Mitochondrial biogenesis and fusion are essential for maintaining healthy mitochondria and ATP production. High-intensity interval training (HIIT) can enhance mitochondrial function in mouse hippocampi, but its underlying mechanism is not completely understood. Lactate generated during HIIT may mediate the beneficial effects of HIIT on neuroplasticity by activating the lactate receptor GPR81. Furthermore, growing evidence shows that lactate contributes to mitochondrial function. Given that mitochondrial function is crucial for cerebral physiological processes, the current study aimed to determine the mechanism of HIIT in hippocampal mitochondrial function. In vivo, GPR81 was knocked down in the hippocampi of mice via the injection of adeno-associated virus (AAV) vectors. The GPR81-knockdown mice were subjected to HIIT. The results demonstrated that HIIT increased mitochondria numbers, ATP production, and oxidative phosphorylation (OXPHOS) in the hippocampi of mice. In addition, HIIT induced mitochondrial biogenesis, fusion, synaptic plasticity, and ERK1/2 phosphorylation but not in GPR81-knockdown mice. In vitro, Neuro-2A cells were treated with L-lactate, a GPR81 agonist, and an ERK1/2 inhibitor. The results showed that both L-lactate and the GPR81 agonist increased mitochondrial biogenesis, fusion, ATP levels, OXPHOS, mitochondrial membrane potential, and synaptic plasticity. However, the inhibition of ERK1/2 phosphorylation blunted L-lactate or the GPR81 agonist-induced promotion of mitochondrial function and synaptic plasticity. In conclusion, our findings suggest that lactate mediates HIIT-induced promotion of mitochondrial function through the GPR81-ERK1/2 pathway.

The initiation and progression of neurodegenerative diseases (NDs), distinguished by compromised nervous system integrity, profoundly disrupt the quality of life of patients, concurrently exerting a considerable strain on both the economy and the social healthcare infrastructure. Exercise has demonstrated its potential as both an effective preventive intervention and a rehabilitation approach among the emerging therapeutics targeting NDs. As the largest secretory organ, skeletal muscle possesses the capacity to secrete myokines, and these myokines can partially improve the prognosis of NDs by mediating the muscle-brain axis. Besides the well-studied exerkines, which are secreted by skeletal muscle during exercise that pivotally exert their beneficial function, the physiological function of novel exerkines, e.g., apelin, kynurenic acid (KYNA), and lactate have been underappreciated previously. Herein, this review discusses the roles of these novel exerkines and their mechanisms in regulating the progression and improvement of NDs, especially the significance of their functions in improving NDs’ prognoses through exercise. Furthermore, several myokines with potential implications in ameliorating ND progression are proposed as the future direction for investigation. Elucidation of the function of exerkines secreted by skeletal muscle in the regulation of NDs advances the understanding of its pathogenesis and facilitates the development of therapeutics that intervene in these processes to cure NDs.

This investigation delineates the influence of resistance training on the expression of synaptic plasticity-related proteins in the hippocampi of insulin-resistant mice and explores the underlying molecular mechanisms. Six-week-old male C57BL/6 J mice were stratified into a control group and a high-fat diet group to induce insulin resistance over a 12-week period. Subsequently, the mice were further divided into sedentary and resistance training cohorts, with the latter engaging in a 12-week ladder-climbing regimen. Post-intervention, blood, and hippocampal specimens were harvested for analytical evaluation. In the insulin-resistant mice, elevated blood lactate levels were observed alongside diminished expression of synaptic plasticity-related proteins, monocarboxylate transporters (MCTs), and reduced phosphorylation of protein kinase B (Akt) and mechanistic target of rapamycin (mTOR). In contrast, the expression of eukaryotic translation initiation factor 4 E-binding protein 2 was significantly augmented. Resistance training mitigated insulin resistance, decreased blood lactate levels, and enhanced the expression and phosphorylation of mTOR, regulatory-associated protein of mTOR, MCTs, and synaptic plasticity-related proteins. Resistance training mitigates insulin resistance and improves hippocampal synaptic plasticity by normalizing blood lactate levels and enhancing mTOR, MCTs, and synaptic plasticity-related proteins. It may also activate mTORC1 via the PI3K/Akt pathway, promote lactate utilization, and enhance synaptic plasticity proteins, potentially alleviating peripheral insulin resistance. Further research is needed to confirm these mechanisms.

