Exercise inhibits doxorubicin-induced cardiotoxicity by preventing cardiac and endothelial cell senescence by activating FNDC5/Irisin signaling

Q: What are the key findings of this study?

Exercise significantly prevented doxorubicin-induced cardiac cellular senescence (p<0.0001) and preserved cardiac function via the FNDC5/irisin signaling pathway.

Q: What is the clinical evidence from this study?

Population: Doxorubicin-induced cardiotoxicity. Intervention: Exercise vs. Doxorubicin only (no exercise) and PBS control. Primary outcome: Cardiac cellular senescence (p16-RFP+ cells) and cardiac function (ejection fraction and fractional shortening) (p=<0.0001).

Q: What does this research mean for the field?

Exercise mitigates doxorubicin-induced cardiotoxicity and preserves cardiac function by preventing cardiomyocyte and endothelial cell senescence through activation of the FNDC5/irisin signaling pathway. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To examine whether exercise prevents doxorubicin-induced cardiotoxicity and senescence across cardiac cell types through FNDC5/irisin signaling.

Prince Jeyabal; Pradeep Shrestha; Yuanzheng Yang; Fei Wang; Zhanglong Peng; You Zhou; Yan Zheng; Eugenie S. Kleinerman

doi:10.21203/rs.3.rs-10910107/v1

September 29, 2026Open Access

Exercise inhibits doxorubicin-induced cardiotoxicity by preventing cardiac and endothelial cell senescence by activating FNDC5/Irisin signaling

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Key result

Exercise prevents doxorubicin-induced cardiac senescence and preserves function via FNDC5/irisin signaling.

P<0.0001

Why the study?

Doxorubicin induces cardiac and endothelial cell senescence leading to cardiotoxicity, and the mechanisms by which exercise may prevent this are not fully understood.

Does exercise prevent doxorubicin-induced cardiotoxicity and cellular senescence in preclinical models?

Key Points

To examine whether exercise prevents doxorubicin-induced cardiotoxicity and senescence across cardiac cell types through FNDC5/irisin signaling.
Treated p16-3MR transgenic mice with PBS, doxorubicin (Dox), or Dox with exercise (Dox+Ex), measuring ejection fraction (EF) and fractional shortening (FS) via echocardiography.
Quantified cellular senescence in cardiac tissue and isolated cells using p16-RFP expression, beta-galactosidase activity, HMGB1, and calreticulin across endothelial cells (CD31+), cardiomyocytes (troponin+), and fibroblasts (vimentin+).
Assessed cardiac axonal innervation and cytoskeletal integrity by evaluating Sema3a, TUJ1, F-actin distribution, and phosphorylated cofilin levels.
Doxorubicin significantly increased total p16-RFP+ cells (p<0.0001), senescent endothelial cells (p<0.0001), senescent cardiomyocytes (p<0.01), and senescent fibroblasts (p<0.05), whereas exercise completely prevented these increases.
Exercise prevented the Dox-induced decline in EF and FS, while also blocking the reduction of intracellular HMGB1 and calreticulin in cardiac tissue.
Dox therapy significantly elevated Sema3a (p<0.05) and phosphorylated cofilin (p<0.05) while reducing axonal TUJ1 (p<0.05) and disrupting F-actin; concurrent exercise preserved axon density and F-actin architecture.

Structured PICO

Does exercise prevent doxorubicin-induced cardiotoxicity and cellular senescence in preclinical models?

P

Population

Preclinical study utilizing 4-week-old p16-3MR transgenic mice and in vitro human cell models to evaluate the cardioprotective effects of exercise during doxorubicin therapy.

I

Intervention

Exercise (walking for 45 minutes at 12 meters per minute, 5 days a week for 2 weeks) simultaneous with doxorubicin treatment (2.5 mg/kg injected twice a week for 2 weeks). In vitro models were treated with irisin.

C

Comparator

Doxorubicin alone (2.5 mg/kg injected twice a week for 2 weeks) and vehicle control (PBS injection).

O

Outcome

Cardiac function (left ventricular ejection fraction and fractional shortening) and cellular senescence (accumulation of p16-RFP+ cells, HMGB1, and calreticulin expression).surrogate

Main Result

p-value: p=<0.0001

Exercise mitigates doxorubicin-induced cardiotoxicity by preventing cardiac, fibroblast, and endothelial cell senescence through the FNDC5/irisin signaling pathway in preclinical models.

Limitations

Findings are based on juvenile transgenic mouse models and in vitro cell cultures, which may not completely translate to human clinical outcomes.

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

Hypothesis-generating for exercise to mitigate doxorubicin cardiotoxicity; extends preclinical senescence data but leaves clinical translation open.

Abstract

Exercise’s effect on Dox-induced cardiac senescence in the heart was investigated using p16-3MR transgenic mice. Mice treated with doxorubicin (Dox) had decreased cardiac function, increased p16INK4a + and b-Galactosidase+ senescent cells in the heart, decreased HMGB1 and calreticulin expression, endothelial cell senescence, and decreased TUJ1 expression (indicating reduced axonal density), increased expression of Semaphorin3A and p-cofilin with impaired F-actin depolarization and cytoskeleton disorganization. None of these changes were seen in mice treated with Dox + Exercise. Exercise sustained the levels of FNDC5 in the heart compared with the Dox-treated hearts suggesting a link between exercise, decreased senescence, and the FNDC5/ irisin pathway. In vitro studies using human cardiomyocytes and endothelial cells confirmed that irisin attenuated Dox-induced senescence. Taken together, these data provide evidence that exercise mitigates Dox-induced cardiotoxicity by suppressing cardiovascular senescence via a mechanism involving the exercise-induced myosin irisin, and that exercise is a potential intervention for preventing Dox-induced cardiotoxicity.

Discussion

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Cite This Study

Jeyabal et al. (2026) studied Doxorubicin-induced cardiotoxicity. Exercise vs. Doxorubicin only (no exercise) and PBS control was evaluated on Cardiac cellular senescence (p16-RFP+ cells) and cardiac function (ejection fraction and fractional shortening) (p=<0.0001). Exercise significantly prevented doxorubicin-induced cardiac cellular senescence (p<0.0001) and preserved cardiac function via the FNDC5/irisin signaling pathway.

synapsesocial.com/papers/6ad1156b00741cc3fba7d384 https://doi.org/10.21203/rs.3.rs-10910107/v1

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Exercise inhibits doxorubicin-induced cardiotoxicity by preventing cardiac and endothelial cell senescence by activating FNDC5/Irisin signaling

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Exercise inhibits doxorubicin-induced cardiotoxicity by preventing cardiac and endothelial cell senescence by activating FNDC5/Irisin signaling

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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