Exercise induces new cardiomyocyte generation in the adult mammalian heart

Ana Vujic,Matthew L Steinhauser,Ting-Di Wu,Carolin Lerchenmüller,Jean-Luc Guerquin-Kern,Christelle Guillermier,Charles P Rabolli,Samuel E Senyo,Richard T Lee,Anthony Rosenzweig,Xiaojun Liu,Emilia Gonzalez

doi:10.1038/s41467-018-04083-1

Abstract

Loss of cardiomyocytes is a major cause of heart failure, and while the adult heart has a limited capacity for cardiomyogenesis, little is known about what regulates this ability or whether it can be effectively harnessed. Here we show that 8 weeks of running exercise increase birth of new cardiomyocytes in adult mice (~4.6-fold). New cardiomyocytes are identified based on incorporation of 15N-thymidine by multi-isotope imaging mass spectrometry (MIMS) and on being mononucleate/diploid. Furthermore, we demonstrate that exercise after myocardial infarction induces a robust cardiomyogenic response in an extended border zone of the infarcted area. Inhibition of miR-222, a microRNA increased by exercise in both animal models and humans, completely blocks the cardiomyogenic exercise response. These findings demonstrate that cardiomyogenesis can be activated by exercise in the normal and injured adult mouse heart and suggest that stimulation of endogenous cardiomyocyte generation could contribute to the benefits of exercise.

Highlights

Loss of cardiomyocytes is a major cause of heart failure, and while the adult heart has a limited capacity for cardiomyogenesis, little is known about what regulates this ability or whether it can be effectively harnessed
In conjunction with the increase in cardiomyocyte DNA synthesis, we detected an increase in 15N-thymidine labeled noncardiomyocytes in exercised hearts compared to sedentary controls (Supplementary Fig. 2c)
To determine if this increase in 15N-thymidine labeled non-CMs was accompanied by an exercise-induced neo-angiogenic response, we analyzed the capillary density by immunohistochemistry and found an increased number of capillaries per cardiomyocyte following exercise training (4.14 ± 0.07 vs. 3.75 ± 0.08 capillaries/cardiomyocyte in exercised vs. sedentary controls, mean ± s.e.m., p < 0.05, two-sided t test) (Supplementary Fig. 2d)

Summary

Introduction

Loss of cardiomyocytes is a major cause of heart failure, and while the adult heart has a limited capacity for cardiomyogenesis, little is known about what regulates this ability or whether it can be effectively harnessed. Inhibition of miR-222, a microRNA increased by exercise in both animal models and humans, completely blocks the cardiomyogenic exercise response These findings demonstrate that cardiomyogenesis can be activated by exercise in the normal and injured adult mouse heart and suggest that stimulation of endogenous cardiomyocyte generation could contribute to the benefits of exercise. Multiple studies have used quantitative analyses of DNA isotope labeling to demonstrate a similar baseline rate of cardiomyogenesis in adult humans[4,5] and mice[3]. Whether this basal level of cardiomyogenesis can be enhanced by physiological stimuli remains unclear. We conclude that exercise stimulates cardiomyogenesis in the injured and uninjured adult mouse heart and that miR-222 is necessary for the cardiomyogenic response

Methods

Results

Conclusion