Multiple Roles in Neuroprotection for the Exercise Derived Myokine Irisin

Abstract

Exercise has multiple beneficial effects on health including decreasing the risk of neurodegenerative diseases. Such effects are thought to be mediated (at least in part) by myokines, a collection of cytokines and other small proteins released from skeletal muscles. As an endocrine organ, skeletal muscle synthesizes and secretes a wide range of myokines which contribute to different functions in different organs, including the brain. One such myokine is the recently discovered protein Irisin, which is secreted into circulation from skeletal muscle during exercise from its membrane bound precursor Fibronectin type III domain-containing protein 5 (FNDC5). Irisin contributes to metabolic processes such as glucose homeostasis and browning of white adipose tissue. Irisin also crosses the blood brain barrier and initiates a neuroprotective genetic program in the hippocampus that culminates with increased expression of brain derived neurotrophic factor (BDNF). Furthermore, exercise and FNDC5/Irisin have been shown to have several neuroprotective effects against injuries in ischemia and neurodegenerative disease models, including Alzheimer’s disease. In addition, Irisin has anxiolytic and antidepressant effects. In this review we present and summarize recent findings on the multiple effects of Irisin on neural function, including signaling pathways and mechanisms involved. We also discuss how exercise can positively influence brain function and mental health via the “skeletal muscle-brain axis.” While there are still many unanswered questions, we put forward the idea that Irisin is a potentially essential mediator of the skeletal muscle-brain crosstalk.

An examination of the relationship among plasma brain derived neurotropic factor, peripheral vascular function, and body composition with cognition in midlife African Americans/Black individuals

“…It should be highlighted that the precise mediating pathway facilitating the relationship between cognitive functioning and BDNF remains to be fully elucidated. It is, however, widely agreed that BDNF is strongly associated with neuroplasticity, and thus, higher levels of this factor may enhance/maintain the function of brain regions related to attention and processing speed such as the prefrontal cortex ( Anderson-Hanley et al, 2012 ; Miranda et al, 2019 ; Stringham et al, 2019 ; Ismail et al, 2020 ; Jodeiri Farshbaf and Alviña, 2021 ). Additionally, based on previous results ( Miranda et al, 2019 ; Ismail et al, 2020 ; Lai et al, 2020 ), we do continue to hypothesize that, in part, BDNF elicits its proposed neurocognitive benefits in healthy individuals as well as those exhibiting signs and symptoms of neurodegeneration along the vascular neurocognitive continuum despite us not currently presenting a corresponding pathway.…”

“…Further, it has emerged as a popular outcome variable in investigations examining the influence of exercise and/or pharmacological interventions aiming to improve brain health, likely due to its sensitivity to adjustments in modifiable risk factors and its dynamic interaction between neuro- and angiogenesis. Outside of the central nervous system (e.g., glia cells and neurons), BDNF is commonly reported to be released from skeletal and vascular smooth muscle cells as well as endothelial cells ( Jodeiri Farshbaf and Alviña, 2021 ). In fact, a reduction in BDNF release from these cells is one of the hallmark physiological changes seen in neurodegenerative disorders, including AD ( Ismail et al, 2020 ; Lourenco et al, 2020 ; Huuha et al, 2022 ; Oudbier et al, 2022 ).…”

FNDC5/Irisin: Physiology and Pathophysiology

“…Various studies have discovered important biological roles of irisin, such as in the regulation of depressive behavior [ 6 ], proliferating osteoblasts [ 7 ], and cortical bone mass [ 8 ]. It was suggested that irisin also has some beneficial roles in the central nervous system [ 9 , 10 ], and that it activates the Akt and ERK1/2 signaling pathways in brain tissues [ 9 ]. Moreover, irisin regulates some risk factors of AD (Alzheimer’s disease) [ 11 ], which includes altered neurogenesis, oxidative stress, insulin resistance, and imbalance of neurotrophic factors.…”

Irisin stimulates protective signaling pathways in rat hippocampal neurons

“…Irisin is an exercise-induced myokine that modulates adipose, bone and brain functions ( Boström et al, 2012 ; Kim et al, 2018 ; De Freitas et al, 2020 ; Isaac et al, 2021 ; Jodeiri Farshbaf and Alvina, 2021 ). Upon exercise, irisin is cleaved from a precursor protein, fibronectin type III domain containing protein 5 (FNDC5), and released into the circulation ( Boström et al, 2012 ; Jedrychowski et al, 2015 ).…”