The Muscle-Brain Axis: Mechanisms and Implications for APOE ε4 Carriers

By Brian Paquette, DO, MPH

Overview

The muscle-brain axis describes bidirectional endocrine and paracrine signaling between skeletal muscle and the central nervous system. During contraction, muscle releases a class of peptides called myokines into systemic circulation, where they influence neuroplasticity, neurogenesis, neuroinflammation, and mitochondrial function in the brain. Whether peripheral irisin — the most studied of these mediators — crosses the blood-brain barrier directly or acts through intermediary signaling remains debated; irisin has been detected in human cerebrospinal fluid by tandem mass spectrometry, and vagal and neural afferent pathways also contribute to muscle-brain communication (Ruan et al., Peptides, 2018).

Key Molecular Mediators

Irisin/FNDC5. Irisin is cleaved from the muscle membrane protein FNDC5 during exercise. In muscle, FNDC5 expression is driven by the transcriptional coactivator PGC-1α; in mice lacking PGC-1α, brain FNDC5 expression is reduced (Wrann et al., Cell Metabolism, 2013, DOI). Peripherally released irisin acts on the αV/β5 integrin receptor complex through a non-canonical mechanism requiring extracellular Hsp90α as a co-activator (A et al., Molecular Cell, 2023, DOI). In the hippocampus, irisin induces BDNF expression through an endothelial αV/β5–FAK–eNOS signaling pathway — notably, roughly half of cerebral BDNF is thought to originate from cerebral endothelium rather than neurons directly (C et al., Molecular Neurobiology, 2025, DOI).

Irisin also appears to reduce amyloid-β burden. In a three-dimensional cell culture model of Alzheimer's disease, irisin stimulated astrocytic release of the amyloid-degrading enzyme neprilysin via downregulation of ERK-STAT3 signaling, with the αV/β5 integrin again identified as the required astrocytic receptor (Kim et al., Neuron, 2023, DOI).