摘要：Highlights
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The secretion of skeletal muscle FSTL1 was stimulated by dynamic resistance exercise.
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FSTL1 from skeletal muscle supplemented the insufficiency of cardiac FSTL1, which promoted myocardial angiogenesis and protected the heart from myocardial infarction.
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Exogenous FSTL1 improved the proliferation and the small tubes formation ability of HUVECs.
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FSTL1-DIP2A regulated angiogenesis mainly through the Smad2/3 but was not affected by TGFβR1.
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FSTL1, DIP2A, Smad2/3, and
fstl1 gene transcription formed a regulation mode of feedback loop.
Purpose
The aim of this study was to investigate the potential of dynamic resistance exercise to generate skeletal muscle-derived follistatin like-1 (FSTL1), which may induce cardioprotection in rats following myocardial infarction (MI) by inducing angiogenesis.
Methods
Male, adult Sprague-Dawley rats were randomly divided into 5 groups (
n = 12 in each group): sham group (S), sedentary MI group (MI), MI + resistance exercise group (MR), MI + adeno-associated virus (AAV)–FSTL1 injection group (MA), and MI + AAV–FSTL1 injection + resistance exercise group (MAR). The AAV–FSTL1 vector was prepared by molecular biology methods and injected into the anterior tibialis muscle. The MI model was established by ligation of the left anterior descending coronary artery. Rats in the MR and MAR groups underwent 4 weeks of dynamic resistance exercise training using a weighted climbing-up ladder. Heart function was evaluated by hemodynamic measures. Collagen volume fraction of myocardium was observed and analyzed by Masson's staining. Human umbilical vein vessel endothelial cells culture and recombinant human FSTL1 protein or transforming growth factor-β receptor 1 (TGFβR1) inhibitor treatment were used to elucidate the molecular signaling mechanism of FSTL1. Angiogenesis, cell proliferation, and disco interacting protein 2 homolog A (DIP2A) location were observed by immunofluorescence staining. The expression of FSTL1, DIP2A, and the activation of signaling pathways were detected by Western blotting. Angiogenesis of endothelial cells was observed by tubule experiment. One-way analysis of variance and Student's
t test were used for statistical analysis.
Results
Resistance exercise stimulated the secretion of skeletal muscle FSTL1, which promoted myocardial angiogenesis, inhibited pathological remodeling, and protected cardiac function in MI rats. Exercise facilitated skeletal muscle FSTL1 to play a role in protecting the heart. Exogenous FSTL1 promoted the human umbilical vein vessel endothelial cells proliferation and up-regulated the expression of DIP2A, while TGFβR1 inhibitor intervention down-regulated the phosphorylation level of Smad2/3 and the expression of vascular endothelial growth factor-A, which was not conducive to angiogenesis. FSTL1 bound to the receptor, DIP2A, to regulate angiogenesis mainly through the Smad2/3 signaling pathway. FSTL1–DIP2A directly activated Smad2/3 and was not affected by TGFβR1.
Conclusion
Dynamic resistance exercise stimulates the expression of skeletal muscle-derived FSTL1, which could supplement the insufficiency of cardiac FSTL1 and promote cardiac rehabilitation through the DIP2A–Smad2/3 signaling pathway in MI rats.
Graphical Abstract
Image, graphical abstract
