March 8, 2016

Engineered protein restores heart function in mice

At a Glance

  • Using an engineered protein, researchers were able to improve heart function in mice and protect the animals from heart attacks.
  • Further work will be needed to determine whether this approach will work in larger animal models.
Mouse heart muscle The engineered form of the troponin C protein, TnC L48Q (red), became part of the heart’s contractile machinery and improved heart function in mice.Davis laboratory, courtesy of Nature Communications

The heart typically beats more than 100,000 times each day. It alters its rate (beats per minute) and contraction force in response to the needs of the body. For example, when someone runs to catch a bus, the heart beats faster and with more force to provide increased oxygen and nutrients to the working leg muscles.

When someone has had a heart attack or has heart failure, the heart isn’t able to contract with enough force to meet an increased energy demand. Thus the person may become short of breath when doing activities that require even minor physical effort, such as walking across a room. Current treatments to improve heart function include medications and surgery. However, these can cause side effects, such as arrhythmias.

A team led by Dr. Jonathan P. Davis at Ohio State University set out to improve the ability of the heart to contract by using protein engineering. The study was funded in part by NIH’s National Heart, Lung, and Blood Institute (NHLBI). Results appeared on February 24, 2016, in Nature Communications.

Heart cell contraction is regulated by calcium binding to a protein called troponin C. The researchers designed troponin C types with varying sensitivity to calcium. They then used a harmless virus commonly used for gene therapy to deliver the engineered form into heart cells.

They found that TnC L48Q, a troponin C form that was more sensitive to calcium, improved several characteristics of function and performance in rabbit myofibrils (contractile machinery) and mouse heart cells as well as in normal mice.

The scientists injected mice with TnC L48Q and then induced a heart attack. The altered troponin C was protective; it improved heart function and performance without adversely affecting electrical activity and other characteristics.

Mice given TnC L48Q after an induced heart attack also showed improved heart performance, illustrating that the engineered protein could also serve as a treatment.

The researchers found that TnC L48Q improved function even when it only partially replaced the animal’s normal existing troponin C. The engineered form didn’t adversely influence cell death or inflammation, or alter the heart’s electrical activity.

“It’s long been presumed that altering the receptor would be ineffective, that it was better to change the calcium signal,” says lead author Vikram Shettigar. “We’re seeing strong evidence that’s not the case. Changing the calcium receptor does have a significant and safer impact.”

The team is working to customize several forms of troponin C to increase or decrease contraction force to respond to a range of disorders.

—by Carol Torgan, Ph.D.

Related Links

Reference: Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease. Shettigar V, Zhang B, Little SC, Salhi HE, Hansen BJ, Li N, Zhang J, Roof SR, Ho HT, Brunello L, Lerch JK, Weisleder N, Fedorov VV, Accornero F, Rafael-Fortney JA, Gyorke S, Janssen PM, Biesiadecki BJ, Ziolo MT, Davis JP. Nat Commun. 2016 Feb 24;7:10794. doi: 10.1038/ncomms10794. PMID: 26908229.

Funding: NIH’s National Heart, Lung, and Blood Institute (NHLBI) and National Center for Research Resources (NCRR); and the Fred A. Hitchcock Professorship in Environmental Physiology.