Highlights The secretion of skeletal muscle FSTL1 was stimulated by dynamic resistance exercise. FSTL1 from skeletal muscle supplemented the insufficiency of cardiac FSTL1, which promoted myocardial angiogenesis and protected the heart from myocardial infarction. Exogenous FSTL1 improved the proliferation and the small tubes formation ability of HUVECs. FSTL1-DIP2A regulated angiogenesis mainly through the Smad2/3 but was not affected by TGFβR1. FSTL1, DIP2A, Smad2/3, and fstl1 gene transcription formed a regulation mode of feedback loop.

The aim of this study was to investigate whether skeletal muscle-derived follistatin-like 1 (FSTL1) reaches the heart and exerts the angiogenetic function in rats suffering myocardial infarctions (MI) after exercise intervention. Methods Forty-eight male adult Sprague-Dawley rats were randomly divided into four groups. MI was provoked by ligation of left anterior descending coronary artery. MI rats underwent adeno-associated virus injection of FST1 in tibialis anterior muscle and 4 weeks of resistance exercise via a tail-suspended incremental weight-climbing method (0-75% body weight, daily load increased by 10%; 1 h/day, 5 day/w). Heart function was evaluated by hemodynamics including LVSP, LVEDP and ± dP/dt max; the cross-sectional area of muscle cells and myocardium fibrosis were analyzed by DiI and Masson's staining, respectively; the FSTL1 expression, endothelial cell proliferation and angiogenesis were visualized by immunofluorescence staining; and protein expression was quantified by Western blotting. Results Resistance exercise reverted MI-induced skeletal muscle atrophy, increased muscle FSTL1 expression and stimulated skeletal muscle derived FSTL1 entering into the MI heart via blood circulation. The overexpression of skeletal muscle FSTL1 improved myocardial endothelial cell proliferation, increased small vessel density in the fibrotic border, inhibited myocardial fibrosis and improved heart function in the MI rats after the exercise intervention. Meanwhile, DIP2A-PI3K-Akt-mTOR, Erk1/2 and TGFβ-Smad2/3 pathways were activated in the myocardium. Conclusion Resistance exercise stimulates skeletal muscle derived FSTL1 to reach the myocardium which makes a positive contribution to cardioprotection in MI rat.

Objective Exercise has been reported to have positive function after myocardial infarction (MI), but the mechanisms of exercise-induced cardioprotection are poorly understood. ELABELA (ELA) is a hormone and plays a vital role in cardiovascular system. The aim of this research is to investigate the effect and the mechanisms of exercise and exogenous ELA administration on cardioprotection in MI rat. Methods MI was established by left coronary artery ligation. MI rats underwent 4 weeks of sustainedaerobic exercise and Fc-ELA-21 or Fc-ELA-32 injection. H9C2 cells were treated by ELA-14 peptide. Akt signal was inhibited by LY294002. Heart function was evaluated by hemodynamics; Myocardium fibrosis, cell proliferation, angiogenesis and apoptosis were visualized by Masson’s staining, immunohistochemistry and TUNEL, respectively; Protein expression was quantified by Western blotting. Results Exercise induced angiogenesis and cardiomyocyte proliferation, reduced fibrosis and improved the function of MI heart. Fc-ELA-21 injection further facilitated the exercise-induced cardioprotection effects. APJ expression was up-regulated and Akt-mTOR-P70S6K signal was activated by both exercise and Fc-ELA-21. In H9C2 cells, ELA-14 activated Akt signal by dose dependent manner. Akt signal inhibitioninvalidated ELA-14 function. Fc-ELA-32 directly improved structural and functional recovery of post-MI hearts. Conclusions ELA is a heart protector and facilitates exercise-induced cardioprotectionthrough Akt-mTOR-P70S6K signal inpost-infarction cardiac remodeling.

Objective The aim of this study is to investigate the effect of skeletal muscle-derived FSTL1 on cardioprotection in myocardial infarction rats after resistance exercise or tibialis anterior muscle injection of follistatin-like protein 1 (FSTL1) adeno-associated virus vector and its possible signaling mechanisms. Methods The male Sprague-Dawley rats were randomly divided into five groups (n=10): Sham-operated group(S), sedentary MI group (MI), MI with resistance exercise group (MR), MI with empty adeno-associated virus (AAV) vector group (MV) and MI with FSTL1-AAV group (MF) after the MI model established which was induced by left anterior descending (LAD) coronary artery ligation. S group underwent threading without ligation. 1 week post MI, rats in MR group underwent resistance exercise for 4 weeks, rats in MV and MF group were injected AAV empty vector and FSTL1-AAV in the tibialis anterior muscle of the left limb, respectively. The next day after exercise, rats were anesthetized and heart function was measured. Collagen volume fraction(%) of myocardium were observed and calculated by Masson staining; cardiomyocyte proliferation was measured by immunofluorescence; cardiomyocyte apoptosis was detected by TUNEL staining; The protein expression of skeletal muscle and serum FSTL1 and myocardium FSTL1, DIP2A, pAkt/Akt, p-mTOR/mTOR, CyclinD1, CDK4 and Bcl2/Bax in myocardium were measured by Western blotting. Results The skeletal muscle FSTL1 protein expression was decreased but the serum and myocardium FSTL1 were upregulated in MI group. The myocardium fibrosis, cardiomyocyte proliferation and cardiomyocyte apoptosis were increased and the heart function was declined after MI. After resistance exercise or tibialis anterior muscle injection of FSTL1-AAV, the skeletal muscle, serum and myocardium FSTL1 protein expression were significantly increased, and there was a significant positive correlation between each data. Myocardium fibrosis and cardiomyocyte apoptosis were also decreased, cardiomyocyte proliferation was increased and the heart function was significantly improved after FSTL1-AAV injection. Conclusions Resistance exercise increases skeletal muscle FSTL1 expression. Skeletal muscle-derived FSTL1 can reach the heart through blood circulation, promote cardiomyocyte proliferation, inhibit cardiomyocyte apoptosis, reduce myocardium fibrosis and improve heart function in MI rats. Myocardium FSTL1 binds to its receptor, DIP2A, and activates the Akt-mTOR signaling pathway might be the potential mechanism of this protective effect.