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.