A Novel Fast Skeletal Muscle Activator, CK‐2017357, Improves Muscle Function in a Rodent Model of Myasthenia Gravis

Abstract

Myasthenia gravis is a chronic autoimmune disease wherein the body produces antibodies that inhibit transmission at the neuromuscular junction, causing skeletal muscle weakness and fatigue. CK‐2017357 (CK‐357) is a small molecule activator of fast skeletal muscle that sensitizes the sarcomere to calcium and increases sub‐maximal force production. The objective of this study was to determine if administration of CK‐357 could increase muscle strength and improve functional capacity in a rodent model of myasthenia gravis. Female, Sprague‐Dawley rats injected with a single intra‐peritoneal dose of inhibitory acetylcholine receptor antibody displayed decreased tension‐generating capacity of intact, fast twitch muscle in situ and decreased conscious functional capacity assessed by forelimb grip strength. Single doses of CK‐357 improved conscious grip function in a dose‐dependent manner. In addition, CK‐357 increased force‐generating capacity and decreased tension decline during repeated stimulation of intact muscle in situ. Together these data suggest CK‐357 may ameliorate muscle weakness and fatigue associated with myasthenia gravis to provide a novel therapeutic approach for treatment of these patients. Supported, in part, by NIH Award 1RC3NS070670. Content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.