Microtubules, part of heart muscle cells' internal "skeleton," help determine how the heart changes shape under stress, and a common signaling pathway called the ERK pathway acts as a key controller of where the building materials for these cells' growth are delivered inside them, a pair of new studies show. These findings, from a team at the Perelman School of Medicine at the University of Pennsylvania, point to possible new ways to address harmful heart remodeling that can be linked to heart failure.
"The molecular decision behind how a heart cell, and by extension the heart, changes in size and shape has been a mystery, even though we've known that heart cells do change in length and width over a person's life in response to different conditions," said the studies' senior author Benjamin Prosser, PhD , a professor of Physiology. "But now that we know what is doing the work and what guides it, that opens the door to targeting these mechanisms and correcting abnormal growth."
Prosser's team demonstrated that they could redirect where the microtubules delivered materials from the nucleus to remodel heart cells, which influenced which direction growth was taking place in a heart cell. That meant either making heart cells' natural cylinder shape wider or longer.
Since two common heart conditions are dilated cardiomyopathy (when the heart's muscle stretches too much) and hypertrophic cardiomyopathy (when the heart's muscles thicken too much), being able to control the direction of growth could be a key tool against the development of heart failure.
Stability and instability as the deciders
In their paper published in Science , Prosser and first author Emily Scarborough, PhD , a senior research investigator in Prosser's lab, demonstrated that the stability of microtubules actually held the key to which direction heart muscle cell growth occurred. When the microtubules were stabilized, lateral growth was favored, increasing cell width. But, when the microtubules were destabilized, growth occurred long-ways to lengthen the cells.
At the same time, in both mouse models and human heart samples, stabilized microtubules also strengthened intercalated discs, which serve as key points of contact between muscle cells. And, as followed, destabilized microtubules led to weakening of these cell-cell contacts.
"We were not expecting to find two unique ways for the heart to grow thicker or thinner when we started this research," Scarborough said. "Now we think we have discovered 'tunable' targets to affect each."
The destination after the depot
Most human cells grow in a relatively conventional way: If they have more nutrients, they can grow. This is usually governed by a signaling pathway called mTOR . But, in a second paper, published in Science Signaling , Prosser and first author Keita Uchida, PhD , a research associate in Physiology, found that heart cells use a secondary pathway called ERK .
In the heart cell, resources are exported from the nucleus, which acts as the cells' supply depot. The delivery address of the resources was determined by the ERK pathway. This pathway appeared to favor sending those materials to locations closer to the nucleus, as opposed to the far ends of the cells, meaning that it leaned toward growing cell width.
"New growth was favored in the interior of the cell," Uchida said. "This suggests that heart muscle cells are growing from the inside out."
This thickening occurs especially in conditions like hypertension, and the researchers determined that ERK does not involve itself in healthy heart growth, such as what occurs as a result of long-term exercise.
Uchida also explained that more work is needed to determine whether an overactive ERK pathway could be to blame for conditions like hypertrophic cardiomyopathy.
The FDA already has several approved treatment options that either tune microtubules' stability or address ERK signaling, but they may need to be tweaked before they're useful in what Prosser and his colleagues discovered.
"Microtubules and ERK signaling regulate numerous biological processes in multiple cell types across the body, so we would likely want to more directly focus any therapeutics to more directly target muscle cells in order to avoid any unintended side effects," Prosser said.