The remodeling of synapses in the hippocampus is intricately linked to processes of learning and memory. Research indicates that high-intensity interval training (HIIT) enhances cognitive functions reliant on the hippocampus in mice, although the specific receptor-mediated molecular pathways involved are not fully elucidated. Lactate, which is produced in significant amounts during HIIT, may function as a signaling agent in the brain through the lactate receptor G protein-coupled receptor 81 (GPR81), classified as a Gi-type G protein-coupled receptor. This investigation focused on the lactate/GPR81 pathway’s contribution to synaptic remodeling in the hippocampus induced by HIIT and examined its downstream signaling characteristics. In vivo results demonstrated that HIIT led to an increase in dendritic spine density and presynaptic vesicle density, enhancing learning and memory; however, these structural and cognitive improvements were negated by the knockdown of GPR81 in the hippocampus. In vitro experiments with Neuro-2a (N2a) cells, when treated with a GPR81 agonist alongside an adenyl cyclase (AC) agonist, a phospholipase C (PLC) inhibitor, and an extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor, revealed that GPR81 activation resulted in elevated ERK1/2 phosphorylation and increased levels of proteins associated with synaptic remodeling. Further pharmacological interventions reinforced a dual downstream signaling mechanism that involves the inhibition of the AC pathway and the activation of the PLC pathway, both of which converge on ERK1/2. Overall, these results suggest that the lactate/GPR81 pathway is essential for the critical aspects of HIIT-induced synaptic remodeling in the hippocampus and the enhancement of memory, supporting a GPR81-dependent dual-branch model that converges on ERK1/2 in a simplified in vitro context.

Background: Beyond its traditional role as a glycolysis end-product, lactate is now recognized as an important signaling molecule influencing synaptic plasticity and mitochondrial activity. Objective: We examined whether lactate, acting through its receptor GPR81, improves synaptic plasticity-related protein expression by augmenting mitochondrial biogenesis and fusion. Methods: Primary hippocampal cells and Neuro-2A cells were studied. Hippocampal cells received L-lactate or the GPR81 agonist 3OBA. We measured ATP production and levels of proteins involved in mitochondrial biogenesis (PGC-1α, NRF1/2, TFAM), fusion (OPA1, MFN2), and synaptic plasticity (BDNF, PSD95, SYN). In Neuro-2A cells, pathways were blocked using the PGC-1α inhibitor SR-18292 or the fusion inhibitor MF18 after lactate/GPR81 activation. Results: L-lactate and 3OBA significantly enhance mitochondrial function, including increasing ATP production, upregulating key regulators of mitochondrial biogenesis (PGC-1α, NRF1/2, and TFAM), and promoting fusion proteins (OPA1 and MFN2) that maintain mitochondrial network integrity. These mitochondrial improvements were paralleled by elevated expression of synaptic plasticity-related protein expression (BDNF, PSD95, and SYN), suggesting functional coupling between metabolic and synaptic processes. Conversely, pharmacological inhibition of mitochondrial biogenesis (via PGC-1α inhibitor SR-18292) or fusion (using MF18) abolished lactate/GPR81-mediated benefits, resulting in reduced ATP levels, impaired mitochondrial membrane potential, and downregulation of synaptic proteins. Conclusion: Our findings reveal that lactate promotes mitochondrial biogenesis and fusion via GPR81 to enhance synaptic plasticity-related protein expression in hippocampal cells, highlighting a novel mechanism by which lactate supports neuronal energy demands and synaptic plasticity.