Communication Pathways in Heart Shown to Decrease with Age

Heart muscle cells, or cardiomyocytes, undergo natural wear and tear throughout aging, with some functions suffering more than others. Nuclear pores have been proven as an essential communication pathway for nuclear-cytoplasmic transport, but scientists at the University of Pittsburgh and UMPC discovered that the number of paths decreases dramatically as heart cells develop. While this function might help protect the organ from damaging signals, it could also prevent adult heart cells from regenerating.

The team was particularly interested in these specialized pores along the nuclear envelope since they are responsible for regulating the passage of molecules to and from the nucleus. “The nuclear envelope is an impermeable layer that protects the nucleus like asphalt on a highway,” says Bernhard Kühn, M.D., professor of pediatrics and director of the Pediatric Institute for Heart Regeneration and Therapeutics at Pitt School of Medicine and UPMC Children’s Hospital of Pittsburgh. “Like manholes in this asphalt, nuclear pores are pathways that allow information to get through the barrier and into the nucleus.”

Using super-resolution microscopy, the team, comprised of experts such as Yang Liu, Ph.D., associate professor of medicine and bioengineering, and Donna Stolz, Ph.D., associate professor of cell biology and pathology and associate director of the Center for Biologic Imaging, was able to count the number of nuclear pores in mouse cardiomyocytes throughout the lifespan. They found that the number of pores decreased by 63% across development, from an average of 1,856 in fetal cells to just 678 in adult cells.

In previous work, Kühn and colleagues identified a gene essential for cardiomyocyte regeneration called Lamin b2. At the time, the team noted that this gene was highly expressed in newborn mice but dwindled significantly with age. The team explored these patterns again in the new study, published in Developmental Cell, by further examining how this gene impacts the number of nuclear pores found in mice. They found that blocking Lamin b2 led to fewer nuclear pores and, thus, diminished transport of signaling proteins in the nucleus. The decreased number of pores appeared to have a profound impact on gene expression, suggesting that reduced communication associated with age may drive a decrease in cardiomyocytes’ regenerative capacities.

“These findings demonstrate that the number of nuclear pores controls information flux into the nucleus,” says Kühn. “As heart cells mature and the nuclear pores decrease, less information is getting to the nucleus.”

To investigate how these signaling pathways are altered during stress, the researchers used a mouse model of high blood pressure to see how nuclear pores contributed to the structural remodeling of the heart, which is known to be a significant cause of heart failure. Mice engineered to express fewer nuclear pores showed less modulation of gene pathways involved in harmful cardiac remodeling, as well as obtained better heart function and survival than their peers with additional nuclear pores.

“We were surprised at the magnitude of the protective effect of having fewer nuclear pores in mice with high blood pressure,” says Kühn. “However, having fewer communication pathways also limits beneficial signals such as those that promote regeneration.”

Taken together, these findings reflect a dynamic communication system between cardiomyocytes and the rest of the aging body. “This paper provides an explanation for why adult hearts do not regenerate themselves, but newborn mice and human hearts do,” explains Kühn, who is also a member of the McGowan Institute for Regenerative Medicine. “These findings are an important advance in fundamental understanding of how the heart develops with age and how it has evolved to cope with stress.”