Ca2+-dependent regulations and signaling in skeletal muscle: from electro-mechanical coupling to adaptation

Abstract

Calcium (Ca2+) plays a pivotal role in almost all cellular processes and ensures the functionality of an organism. In skeletal muscle fibers, Ca(2+) is critically involved in the innervation of skeletal muscle fibers that results in the exertion of an action potential along the muscle fiber membrane, the prerequisite for skeletal muscle contraction. Furthermore and among others, Ca(2+) regulates also intracellular processes, such as myosin-actin cross bridging, protein synthesis, protein degradation and fiber type shifting by the control of Ca(2+)-sensitive proteases and transcription factors, as well as mitochondrial adaptations, plasticity and respiration. These data highlight the overwhelming significance of Ca(2+) ions for the integrity of skeletal muscle tissue. In this review, we address the major functions of Ca(2+) ions in adult muscle but also highlight recent findings of critical Ca(2+)-dependent mechanisms essential for skeletal muscle-regulation and maintenance.

Figure 1

(A) Voltage-dependent activation of the dihidropyridine receptor (DHPR-Cav1.1) facilitates the release of Ca²⁺ ions out of the sarcoplasmatic reticulum (SR), which critically regulates skeletal muscle contraction. Reuptake of Ca²⁺ ions in the SR controls skeletal muscle relaxation and is mainly regulated by ATP-dependent sarcoplasmic/endoplasmic reticulum calcium ATPase pumps (SERCA1/2). Increased neuromuscular activity establishes an oscillating pattern of Ca²⁺ ion levels and causes elevated sarcoplasmic Ca²⁺ ion concentrations in the microenvironment of myofibrils; (B) Increasing levels of Ca²⁺ ions in the sarcoplasm bind to and activate calmodulin (CaM) which regulates activation of calcineurin and calmodulin kinase II and IV. Calmodulin kinase II (CaMKII) contributes to the phosphorylation of ryanodine receptor 1 (RyR1) which increases RyR1 channel activity and open probability. CaMKII further inhibits histone deacetylase II (HDACII) and increases nuclear abundance of myocyte enhancer factor 2 (MEF2). Calcineurin (CaN) dephosphorylates nuclear factor of activated T-cells (NFAT) hereby regulating its nuclear localization. NFAT and MEF2 facilitate the increased expression of “slow genes” coding protein isoforms of the oxidative fiber type; (C) CaMKIV increases the expression of mitochondrial genes, which contributes to mitochondrial adaptation. Free Ca²⁺ ions also directly stimulate or inhibit Ca²⁺ release via RyR1 in dependency of their luminal and sarcoplasmic Ca²⁺ concentration. Ca²⁺ ions further co-regulate the activation of energy metabolism by activating mitochondrial respiration and increasing the activity of glycolytic enzymes in sarcoplasm; and (D) store-operated calcium entry (SOCE) is regulated by stromal interaction molecule 1 (STIM1) which senses declined Ca²⁺ ion concentrations in the SR. Interaction of STIMP1 with Orai1 and canonical transient receptor potential channels (TRPC) leads to trans-sarcolemmal Ca²⁺ influx to increase intracellular Ca²⁺ levels upon declining Ca²⁺ content of the SR. Junctophilin maintains junctional triad integrity by overspanning the space between SR and plasma membrane and supports DHPR and RyR1 interaction. Ca²⁺ uptake and handling is enhanced by sarcalumenin which interacts with SERCA channels and calsequestrin.

Figure 2

RyR1 channels induce rapid and high gradients in Ca²⁺ ion concentration between luminal compartments of the SR and surrounding sarcoplasm of myofbrills. (A) RyR1 opening is primarily controlled by the voltage dependent activation of DHPR which mechanically interacts with RyR1 and regulates channel opening (voltage gating). Further and adjacent RyR1 channels are opened by voltage-independent RyR1-RyR1 interactions (coupled gating) which create locally high Ca²⁺ ion gradients. On the luminar side of the SR, RyR1 channel opening is supported by the combined mechanical interaction with triadin, junctin and the SR membrane. High Ca²⁺ ion concentrations in the SR further supports channel open probability. On the sarcoplasmic side and at low Ca²⁺ concentrations, high amounts of Ca²⁺ unbound apoCaM supports increased open probability and activity of RyR1 while Ca²⁺-activated CaM inhibits RyR1. PKA and CaMKII have binding sites on RyR1 subunits and are able to phosphorylate RyR1 and modulate channel activity; and (B) Upon elevation of sarcoplasmic Ca²⁺ levels due to RyR1 channel opening, decreased Ca²⁺ ion levels in SR inhibit RyR1 channel activity. Sarcoplasmic Ca²⁺ levels increase CaM levels which activate CaMKII, IV and calcineurin. CaM inhibits RyR1 channel activity on the sarcoplasmic side of RyR1 while CaMKII binds to and phosphorylates RyR1. Hyperphosphorylation of RyR1 via PKA and CaMKII may lead to increased dissociation of FKBP12, higher open probability of RyR1 channels and decreased contractility of skeletal muscle under resting conditions. Increased SERCA activity facilitates rapid reuptake of Ca²⁺ ions into the SR.

Figure 2

RyR1 channels induce rapid and high gradients in Ca²⁺ ion concentration between luminal compartments of the SR and surrounding sarcoplasm of myofbrills. (A) RyR1 opening is primarily controlled by the voltage dependent activation of DHPR which mechanically interacts with RyR1 and regulates channel opening (voltage gating). Further and adjacent RyR1 channels are opened by voltage-independent RyR1-RyR1 interactions (coupled gating) which create locally high Ca²⁺ ion gradients. On the luminar side of the SR, RyR1 channel opening is supported by the combined mechanical interaction with triadin, junctin and the SR membrane. High Ca²⁺ ion concentrations in the SR further supports channel open probability. On the sarcoplasmic side and at low Ca²⁺ concentrations, high amounts of Ca²⁺ unbound apoCaM supports increased open probability and activity of RyR1 while Ca²⁺-activated CaM inhibits RyR1. PKA and CaMKII have binding sites on RyR1 subunits and are able to phosphorylate RyR1 and modulate channel activity; and (B) Upon elevation of sarcoplasmic Ca²⁺ levels due to RyR1 channel opening, decreased Ca²⁺ ion levels in SR inhibit RyR1 channel activity. Sarcoplasmic Ca²⁺ levels increase CaM levels which activate CaMKII, IV and calcineurin. CaM inhibits RyR1 channel activity on the sarcoplasmic side of RyR1 while CaMKII binds to and phosphorylates RyR1. Hyperphosphorylation of RyR1 via PKA and CaMKII may lead to increased dissociation of FKBP12, higher open probability of RyR1 channels and decreased contractility of skeletal muscle under resting conditions. Increased SERCA activity facilitates rapid reuptake of Ca²⁺ ions into the SR.