The Fast Skeletal Troponin Activator, CK-1909178, Increases Skeletal Muscle Force in-vitro and in-situ

Abstract

Previously, we have discovered small molecules that increase cardiac contractility by directly activating the cardiac sarcomere; this mechanism is now being investigated as a therapy for treating systolic heart failure. Using this precedent, we have focused on the identification of compounds that directly increase skeletal muscle contractility for the potential therapy of diseases that result in muscle weakness and fatigue.CK-1909178 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 skinned and live muscle fibers. Treatment of skinned rabbit psoas fibers with 0.1 μM CK-1909178 caused a dose-dependent left-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 flexor digitorum brevis (FDB) preparations, CK-1909178 (10 μM) caused significant increases in sub-tetanic force (150% of control at 10 Hz) without altering maximum force. Similar experiments were then performed using a rat extensor digitorum longus (EDL) preparation in-situ, where nervous and vascular connections were left intact and the muscle was stimulated via the peroneal nerve. Infusions of CK-1909178 up to 10 mg/kg rapidly increased sub-tetanic isometric force (190% of control 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 mechanism may translate to improved physical power and strength in diseases where muscle function is compromised due to injury, disease or age.