The Fast Skeletal Troponin Activator, CK‐2017357, Increases Skeletal Muscle Force in‐vitro and in‐situ

Abstract

CK‐2017357 is a member of a class of fast skeletal troponin activators that were identified by high throughput screening of skeletal sarcomere preparations. We sought to understand how this compound altered force development in isometric muscle fibers. Treatment of skinned rabbit psoas fibers with CK‐2017357 caused a dose‐dependent shift of the force‐pCa relationship without altering the Hill slope or maximum force, consistent with a calcium sensitizing effect on force production. In living rat FDB muscle, CK‐2017357 (10 μM) increased sub‐tetanic force (150% of control at 10 Hz) without altering maximum force. Similar experiments were performed using rat EDL muscle in‐situ, where nervous and vascular connections were left intact. Infusions of 10 mg/kg increased sub‐tetanic force by 200% at 30 Hz. In summary, we have identified a skeletal troponin activator that sensitizes the sarcomere to calcium and results in increased sub‐maximal muscle force development in‐vitro and in‐situ. We believe that this may translate to improved muscle function in diseases where muscle is compromised due to injury, disease or age.