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

Gehlert S, Bloch W, Suhr F - Int J Mol Sci (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medcine, German Sport University Cologne, Am Sportpark Müngersdorf 6, Cologne 50933, Germany. Gehlert@dshs-koeln.de.

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.

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Related in: MedlinePlus

(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.
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ijms-16-01066-f001: (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.

Mentions: Calcium ion Ca2+ distribution, movement and signaling are prerequisites for function and plasticity of skeletal muscle fibers. While the fast and acute oscillation of free Ca2+ levels in skeletal muscle is the major step in initiation of muscle contraction and relaxation, slower shifts of cytosolic Ca2+ levels are important contributors in the regulation of skeletal muscle plasticity by activation of specific signaling pathways such as the calmodulin/calcineurin signaling pathway (Figure 1).


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

Gehlert S, Bloch W, Suhr F - Int J Mol Sci (2015)

(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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307291&req=5

ijms-16-01066-f001: (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.
Mentions: Calcium ion Ca2+ distribution, movement and signaling are prerequisites for function and plasticity of skeletal muscle fibers. While the fast and acute oscillation of free Ca2+ levels in skeletal muscle is the major step in initiation of muscle contraction and relaxation, slower shifts of cytosolic Ca2+ levels are important contributors in the regulation of skeletal muscle plasticity by activation of specific signaling pathways such as the calmodulin/calcineurin signaling pathway (Figure 1).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medcine, German Sport University Cologne, Am Sportpark Müngersdorf 6, Cologne 50933, Germany. Gehlert@dshs-koeln.de.

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.

Show MeSH
Related in: MedlinePlus