Fixing ryanodine receptor Ca2+ leak – a novel therapeutic strategy for contractile failure in heart and skeletal muscle

Abstract

A crucial component in regulating cardiac and skeletal muscles contractility is the release of Ca²⁺ via ryanodine receptor (RyR) Ca²⁺ release channels in the sarcoplasmic reticulum (SR). In heart failure and myopathy, the RyR has been found to be excessively phosphorylated or nitrosylated and depleted of the RyR-stabilizing protein calstabin (FK506 binding protein 12/12.6). This remodeling of the RyR channel complex results in an intracellular SR Ca²⁺ leak and impaired contractility. Despite recent advances in heart failure treatment, there are still devastatingly high mortality rates with this disease. Moreover, pharmacological treatment for muscle weakness and myopathy is nearly nonexistent. A novel class of RyR-stabilizing drugs, rycals, which reduce Ca²⁺ leak by stabilizing the RyR channels due to preservation of the RyR-calstabin interaction, have recently been shown to improve contractile function in both heart and skeletal muscles. This opens up a novel therapeutic strategy for the treatment of contractile failure in cardiac and skeletal muscle.