Targeting the muscle-brain axis to improve post-stroke cognition via the FNDC5/irisin/BDNF pathway

The muscle-brain axis involving FNDC5/irisin/BDNF supports brain health and cognition. Stroke often causes hemiplegic muscle atrophy, which may disrupt this axis and impair cognition.

To determine whether stroke-induced muscle atrophy disrupts the FNDC5/irisin/BDNF axis and contributes to post-stroke cognitive impairment (PSCI) in patients, cynomolgus monkeys and rats.

We conducted a cross-sectional study of stroke patients 3-6 months post-onset from outpatient (n = 24) and matched healthy controls from the community (n = 22). Cognitive function was assessed using the MoCA, TMT-A, TMT-B, and AVLT-H. Serum irisin was quantified using ELISA. Bilateral mid-thigh MRI scanning (mDIXON-QUANT) evaluated muscle cross-sectional area and fat fraction. Next, in stroke cynomolgus monkeys and rats, muscle atrophy, FNDC5/irisin/BDNF expression, and cognition were measured. Finally, we evaluated whether upregulation of the FNDC5/irisin/BDNF axis via physical exercise or peripheral irisin overexpression alleviated PSCI in rats.

Stroke patients exhibited a 6.5 % decrease in cross-sectional area (CSA) and a 13.6 % increase in fat fraction in the paretic thigh compared with the non-paretic side. Serum irisin levels dropped by 40 % compared to controls and were positively linked to paretic muscle CSA and cognitive function. In cynomolgus monkeys, paretic muscle CSA fell by 40 % at 12 weeks post-stroke, along with a notable decrease in PGC-1α and FNDC5 protein in atrophic muscle. These monkeys also exhibited a 50 % decrease in serum irisin levels, reduced hippocampal BDNF expression, and fewer immature neurons compared to sham-operated controls. Similarly, stroke rats demonstrated paretic muscle atrophy and suppression of the FNDC5/irisin/BDNF signaling pathway. Enhancing irisin via exercise or peripheral irisin overexpression significantly increased BDNF expression and immature neurons in the hippocampus of stroke rats, ultimately improving PSCI (all p < 0.05).

Hemiplegic muscle atrophy contributes to PSCI through the FNDC5/irisin/BDNF axis downregulation. Elevating irisin shows therapeutic potential for PSCI.