on October 12th, 2015 No Comments
The healthy human heart is a hard-working muscle: Beating just over 100,000 beats per day, it pumps five quarts of blood per minute – enough to fill three supertankers worth of blood over the course of an average person’s lifetime.
Like any other mechanical pump, the heart is made up of various components, including different kinds of proteins. One of those proteins, a “molecular motor” called cardiac myosin (there are several varieties of myosin), plays a crucial role. A myosin molecule can oscillate lengthwise, contracting and relaxing by turns. It’s the coordinated oscillations of myriad cardiac myosin molecules that are, in the aggregate, responsible for the heartbeat.
Defective cardiac myosin exacts a severe medical price. Hypertrophic cardiomyopathy, caused by mutations in a gene encoding cardiac myosin, occurs in at least one in 500 people and is a leading cause of heart failure in the United States and worldwide. It’s also the primary cause of sudden deaths due to heart attack in people under age 30.
A mutation known as R403Q, identified a couple of decades ago, ranks among the nastiest and most widely studied of literally hundreds of cardiac-myosin mutations. The general thinking has been that the mutation results in a “gain of function,” meaning stronger-than-normal myosin contractility.
Now, researchers under the direction of Stanford biochemist Jim Spudich, PhD, have for the first time been able to look at the effects of this mutation in human cardiac myosin as opposed to animal models. Spudich, whom I wrote up in 2012 as the winner of that year’s prestigious Lasker Award for Basic Medical Research, is a pioneer in the analysis of myosin and its associated motility-related proteins. Integrating approaches drawn from cell physiology, physics, biochemistry, structural biology and genetics, Spudich and his colleagues have developed methods of measuring the exact amount of energy consumed in each contraction of a single molecule of myosin. (In my 2012 Lasker Award write-up, I explained myosin’s critical involvement not only in heartbeat but also in all muscular movement and, indeed, all transport of molecular materiel within every living plant or animal cell.)
In a study published in Science Advances, Spudich’s team measured the effects of the R403Q mutation at the single-molecule level and was able to demonstrate tiny, but relevant changes in the power of the mutant myosin molecule.The next step is to, in an even more sophisticated way, measure these effects in a microenvironment more closely approximating that of a living human heart.
R403Q is just the first of several hypertrophic-cardiomyopathy-inducing mutations the team is analyzing, one by one, with their state-of-the-art techniques.
Previously: Stanford molecular-motor maven Jim Spudich wins Lasker Award, Sudden cardiac death has cellular cause, say Stanford researchers and Stanford patient on having her genome sequenced: “This is the right thing to do for our family”
Photo by Sharon Sinclair