Ca-CaM-AMPK signaling models

Introduction

Calcium (Ca²⁺) plays a pivotal role in almost all cellular processes and ensures the functionality of an organism. In skeletal muscle fibers, Ca²⁺ 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, Ca²⁺ regulates also intracellular processes, such as myosin-actin cross bridging, protein synthesis, protein degradation and fiber type shifting by the control of Ca²⁺-sensitive proteases and transcription factors, as well as mitochondrial adaptations, plasticity and respiration. These data highlight the overwhelming significance of Ca²⁺ ions for the integrity of skeletal muscle tissue. 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 (Gehlert et al., 2015) [1]. Computational modelling is likely to play an important role in analysing the quantitative behaviour of such pathways, in turn providing data for the basis of potential therapeutic drug design. On this page we would like to summarize all developed mathematical models dedicated to this topic of the research.

Ca-CaM-AMPK signaling pathway

The orchestra of Ca²⁺ signaling mechanisms in skeletal muscle determines a multitude of cellular processes. Already the initiation of muscle contraction at the neuromuscular junction is a Ca²⁺-dependent process at the motor endplate inducing a change in membrane polarization and a subsequent opening of L-type Ca²⁺ channels triggering the release of Ca²⁺ from the sarcoplasmatic reticulum (SR). This mechanism allows a distinct rise of cytosolic Ca²⁺ concentration that initiates actin/myosin interaction and movement of the myosin head. To facilitate the interplay of contraction and relaxation the SR is provided by several Ca²⁺ transport and binding molecules which are adjusted by a multitude of regulatory molecules. ATP production and hence energy supply of contracting muscle is also regulated by Ca²⁺-dependent enhancement of glycolytic enzyme activity and mitochondrial respiration. The high plasticity of skeletal muscle is enabled by Ca²⁺-dependent regulation of gene expression, translation and posttranslational processes including protein degradation (Gehlert et al., 2015) [1] (Figure 1).

Figure 1 from (Gehlert et al., 2015) [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.

To ensure sustained contractility of skeletal muscle, the generation of ATP has to match the demands during contraction. A major metabolic pathway in skeletal muscle that provides a high amount of ATP generation per time is the anaerobic glycolysis which converts one molecule glucose to two molecules pyruvate or lactate and two molecules ATP and, in case of glycogen utilization, three molecules ATP per molecule glycogen (Baker et al., 2010) [2]. The regulation of glucose or glycogen breakdown is relatively short-stepped and requires fewer enzymatic driven reactions when compared to aerobic oxidation (e.g., free fatty acids). Ca²⁺ ions contribute to the regulation of glycolysis as they affect the enzymatic speed of crucial enzymes of the glycolysis (Schonekess et al., 1995) [3]. Glycogen degradation to pyruvate requires glycogenphosphorylase (GP) which converts one molecule of glycogen to glucose-1-phosphate and primes its further degradation via glycolysis to lactate. The phosphorylation and activation of GPL depends on the activity of the enzyme phosphorylase kinase (PhK). Years ago, it was demonstrated that the important Ca²⁺-binding molecules CaM and troponin C regulate the activity of PhK in interplay with Ca²⁺ ions and the phosphorylation by PKA (Cohen, 1980) [4]. PhK in its unphosphorylated form (PhK b) form is relatively inactive when Ca²⁺ concentration is low. PKA can phosphorylate PLK on its β-subunit transforming it to its active form (PhK a). However, dependent on Ca²⁺ concentration, Ca²⁺ ions bind to the δ-subunit of PhK which has a high sequence homology to calmodulin. This mediates an important step in the activation of PhK, however, the additional interaction of PhK with sarcomeric troponin-c seems to be required for the further activation of PhK. The muscle specific isoform of phosphofructokinase (PFK-M) is the most important pacemaker of glycolysis rate. It catalyzes the reaction from fructose 6 phosphate to fructose 1–6 bisphosphate which together with AMP allosterically regulate PFK activity in contracting muscle. Ca²⁺ ions are able to modulate PFK activity by the Ca²⁺-dependent activation of CaM which interacts with PFK (Sola-Penna et al., 2010) [5]. PFK monomers have two binding sites for CaM. CaM binding to the high affinity site of PFK forms the generation of stable PFK dimers which exhibit increased catalytic activity of PFK, in part preventing allosteric inhibition of the enzyme, e.g., by ATP, citrate and lactate. The formerly described regulations facilitate the full activation of PhK and contribute to increased PFK activity via increased abundance of Ca²⁺. Hence, these Ca²⁺-dependent mechanisms serve as an important contribution to coordinate the onset of muscle contractions with mechanisms that augment energy metabolism in working muscle.

