Heart failure–mediated skeletal myopathy often manifests as dyspnea and limb muscle fatigue. The objective of this study was to investigate the effect of a fast skeletal troponin activator, CK-2127107 (2-aminoalkyl-5-N-heteroarylpyrimidine), on skeletal muscle function and exercise performance in rats exhibiting heart failure–mediated skeletal myopathy. Rats underwent coronary artery ligation resulting in myocardial infarction and a progressive decline in cardiac function [left anterior descending coronary artery heart failure (LAD-HF)]. LAD-HF rat hindlimb and diaphragm muscles exhibited muscle atrophy, and fatigability was increased during repeated in situ isokinetic plantar flexor muscle contractions. CK-2127107 produced a leftward shift in the force-Ca2+ relationship of diaphragm and extensor digitorum longus fibers. In the LAD-HF rats, a single oral dose of CK-2127107 increased rotarod running time. In summary, CK-2127107 increases exercise performance in this heart failure model, suggesting that modulation of skeletal muscle function by a fast skeletal troponin activator may be a useful therapeutic in heart failure–associated exercise intolerance.
See article at J Pharmacol Exp Ther 2015, 353:159–168.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics