Blackmore, K. A. | bioRxiv Science

bioRxiv2026

Exercise Myokine Irisin Enables Behavioral Stress Resistance in Mice

Physical activity produces widespread benefits to physical and mental health, including protection against stress-related behavioral outcomes. However, the peripheral signals through which physical activity is translated into stress resistance remain incompletely understood. Irisin, an exercise-induced myokine cleaved from the transmembrane protein FNDC5 and released into circulation, has been implicated in improved cognition and neuroprotection, but its role in resistance to behavioral consequences of future adversity has not been examined. Here, we tested whether forced peripheral elevation of irisin is sufficient to protect against stress-induced behavioral outcomes. Adult male C57BL/6 mice received adeno-associated viral (AAV)-mediated peripheral expression of irisin or GFP control. AAV-irisin significantly increased circulating irisin levels, and six weeks later, mice were exposed to inescapable stress, a well-characterized model that produces anxiety-like behaviors, including reducing rodents natural inclination toward sociability. Elevated circulating irisin prevented the stress-induced reduction in social preference without altering general locomotor activity. Moreover, circulating irisin levels positively predicted individual differences in sociability. Additionally, peripheral irisin elevation increased brain-derived neurotrophic factor (Bdnf) expression, which also positively correlated with circulating irisin levels. Finally, we identified expression of the irisin receptor subunit integrin V within the dorsal raphe nucleus, a key brain region implicated in the behavioral outcomes of inescapable stress that is modulated by prior exercise. Together, these findings identify peripheral irisin as a mediator sufficient to confer resistance to future stress, even in the absence of physical activity. Significance StatementPhysical activity protects against the anxiety-like behavioral outcomes of future stress, but the peripheral mediators of this effect remain unclear. Here we show that forced peripheral elevation of circulating irisin, an exercise-induced myokine, is sufficient to produce behavioral stress resistance in mice. Irisin prevented the stress-induced reduction in social preference and positively correlated with individual differences in sociability. Forced expression of peripheral irisin also increased Bdnf expression in the brain, consistent with engagement of central neuroplasticity pathways that support adaptive behavioral responses. These findings demonstrate that an exercise-induced circulating factor can confer resistance to future stress, identifying irisin as a potential prophylactic target for stress-related mental health disorders.

neuroscience↗

bioRxiv2024

Cardiomyocyte PGC-1α enables physiological adaptations to endurance exercise through suppression of GDF15 and cardiac atrophy

Exercise training induces physiological cardiac hypertrophy, enhanced mitochondrial biogenesis and myocardial contractility. In skeletal muscle, the transcriptional coactivator PGC-1 is a key orchestrator of these responses. The heart expresses abundant and exercise-responsive PGC-1, but it is unclear whether cardiomyocyte PGC-1 is necessary for cardiac adaptation to endurance training. Here we demonstrate that cardiomyocyte PGC-1 is required for physiological cardiac hypertrophy during exercise training in mice. In the absence of cardiomyocyte PGC-1, voluntary wheel running does not improve exercise capacity and instead confers immune-fibrotic-atrophic heart failure after just 6 weeks of training. We identify cardiomyocyte PGC-1 as a negative regulator of stress-responsive senescence gene expression. The most enriched of these is the myomitokine GDF15. GDF15 is secreted locally but not systemically in PGC-1-deficient mouse hearts and reduces cardiomyocyte size. Cardiomyocyte-specific reduction of GDF15 expression preserves exercise tolerance and cardiac contractility in PGC-1-deficient mice during endurance training. Finally, we show that cardiomyocyte PPARGC1A expression correlates with cardiomyocyte number and negatively with GDF15 expression in human cardiomyopathies through single nucleus RNA sequencing. Our data implicate cardiomyocyte PGC-1 as a vital safeguard against stress-induced atrophy and local GDF15-induced dysfunction during exercise.

physiology↗