Exercise Factors Released by the Liver, Muscle, and Bones Have Promising Therapeutic Potential for Stroke

Abstract

Stroke is one of the leading causes of death and disability in the world. Stroke not only affects the patients, but also their families who serve as the primary caregivers. Discovering novel therapeutic targets for stroke is crucial both from a quality of life perspective as well as from a health economic perspective. Exercise is known to promote neuroprotection in the context of stroke. Indeed, exercise induces the release of blood-borne factors that promote positive effects on the brain. Identifying the factors that mediate the positive effects of exercise after ischemic stroke is crucial for the quest for novel therapies. This approach will yield endogenous molecules that normally cross the blood brain barrier (BBB) and that can mimic the effects of exercise. In this minireview, we will discuss the roles of exercise factors released by the liver such as beta-hydroxybutyrate (DBHB), by the muscle such as lactate and irisin and by the bones such as osteocalcin. We will also address their therapeutic potential in the context of ischemic stroke.

Keywords: BDNF; beta-hydroxybutyrate; exercise factors; irisin; lactate; osteocalcin; stroke.

Figure 1

Exercise induces the release of metabolites and proteins that promote learning and memory formation through activation of Bdnf expression and signaling in the hippocampus. Bones release osteocalcin that promotes Bdnf expression through an epigenetic mechanism involving RbAP48 (5, 6). The liver releases the ketone body betahydroxy-butyrate that induces hippocampal Bdnf expression by inhibiting class I HDACs, namely HDAC2 and HDAC3 (4, 7). The muscle releases FNDC5/irisin that activate hippocampal Bdnf expression through an unknown mechanism (8). In addition, the muscle release lactate that activates the hippocampal SIRT1/PGC1-alpha/FNDC5 pathway and in turn Bdnf expression (9). Finally activated platelets have been shown to store and secrete BDNF (10, 11). Whether these factors mediate the positive effects of exercise in stroke is not clear and needs to be addressed. In addition, the role of BDNF signaling in exercise-mediated neuroprotection also needs to be assessed. BDNF, brain-derived neurotrophic factor; FDNC5, fibronectin type III domain-containing protein 5; HDACs, histone deacetylases; SIRT1, sirtuin 1; PGC1-alpha, Peroxisome proliferator-activated receptor gamma coactivator 1-alpha.

Figure 2

The exercise factors, beta-hydroxybutyrate, irisin and lactate protect against ischemic stroke.