Crosstalk between skeletal muscle and the brain during physical activity - in search of epigenetic mechanisms

Recent research highlights the crucial role of muscle-brain crosstalk in metabolic regulation, particularly in individuals with type 2 diabetes and obesity. Myokines, protein hormones secreted by skeletal muscle, play a crucial role in this communication, influencing brain functions such as neuroplasticity, memory, and mood. Specific myokines like cathepsin B, FNDC5/irisin and interleukin-6 have been identified as key players in this muscle-brain axis. Physical activity modulates the production of these molecular factors, enhancing muscle-brain crosstalk and influencing cellular interactions. Moreover, exercise training may lead to adaptive long-term changes in gene expression, mediated by epigenetic regulators. Metabolic pathways activated during exercise can directly impact epigenetic marks by modulating the availability of metabolic intermediates required for these modifications. In the present review, we summarize the latest findings on the association between obesity/diabetes and cognitive impairment due to hippocampal dysfunction, and elaborate on how exercise influences cognitive functions via the communication between skeletal muscle and the brain. We focus on the underlying mechanisms responsible for the muscle-brain crosstalk, emphasizing dynamic changes in the epigenome and epitranscriptome, which sheds light on novel preventive and therapeutic approaches to combat obesity and cognitive decline.