The Fast Skeletal Troponin Activator, CK-1909178 Reduces Muscle Fatigue in a Model of Peripheral Artery Disease in Situ

CK-1909178 is a member of a class of fast skeletal troponin activators that sensitize skinned skeletal muscle fibers to calcium. In rat muscle preparations in vitro and in situ, CK-1909178 increased sub-tetanic force without altering maximum force. Given that a major cause of muscle fatigue during repeated muscle contraction is reduced myoplasmic Ca2+ due to impaired sarcoplasmic reticulum Ca2+ release, we tested whether increased calcium sensitivity with CK-1909178 would slow the development of fatigue. Rat flexor digitorum brevis muscle was pretreated in vitro with CK-1909178 and stimulated every 3 seconds at a frequency sufficient to achieve 50% of maximum force for 6 min at 30°C. CK-1909178 diminished the extent of fatigue as compared to control (terminal force 29.5±8% vs. 12.7±4%, p<0.001). We next tested whether CK-1909178 treatment would slow the development of muscle fatigue using rat extensor digitorum longus muscle in situ, where the muscle was stimulated via the peroneal nerve. To accelerate the development of muscle fatigue, vascular insufficiency was produced by femoral artery ligation (FAL). Muscle fatigue with FAL and sham ligation in the presence and absence of CK-1909178 was assessed. CK-1909178 was administered as a 5mg/kg intravenous bolus before assessment of fatigue at a frequency adjusted to achieve the same force at 30Hz prior to dosing. FAL resulted in significantly reduced terminal tension as compared to sham (33±4% vs. 77±5%, p<0.01). CK-1909178 administration significantly attenuated FAL-induced fatigue at 10 minutes (61±7% vs. 33±4%, p<0.01). In summary, CK-1909178 increased sub-maximal muscle force development and reduced the extent of fatigue in the presence of limited blood flow in situ. We believe that this mechanism may improve muscle fatigue in diseases where blood flow to muscles is compromised such as intermittent claudication.