Heart failure-mediated skeletal
myopathy, which is characterized by
muscle atrophy and muscle metabolism dysfunction, often manifests as
dyspnea and limb muscle fatigue. We have previously demonstrated that increasing Ca(2+) sensitivity of the sarcomere by a small-molecule fast skeletal
troponin activator improves skeletal muscle force and exercise performance in healthy rats and models of
neuromuscular disease. The objective of this study was to investigate the effect of a novel 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 a left anterior descending coronary artery
ligation, resulting in
myocardial infarction and a progressive decline in cardiac function [left anterior descending coronary artery
heart failure (LAD-HF)]. Compared with
sham-operated control rats, LAD-HF rat hindlimb and diaphragm muscles exhibited significant
muscle atrophy. Fatigability was increased during repeated in situ isokinetic plantar flexor muscle contractions.
CK-2127107 produced a leftward shift in the force-Ca(2+) relationship of skinned, single diaphragm, and extensor digitorum longus fibers. Exercise performance, which was assessed by rotarod running, was lower in vehicle-treated LAD-HF rats than in
sham controls (116 ± 22 versus 193 ± 31 seconds, respectively; mean ± S.E.M.; P = 0.04). In the LAD-HF rats, a single oral dose of
CK-2127107 (10 mg/kg p.o.) increased running time compared with vehicle treatment (283 ± 47 versus 116 ± 22 seconds; P = 0.0004). In summary,
CK-2127107 substantially 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.