Cellular and Molecular Regulation of Exercise-A Neuronal Perspective

Abstract

The beneficial effects of exercise on the proper functioning of the body have been firmly established. Multi-systemic metabolic regulation of exercise is the consequence of multitudinous changes that occur at the cellular level. The exercise responsome comprises all molecular entities including exerkines, miRNA species, growth factors, signaling proteins that are elevated and activated by physical exercise. Exerkines are secretory molecules released by organs such as skeletal muscle, adipose tissue, liver, and gut as a function of acute/chronic exercise. Exerkines such as FNDC5/irisin, Cathepsin B, Adiponectin, and IL-6 circulate through the bloodstream, cross the blood-brain barrier, and modulate the expression of important signaling molecules such as AMPK, SIRT1, PGC1α, BDNF, IGF-1, and VEGF which further contribute to improved energy metabolism, glucose homeostasis, insulin sensitivity, neurogenesis, synaptic plasticity, and overall well-being of the body and brain. These molecules are also responsible for neuroprotective adaptations that exercise confers on the brain and potentially ameliorate neurodegeneration. This review aims to detail important cellular and molecular species that directly or indirectly mediate exercise-induced benefits in the body, with an emphasis on the central nervous system.

Keywords: Exercise; Exercise mimetics; Exerkines; Metabolism; Neuron.

Fig. 1

Schematic representation depicting role of exercise responsome on CNS/brain: During physical exercise, body releases different cytokines from different tissues like skeletal muscles (myokines), adipose tissues (adipokines), liver (hepatokines), and bone (osteokines). These cytokines altogether are known as “exerkines.” These exerkines are released in blood and then travel through blood–brain barrier (BBB) and regulate the cellular signaling pathways e.g., IGF-1/PI3K/AKT axis and AMPK/SIRT1/PGC1α axis in CNS/brain causing increased neurogenesis, improved synaptic plasticity, and reduced neuroinflammation. Created with BioRender.com

Fig. 2

Exercise-mediated release of various exerkines from different tissues and their effects on hippocampal region of brain: Exercise releases various exerkines like FNDC5/irisin, CTSB, Adiponectin, Osteocalcin, FGF21 from different tissues like skeletal muscles (myokines), adipose tissues (adipokines), liver (hepatokines), and bone (osteokines), respectively. These exerkines cross the BBB and modulate the activities of important signaling molecules such as AKT/ERK, AMPK, cAMP/PKA/CREB, BDNF, and gpr158 which further lead to exercise-induced benefits for brain. Leptin is synthesized and secreted in the brain in response to exercise causing neuroprotection. Created with BioRender.com

Fig. 3

Exercise mimetics targeting the AMPK-SIRT1-PGC1α-BDNF signaling pathway to enhance cognitive performance. Exercise mimetics such as AICAR, R419, AdipoRon, GTDF, and GW501516 act on signaling molecules involved in translating exercise-mediated benefits on the brain. They target AMPK, PPARα, PPARẟ, PGC1α, ultimately converging upon BDNF expression. Created with BioRender.com