropomyosin receptor kinase-B; VEGF: vascular endothelial growth factor; Zif268: zinc-finger-containing transcription factor 268; ?: receptor not characterized.