Benjamin Prosser's team at the University of Pennsylvania has cracked open one of cardiology's enduring mysteries: how heart cells decide whether to grow wider or longer, and what controls the delivery of the materials they need to do it. The answer lies in two elegant mechanisms—microtubule stability and a signaling pathway called ERK—that act like a cellular traffic system, directing growth materials from the heart cell's nucleus to different destinations depending on what signals the cell receives.
Heart cells are living architecture, constantly reshaping themselves in response to the stresses and demands of life. Whether someone develops a heart that stretches dangerously thin (dilated cardiomyopathy) or thickens excessively (hypertrophic cardiomyopathy), both conditions can lead to heart failure. Yet until now, researchers understood that these changes happen without knowing precisely what orchestrates them. "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," Prosser, a professor of Physiology at the Perelman School of Medicine, explained in the studies.
The breakthrough came through two complementary papers. In the first, published in Science, Prosser and senior research investigator Emily Scarborough demonstrated that microtubules—part of the cell's internal skeleton—act as the directors of growth direction. When microtubules are stabilized, they favor lateral growth, making cells wider. When destabilized, they encourage lengthwise growth, making cells longer. The findings went deeper still: stabilized microtubules also strengthened intercalated disks, the crucial contact points where heart muscle cells connect to one another. Destabilized microtubules weakened these connections. "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 second mechanism involves the ERK signaling pathway, which functions as a kind of postal service for cellular resources. Unlike most cells in the body, which rely on the mTOR pathway to manage growth based on nutrient availability, heart cells have evolved a secondary system. As described in a companion paper published in Science Signaling, Prosser and research associate Keita Uchida found that the ERK pathway determines where growth materials exported from the nucleus actually go. Crucially, ERK favors delivering these resources to locations closer to the nucleus rather than to the cell's far ends—meaning it leans toward thickening growth. "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 pattern appears especially in conditions like hypertension, and the researchers found that ERK plays no role in healthy growth from exercise.
What makes these discoveries immediately promising is that the FDA already has approved drugs that either tune microtubule stability or address ERK signaling. Though these medications will likely need refinement before they can be safely targeted to the heart, the existence of such tools means researchers now have a concrete path toward intervention. Understanding the mechanics of harmful remodeling opens the possibility of correcting it—potentially transforming how cardiologists approach one of the heart's most dangerous adaptive responses.