Cardiac and Skeletal Muscle Myofilament Activators for the Treatment of Barth syndrome
Leonardo Ferreira, PhD, Duke University
Development Award, $99,519, over two years
Barth syndrome (BTHS) causes muscle weakness, fatigue, and difficulty with exercise. Currently, there are no approved treatments for these symptoms. Past research has shown that the ability of the heart and muscles to contract is greatly reduced in patients with BTHS. While it’s generally believed that these issues are due to a lack of energy in the cells, some researchers think that problems with special ions like calcium or cellular engines that generate force could also be contributing to the muscle issues. Most attempts to treat BTHS have focused on improving how cells make energy. However, this project proposes to improve the muscles’ ability to contract or squeeze, which could help with the energy issue and provide additional benefits. Recently, certain small molecules (and potential drug compounds) called “muscle activators” have been found to improve heart contraction and exercise tolerance in patients with heart failure not related to BTHS. These activators have also been shown to increase muscle strength and endurance in animal models and human studies. Importantly, unlike some other treatments, they improve muscle contraction without negatively affecting the cells’ energy production. The Ferreira lab proposes to study these muscle activators in a mouse model of BTHS. They will compare four groups of mice: normal mice, BTHS mice given a placebo, BTHS mice given a skeletal muscle activator, and BTHS mice given a cardiac muscle activator. The main study outcomes will be exercise capacity, heart function, muscle contraction force, and power. This approach is innovative because it targets the muscle contraction mechanism, rather than the cellular energy production. Previous treatments that focused on energy production have been successful in animals but have failed in clinical trials. The researchers hope that this new approach might help to alleviate the heart and muscle problems in BTHS.
