STIM1 signalling controls store-operated calcium entry required for development and contractile function in skeletal muscle

Abstract

It is now well established that stromal interaction molecule 1 (STIM1) is the calcium sensor of endoplasmic reticulum stores required to activate store-operated calcium entry (SOC) channels at the surface of non-excitable cells. However, little is known about STIM1 in excitable cells, such as striated muscle, where the complement of calcium regulatory molecules is rather disparate from that of non-excitable cells. Here, we show that STIM1 is expressed in both myotubes and adult skeletal muscle. Myotubes lacking functional STIM1 fail to show SOC and fatigue rapidly. Moreover, mice lacking functional STIM1 die perinatally from a skeletal myopathy. In addition, STIM1 haploinsufficiency confers a contractile defect only under conditions where rapid refilling of stores would be needed. These findings provide insight into the role of STIM1 in skeletal muscle and suggest that STIM1 has a universal role as an ER/SR calcium sensor in both excitable and non-excitable cells.

Functional interaction between TRPC1 channel and connexin-43 protein: a novel pathway underlying S1P action on skeletal myogenesis

“…It has been previously reported by our group and others that actin-binding proteins provide a physical linkage between Cx43 and the cortical cytoskeleton and that these interactions are required for maintaining functional Cx43-formed gap junctions in differentiating myoblasts [6,58]. Among the different proteins interacting with connexins are the ZO proteins, vinculin, ezrin, a-actin and cortactin [6,47,58]. In this study we showed that TRPC1 channels could regulate the remodeling of a specific pool of Cx43 protein, likely through the stabilization and coordination of its interaction with cortactin.…”

“…depends upon the activation of peculiar channels which belong to the TRPC family, and function as storedependent and mechanosensitive channels [4,13,34,46]. Of interest, these channels have been recently implicated in the regulation of numerous physiological and pathological processes, such as skeletal muscle differentiation and Duchenne muscular dystrophy [4,30,46,47]. An open question in the field of TRPC signaling is the identification of specific targets by which these Ca 2? gates can affect cell differentiation.…”

New factors contributing to dynamic calcium regulation in the skeletal muscle triad—a crowded place

“…Fast-twitch fibers are known to operate with a ∼30% partially filled SR only, whereas slow-twitch fibers are almost completely filled under resting conditions (Fryer and Stephenson 1996). Whether SR depletion even in exercised fast-twitch muscle would be severe enough to trigger SOCE could not be answered in intact muscle, especially in view of mechanisms that counteract fatigue ) and given the fact that SOCE operates mostly at negative membrane potentials (Stiber et al 2008;Kurebayashi and Ogawa 2001).…”

“…This suggested a slow signalling event during which ER Ca 2+ depletion leads to collection and relocation of Stim1 molecules from regions distant from the plasma membrane towards the membrane to interact with the CRAC channels. During myoblast-tomyotube differentiation, an increased expression and redistribution of Stim1 to the cell periphery was observed (Stiber et al 2008). Myotubes lacking Stim1 do not show SOCE, and muscles from Stim1 knockout mice fatigue more quickly (Stiber et al 2008;Lyfenko and Dirksen 2008).…”

“…During myoblast-tomyotube differentiation, an increased expression and redistribution of Stim1 to the cell periphery was observed (Stiber et al 2008). Myotubes lacking Stim1 do not show SOCE, and muscles from Stim1 knockout mice fatigue more quickly (Stiber et al 2008;Lyfenko and Dirksen 2008). Here as well, Orai1 and Stim1 are the crucial molecular players of SOCE (Lyfenko and Dirksen 2008).…”