Researchers from the University of Pennsylvania have shown that suppressing chemical changes to microtubules (MTs) results in improved cardiomyocyte function in damaged human heart tissue. MTs are a major component of cytoskeleton, a support structure that helps cells maintain their shape. In heart muscle cells, MTs can transmit mechanical signals and also buckle or bear pressure without snapping when there is a contraction. This new research describing a potential new drug target for heart disease is published in Nature Medicine.
Recent studies have suggested that removal of a tyrosine group from MTs, known as detyrosination, makes MTs stiff which prevents heart muscle cells from contracting normally. The researchers at Penn used mass spectrometry and mechanical tests on single cardiomyocytes to study the changes detyrosination has on MTs and how those changes impact heart function. Super-resolution microscopy revealed heavily detyrosinated MTs in diseased heart muscle cells explaining the lack of elasticity and inability to contract normally. Administration of a drug that inhibited detyrosinated MTs resulted in recovery of half of lost contractile function in diseased cells. A genetic approach that reduced MT detyrosination also resulted in softer diseased cells that were able to contract.
"These findings provide compelling evidence from human samples for a new therapeutic target for heart disease," said senior author Ben Prosser, PhD, an assistant professor of Physiology.
The research team will continue to their research with the goal of developing therapies that target damaged MTs and reverse their damaging impact. The next step is to develop a method to specifically target MTs in cardiomyocytes and optimize a gene therapy approach.