Abstract 13726: The Ryanodine Receptor Stabilizer S44121 / Arm036 Improves Peripheral and Respiratory Muscle Function in a Mouse Model of Heart Failure
Background: Congestive heart failure (CHF) is associated with progressive skeletal muscle dysfunction (reduced exercise capacity and increased fatigability). Type 1 ryanodine receptor (RyR1) is the major Ca2+ release channel on the sarcoplasmic reticulum (SR) required for skeletal muscle excitation-contraction (EC) coupling that binds modulatory proteins such as calstabin1. RyR1 derived from animals and patients with CHF, are PKA hyperphosphorylated, oxidized, nitrosylated and depleted of calstabin1, and exhibit increased activity (open probability) indicating that the channels are "leaky" as shown for cardiac RyR2 during HF.
Hypothesis: Rycals are small molecules that can enhance the binding of calstabin1 or 2 to leaky RyR1 or 2, respectively, and stabilize the closed state of the channel. Based on prior work from the Marks group, S44121 (also known as ARM036) is an experimental small molecule stabilizer of RyR. The goal of the present study was to investigate RyR1 activity in MI mice treated with S44121 to evaluate its effect in both a fast-twitch locomotor muscle, EDL (Extensor digitorum longus), and in the mixed-twitch respiratory muscle, diaphragm. As HF also mediates a dyspnea, the effect of S44121 on the force production of diaphragm muscle was further investigated in bundles of diaphragm in isometric conditions.
Methods and Results: In the present study, mice were subjected to a permanent myocardial infarction (PMI) by coronary artery ligation. PMI mice were treated for 3 weeks with S44121 at 10 mg/kg subcutaneously with osmotic minipumps started on day 7 post-MI. In both muscle types, RyR1 was leaky as evidenced by the increased frequency of spontaneous Ca2+ release events, and of Ca2+ sparks, measured by laser scanning confocal microscopy. In both muscles from S44121-treated mice, RyR1 did not exhibit any leaky behavior and the Ca2+ sparks frequency was similar to that observed in sham animals. PMI mice exhibited a significant reduction in force production that was prevented by S44121.
Conclusion: In HF mice models, the Rycal S44121 decreased SR Ca2+ leak in skeletal muscle and improved muscle function. Therefore, Rycals may represent a promising therapeutic strategy to prevent HF-associated skeletal muscle dysfunction.
- Cardiovascular therapeutics
- Experimental heart failure
- Muscle, skeletal
- Excitation-contraction coupling (ECC)
Author Disclosures: M. Pauly: None. S. Matecki: None. J. Thireau: None. M. Bouly: Employment; Significant; Servier. J. Roussel: Employment; Significant; Servier. S. Richard: Research Grant; Significant; Servier. A. Lacampagne: Research Grant; Significant; Servier.
- © 2014 by American Heart Association, Inc.