Antihypertrophic Memory After Regression of Exercise-Induced Physiological Myocardial Hypertrophy Is Mediated by the Long Noncoding RNA Mhrt779

Abstract

Background: Exercise can induce physiological myocardial hypertrophy (PMH), and former athletes can live 5-6 years longer than nonathletic controls, suggesting a benefit after regression of PMH. We previously reported that regression of pathological myocardial hypertrophy has antihypertrophic effects. Accordingly, we hypothesized that antihypertrophic memory exists even after PMH has regressed, increasing myocardial resistance to subsequent pathological hypertrophic stress. Methods: C57BL/6 mice were submitted to 21 days of swimming training to develop PMH. After termination of exercise, PMH regressed within 1 week. PMH regression mice (exercise hypertrophic preconditioning group, EHP) and sedentary mice (control group) then underwent transverse aortic constriction (TAC) or a sham operation for 4 weeks. Cardiac remodeling and function were evaluated using echocardiography, invasive left ventricular hemodynamic measurement and histological analysis. LncRNA sequencing, chromatin immunoprecipitation assay (ChIP), and comprehensive identification of RNA-binding proteins by mass spectrometry (CHIRP-MS) and Western blot were used to investigate the role of Mhrt779 involved in the anti-hypertrophy effect induced by EHP. Results: At 1 and 4 weeks after TAC, the EHP group showed less increase in myocardial hypertrophy and lower expression of the Nppa and Myh7 genes than the sedentary group. At 4 weeks after TAC, EHP mice had less pulmonary congestion, smaller left ventricular dimensions and end-diastolic pressure, and a larger left ventricular ejection fraction and maximum pressure change rate than sedentary mice. Quantitative polymerase chain reaction (qPCR) revealed that the long noncoding myosin heavy chain associated RNA transcript Mhrt779 was one of the markedly upregulated long noncoding RNAs in the EHP group. Silencing of Mhrt779 attenuated the antihypertrophic effect of EHP in mice with TAC and in cultured cardiomyocytes treated with angiotensin II, and overexpression enhanced the antihypertrophic effect. By ChIP and qPCR, we found that EHP increased histone 3 trimethylation (H3K4me3 and H3K36me3) at the a4 promoter of Mhrt779 . CHIRP-MS and Western blot showed that Mhrt779 can bind Brg1 to inhibit the activation of Hdac2/Akt/GSK3β pathway induced by pressure overload. Conclusions: Myocardial hypertrophy preconditioning evoked by exercise increases resistance to pathological stress via an antihypertrophic effect mediated by a signal pathway of Mhrt779 /Brg1/Hdac2/p-Akt/p-GSK3β.

Growth differentiation factor 11 attenuates cardiac ischemia reperfusion injury via enhancing mitochondrial biogenesis and telomerase activity

“…Oe-GDF11, sh-GDF11, and NC virus particles (1 × 10 11 viral genomes/ml) were administered by using a 300 μl syringe with 30 gauge needle to direct inject into the LV free wall (three evenly dispersed sites, 10 μl/site) in 8-week-old mice. Do not insert the syringe needle too deep to avoid piercing the ventricular wall muscles into the LV [ 30 ]. Twenty-four hours after IR or sham, the samples were harvested for total protein or mRNA extraction.…”

The Relationship among Physical Activity, Intestinal Flora, and Cardiovascular Disease

“…The destruction of intestinal barrier function and the change of GM composition may lead to abnormal production and absorption of microbial metabolites in patients with HF. Imbalance of intestinal microbial metabolites and intestinal epithelial dysfunction may lead to cardiac dysfunction, inflammation, malnutrition, and other diseases in patients with HF [57]. HF leads to changes in blood flow such as insufficient tissue perfusion and gastrointestinal congestion, which can change body's intestinal morphology, permeability, and abundance and composition Cardiovascular Therapeutics of GM, which in turn damages the intestinal barrier function, stimulates the inflammatory response, and accelerates its pathological development [58].…”

Modulation of Cardiac Fibrosis in and Beyond Cells

“…A recent animal study found that moderate-intensity exercise training but not high-intensity interval training reduced cardiac fibrosis ( Table 1 ) and oxidative stress, improved cardiac function in aged (32-week-old) male mice ( Pei et al, 2021 ). Exercise hypertrophic preconditioning in mice could also alleviate cardiac fibrosis ( Table 1 ), hypertrophy and dysfunction at 1 week and 4 weeks post-TAC ( Lin et al, 2021 ). Therefore, moderate exercise can decrease cardiac fibrosis, but endurance exercise can induce cardiac fibrosis to some extent which may be related to the sex, age, and the exercise intensity.…”