Biophysicists at Emory University have identified a new molecular mechanism by which the protein leiomodin builds actin filaments in muscle cells. Published in Nature Communications, the discovery explains how muscles maintain precise filament length from birth to death, offering potential new avenues for treating heart failure and dilated cardiomyopathy.
Leiomodin and the Minus-End Growth Mechanism
Researchers led by Shashank Shekhar, an assistant professor of physics at Emory University, discovered that muscle cells bypass the standard treadmilling process. Instead of growing from the plus end, the protein leiomodin enables growth at the minus end. This finding resolves the mystery of how sarcomeres—the smallest organized units of muscle cells—remodel and replenish themselves without altering their overall length.
Clinical Implications for Dilated Cardiomyopathy
The ability of muscles to contract is directly tied to the length of these actin filaments. Because this length is strictly controlled from birth until death, any disruption in the assembly process can lead to severe pathology. The Emory team found that defects in leiomodin can disrupt the contractile machinery of the heart.
Specifically, genetic mutations in leiomodin are linked to dilated cardiomyopathy. This condition causes heart muscles to weaken progressively, impairing the organ’s ability to pump blood effectively. By providing a molecular explanation for this failure, the research may assist in designing treatments for this leading cause of heart failure.
Microtubules and the ERK Pathway in Heart Remodeling
While the Emory study focuses on actin filaments, separate research from the Perelman School of Medicine at the University of Pennsylvania highlights other “skeleton” components that dictate heart shape. A team led by Benjamin Prosser, PhD, found that microtubules and the ERK signaling pathway control how heart cells grow in response to stress.
- Lateral Growth: Stabilized microtubules favor an increase in cell width.
- Longitudinal Growth: Destabilized microtubules cause the cells to lengthen.
Furthermore, the team found that heart cells use the ERK pathway to determine where building materials are delivered from the nucleus. This pathway tends to favor growth closer to the nucleus, meaning heart muscle cells essentially grow from the inside out. This thickening is particularly prevalent in conditions like hypertension, though the researchers noted that ERK does not appear to be involved in healthy growth resulting from long-term exercise.
Therapeutic Targets and Current FDA Options
The discovery of these “tunable” targets—leiomodin for actin length and microtubules/ERK for cell shape—opens potential doors for correcting abnormal heart growth. In the case of dilated cardiomyopathy, where the heart stretches too much, or hypertrophic cardiomyopathy, where muscles thicken, controlling the direction of growth is critical.
According to the University of Pennsylvania team, the FDA already has approved treatments that address ERK signaling or microtubule stability. However, these may require modification to target muscle cells more specifically. Without such precision, these therapeutics could cause unintended side effects because microtubules and ERK signaling regulate numerous processes across various cell types in the body.
The combined findings from these institutions suggest a complex, multi-layered system of structural control in the heart. While leiomodin manages the fundamental length of the contractile filaments, the ERK pathway and microtubule stability dictate the broader geometry and width of the heart cells.
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