Skeletal muscle store-operated channels and Ca2+ handling in muscular dystrophy

Abstract

In this chapter, we review and highlight recent developments regarding the role of store-operated channels (SOC) and stretch-activated channels (SAC) in skeletal muscle, in the context of Duchenne Muscular Dystrophy (DMD). There is a general consensus that an about twofold increase in Ca2+ influx occurring through SOCs and/or SACs in dystrophic muscle cells initiates a vicious cycle affecting local Ca2+ release, and leading to downstream consequences on Ca2+-activated enzymes that is deleterious to muscle. This influx could occur via certain types of transient receptor potential (TRP) or Orai1 channels and provoke excessive Ca2+ release via ryanodine receptors (RyR). Several of the TRP channels and the Orai1 channel have been shown to be overexpressed in dystrophic muscle. Production of superoxide anion radical is increased in dystrophic muscle and this can lead to oxidative damage of numerous proteins, some of which participate in Ca2+ regulation. RyRs appear to be leaky causing increased Ca2+ release from the sarcoplasmic reticulum (SR). The expression of an additional protein, the Ca2+-independent PLA2 (iPLA2), is increased 2-10-fold in skeletal muscle of DMD patients and 2-4-fold in dystrophin-deficient mice at a period of time when the pathology is progressing. This enzyme is activated upon store depletion and might be a key regulator of SOCs via lysophospholipids (LPLs) resulting from PLA2-catalysed hydrolysis; LPLs are known to activate some of the potentially involved channels, namely TRPV2 channels.