Excitation-Contraction Coupling Alterations in Myopathies

Abstract

During the complex series of events leading to muscle contraction, the initial electric signal coming from motor neurons is transformed into an increase in calcium concentration that triggers sliding of myofibrils. This process, referred to as excitation-contraction coupling, is reliant upon the calcium-release complex, which is restricted spatially to a sub-compartment of muscle cells ("the triad") and regulated precisely. Any dysfunction in the calcium-release complex leads to muscle impairment and myopathy. Various causes can lead to alterations in excitation-contraction coupling and to muscle diseases. The latter are reviewed and classified into four categories: (i) mutation in a protein of the calcium-release complex; (ii) alteration in triad structure; (iii) modification of regulation of channels; (iv) modification in calcium stores within the muscle. Current knowledge of the pathophysiologic mechanisms in each category is described and discussed.

Keywords: DHPR; RyR1; calcium; congenital myopathies; sarcoplasmic reticulum; triad.

Fig.1

Excitation–contraction coupling is done at the triads of skeletal muscle, which are localized regularly at the interface of band A and I. The major player is the calcium-release complex, which is composed of two calcium channels, the DHPR (with five subunits α1, α2, β, γ and δ) and RyR1, anchored in two membranes (T-tubule and sarcoplasmic reticulum (SR)), and numerous associated proteins, among which triadin, junctin, calsequestrin, FKBP12 and STAC3 are represented. The alpha 1 subunit of DHPR is in direct interaction with RyR1, allowing the coupling between the two proteins. The blue squares on calsequestrin represent the calcium ions.

Fig.2

Possible origins for alterations in EC coupling. (1) Mutations can occur in one of the proteins of the calcium-release complex (CRC), mainly RyR1 and the DHPR. The arrows represent the calcium fluxes, which can therefore be modified by mutations in the channels. (2) Mutations can occur in proteins involved in triad formation/maintenance resulting in modification of triads’ shape, or in the triad lipid composition or in the triad targeting of CRC proteins (mutations in MTM1, DNM2, BIN1). (3) Alterations in the redox state (ROS/RNS) of the muscle fiber can alter RyR1 regulation by direct mutation in a protein involved in redox regulation (SelN1) or by indirect increase in the oxidative stress (Duchenne muscular dystrophy). RyR1 regulation can also be altered by modification in its splicing, for example, as a result of sequestration of Muscleblind proteins or in splicing regulators (in DM1). (4) Calcium stores can be altered as a result of mutations in the proteins involved in their refilling (SERCA, STIM1, ORAI1).