In the exercise community, it is often preached that working out is a form of medicine and can be crucial to maintaining a healthy lifestyle. Routine exercise helps to retain healthy body weight and has been shown to lower the risk of diseases such as diabetes, obesity, and high blood pressure. It’s even been shown to keep the brain healthy. High-intensity exercise places a “good stress” on the heart allowing robust function – but why is stress from exercise considered good, and stress from high blood pressure considered bad? We already know that epigenetics plays a role in muscle memory and it may provide an explanation here as well.

Researchers from the German Center for Cardiovascular Research (DZHK) and Heidelberg University Hospital in Germany have discovered that a stress-responsive epigenetic switch called histone deacetylase 4 (HDAC4) may be responsible for enabling or preventing heart failure depending on which metabolic pathway is switched on when the heart is put under stress. Their study was published in Nature Medicine.

The research team placed two types of stress on the hearts of mice: “good” physiological stress from exercise and “bad” pathological stress from high blood pressure. They aimed to determine the effects that each form of stress had on overall heart health and examined a chain of metabolic processes.

Ultimately, they found that a previously undetected signal pathway could cause or protect someone from heart failure. At the end of the signal pathway, more HDAC4 fragments were found in the hearts of the healthy mouse after exercise. Conversely, the mice with high blood pressure did not generate any HDAC4, meaning that healthy stress led to the healthy pathway, and the unhealthy stress took the pathway towards heart failure.

To test this further, the researchers created genetically modified mice that were unable to generate any HDAC4 fragments. After the mice underwent physiological stress, they found that exercise no longer had a healthy effect, and the mice ultimately ended up developing a temporary heart failure. This suggests that HDAC4 could be the epigenetic switch responsible for maintaining a healthy heart.

So what makes physiological stress good and pathological stress bad? Professor Johannes Backs from the DZHK speculates that the frequent breaks that exercise offers are the difference maker. During the rest periods experienced in exercise, an enzyme called protein kinase A recovers and enables the activation of the HDAC4 fragments to follow the healthy pathway of the metabolic chain. This may also explain why high-intensity sports without breaks can cause damage to the athlete’s heart.

“We all intuitively know that breaks are important. Perhaps we have now found the molecular causes for this,” said Backs.

Pathological stress due to high blood pressure does not provide the same benefit as physiological stress. High blood pressure applies a constant, permanent strain on the heart without allowing protein kinase A to recover properly, thus diminishing the activity of HDAC4 fragments, sending the signals in the heart cells down a dark path with heart failure waiting at the end. The myocardial cells begin to produce energy using sugars, rather than fats. These sugars produce residues that can attach to and alter protein function, ultimately inhibiting the heart’s calcium metabolism responsible for the heart’s pumping function.

Backs was excited about the discovery and began epigenetic therapy treatments for mice to protect from the waning power of cardiac muscles. “These findings are novel and change the way we think about how a myocardial cell can fail. We were able to demonstrate that there is a link from epigenetics via the metabolism through to contractility, i.e., through to cardiac function.”

The findings in this study could also apply to other stress-related diseases, particularly broken heart syndrome, or Takotsubo cardiomyopathy, which is temporary heart failure brought on by acute, extreme stress—usually emotional. Backs looks to apply the epigenetic insights he gained in this study to investigate the well-known condition.

Source: Lehmann, L.H. et al. (2018). A Proteolytic Fragment of Histone Deacetylase 4 Protects the Heart from Failure by Regulating the Hexosamine Biosynthetic Pathway. Nature Medicine, 24: 62–72.

Reference: German Centre for Cardiovascular Research (DZHK). Exercise is good for the heart, high blood pressure is bad – Researchers find out why. DZHK Latest News. 11 Dec 2017. Web.