Ca²⁺ influx into mitochondria has been shown to result in increased energy conversion potential which is necessary in the maintenance of energetic homeostasis in contracting muscle (Korzeniewski, 2007) [6]. Recent data support this notion of Ca²⁺-activated muscle oxidative phosphorylation cascade. It could be shown that Ca²⁺ increased the conductance of complex IV, complexes I + III, ATP production/transport, and fuel transport/dehydrogenases (Glancy et al., 2013) [7]. Ca²⁺ concentration has also been shown to directly stimulate ATP production through activation of the F1F0-ATP synthase at least in cardiac muscle (Territo et al., 2000) [8]. Extrapolation of these data to the exercising muscle predicts a significant role of Ca²⁺ concentration in maintaining cellular energy homeostasis. The activation of the electron transport chain in mitochondria by Ca²⁺ concentration may significantly contribute to the Ca²⁺ stimulation of ATP production during exercise (Glancy et al., 2013) [7].

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a key regulator of mitochondrial biogenesis, angiogenesis, as well as fat and carbohydrate metabolism in skeletal muscle (Olesen et al., 2010, Popov et al., 2015) [9] [10]. Mouse and human skeletal muscle expresses several PGC-1α (PPARGC1A) gene isoforms originating from the canonical (PGC-1α-a mRNA) and alternative (PGC-1α-b and PGC-1α-c mRNA) promoters (Miura et al., 2008, Yoshioka et al., 2009) [11] [12]. Alternative splicing at the intron between exons 6 and 7 can generate N-truncated (NT) PGC-1α isoforms (Zhang et al., 2009) [13], which possess unique properties, different to those of full-length isoforms (Thom et al., 2014) [14]. Thus, the PGC-1α gene has the potential to produce at least six transcripts (Chang et al., 2012) [15]. Acute endurance exercise leads to increased PGC-1α gene expression in skeletal muscle. AMP-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (p38 MAPK), Ca²⁺/calmodulin-dependent protein kinase (CaMKII) and Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKII) appear to be important for regulation of activity-induced PGC-1α gene expression from the canonical promoter (Zhang et al., 2014) [16]. Several groups (Norrbom et al., 2011, Ydfors et al., 2013, Popov et al., 2014) [17] [18] [19] have shown that in human skeletal muscle, acute exercise induces PGC-1α gene expression, mainly via the alternative promoter. Based on studies in rodent skeletal muscle, it was proposed that activation of exercise-induced expression via the alternative promoter is regulated by the beta-2 adrenergic receptor-protein kinase A (PKA)-cAMP response element-binding protein (CREB1) signalling pathway (Chinsomboon et al., 2009, Tadaishi et al., 2011) [20] [21]. Human myoblast (Norrbom et al., 2011) [17] and mouse (Wen et al., 2014) [22] studies showed that AMPK plays a role in the regulation of expression via the alternative promoter. However, another myoblast study (Yoshioka et al., 2009) [12] and a study in isolated rat muscle (Tadaishi et al., 2011) [21] did not confirm this finding. Furthermore, it has been demonstrated that constitutive expression PGC-1α gene occurs via the canonical promoter, independent of exercise intensity and exercise-induced increase of AMPK^Thr172 phosphorylation level. Expression of PGC-1α gene via the alternative promoter is increased of two orders after exercise. This post-exercise expression is highly dependent on the intensity of exercise. There is an apparent association between expression via the alternative promoter and activation of CREB1 (Popov et al., 2015) [23] (Figure 2).

Figure 2 Schematic diagramme of Ca-CaM-AMPK signaling pathway designed in SBGN standard using BioUML tool. All abbreviations for objects in the main text.

References

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