Possible Role of Kiss1/GPR54 System in Skeletal Muscle: History
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Xuehan Li
,
Chunyu Liang
,
Yi Yan

The skeletal muscle is the storage organ for muscle glycogen and the most prominent motor organ of an organism. Consequently, the relationship between the skeletal muscle and energy metabolism cannot be ignored during physical activities, especially during exercise. The Kiss1/GPR54 system is a multifunctional genetic system with an essential role in regulating energy balance and metabolic homeostasis. Expression of Kiss1 and GPR54 mRNAs can be detected in skeletal muscle of some mammals. However, the Kiss1/GPR54 system in skeletal muscles has not been thoroughly studied. Researchers have proposed the speculation on the possible role of the kiss1 /GPRS4 system in skeletal muscle in association with exercise performance.

  • Kiss1/GPR54 system
  • kisspeptin
  • energy metabolism
  • skeletal muscle

1. Introduction

In 1996, metastin, encoded by the Kiss1 gene, was found to have the ability to suppress metastatic decrease in melanoma cells [1][2]. Since then, metastin has attracted considerable attention as a metastasis suppressor and was subsequently named kisspeptin. Kiss1, located at the human chromosome 1q32, was identified through subtractive hybridization [3]. The encoded common precursor protein (kisspeptin) contains 145 amino acids, which can be hydrolyzed to generate multiple endogenous mature peptides with a common amidated C-terminal [4], including kisspeptin-54/14/13/10 (Kp-54/14/13/10) (Figure 1) [5]. Kp-10 is the smallest peptide that can activate its receptor and function [6]. Therefore, Kp-10 is considered the predominant form of kisspeptin.


Figure 1. Major structural features of human kisspeptin gene. The human Kiss1 gene consists of four exons, the last two encoding a precursor protein translated into a 145 amino acid. This precursor protein includes a predicted signal peptide of amino acids 1-19, a potential dibasic cleavage site of amino acids 65-68, and a terminal cleavage and amidation site of amino acids 121-124. It can be fragmented into different lengths of kisspeptin with a common amidated C-terminal (KP-54/14/13/10) [7].

In 2001, researchers used three independent experiments to confirm the existence of a unique receptor of kisspeptin and named it hOT7T175 or AXOR12 [8]. As a G protein-coupled receptor, this receptor is found in human chromosome group 19p13.3 and intracellularly coupled to the Gαq/11 subfamily of Gq/11G proteins in cells [9]. Thus, it was eventually renamed GPR54 or Kiss1r. GPR54 consists of five exons and encodes a 398 (395 in mice and 396 in rats) amino acid protein in humans [6]. The activation of GPR54 by kisspeptin causes the activation of Gαq/intracellular Ca2+, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase/AKT pathways [10][11]. In previous studies, the Kiss1/GPRS4 system has been shown to play an important role in mammalian reproductive function and cancer biology.

Kiss1 and GPR54 are widely expressed in the hypothalamus, some peripheral tissues, including adipose tissues [12], and the liver [13], stomach, and pancreas [14][15]. Kisspeptin signaling functions as an anorexia factor, reproductive hormone, behavioral hormone, or transfer inhibitor in different tissues [16][17][18]. Hypothalamic Kiss1 neurons are the regulatory centers of reproductive function and the active molecules of energy balance in the central circuit [19]. Peripheral kisspeptin is mainly secreted by endocrine organs, such as adipose tissues and the liver. They are essential peptides that regulate lipid accumulation and fatty acid metabolism and contribute to glucose homeostasis [20][21]. This review summarizes current evidence showing that kisspeptin plays a role in regulating energy homeostasis by modulating multi-organ function in animals and humans and discusses the controversies within the field of the Kiss1/GPR54 system and the potential physiological implications of the Kiss1/GPR54 system.

2.Possible Role of Kiss1/GPR54 System in Skeletal Muscle

GPR54 exists in human vascular smooth muscles [22], skeletal muscles of frogs [23], and skeletal muscles of mice [24], and Kiss1 is expressed in Rohu’s skeletal muscles [25]. In the cardiovascular smooth muscles of humans, kisspeptin can induce inotropic actions on cardiac function [22]. The Kiss1/GPR54 system in skeletal muscles has not been thoroughly studied. Only partial evidence in the skeletal muscle of some animals is available. The mRNA expression levels of Kiss1 and GPR54 are lower in mouse skeletal muscles than those in adipose tissues and the liver. However, whether a small amount of GPR54 in skeletal muscles can react with kisspeptin in the plasma is still unknown. More studies are needed to confirm the intrinsic link between Kiss1/GPR54 system and skeletal muscles.

2.1 Kiss1/GPR54 System Affects Ca2+ Signaling in Cells

In the skeletal muscle, Ca2+ is a key signaling molecule for proliferation and differentiation [26][27][28]. The proliferation of muscle cells requires the proliferation of mesodermal stem cells, which then gradually specialize into myogenic progenitors and further differentiate into different types of muscle cells [29]. The in vitro differentiation of myoblasts is regulated by an increase in intracellular Ca2+ induced by changes in membrane potential [30][31]. In RyR1 homozygous mutant mice, RyR-mediated Ca2+ release is eliminated, and then perinatal death and severe musculature disorders, including small myotubes and disorganized myofibrils, occur [32]. In addition, the moderate-intensity-exercise-induced adaptive hypertrophy of skeletal muscles is closely related to the recruitment of Ca2+ signaling satellite cells for repairing and regenerating skeletal muscle cells torn and damaged during exercise[29][33].

Kisspeptin activates GPR54 on the cytomembrane, which causes GPR54 and phospholipase C to combine with the G proteins of the Gαq/11 subfamily, eliciting the degradation of phospholipase C (PLC) in cells [34]. The degradation of PLC produces two types of second messengers: diacylglycerol (DAG) and trisphosphate (IP-3) [27]. IP-3 can increase the level of cellular Ca2+ [27][28]. Although these results were obtained from studies on the Kiss1/GPR54 system and cancer, given the existence of tissue interactions, researchers can speculate that Kiss1/GPR54 system is involved in the regulation of skeletal muscle Ca2+ concentration; this hypothesis needs to be confirmed by further studies.

In addition, increased kisspeptin signaling activates another second messenger, DAG, which facilitates the PKC pathway, and PKC activates MAPKs [35]. In mammals, MAPKs are involved in hormonal, neural, and cell division signaling. MAPKs interact with Ca2+ in the musculature and coordinate the regulation of skeletal muscle development [36]. Moreover, MAPKs phosphorylate ERK1/2. In myoblasts, ERK2 promotes myogenic progenitor proliferation by upregulating the expression of cyclin D1 [4]. In addition, the activity of MAPK p38 is induced during the differentiation of L8 myogenic cells, thereby promoting myogenesis [37][38]. The changes in Ca2+ signaling induced by Kiss1 at the subcellular level provide important research ideas to investigate the link between Kiss1 and skeletal muscle. Whether Kiss1 can similarly promote changes in Ca2+ concentrations in skeletal muscle and thus affect the proliferation of skeletal muscle cells may be the next step in research.

2.2 Kiss1/GPR54 System in Mitochondrial Activity

There are two distinct populations of mitochondrial subpopulations in skeletal muscle. They are classified as intermyofibrillar mitochondria (MitoIMF) and subsarcolemmal mitochondria (MitoSS) according to the location of their existence [39]. During long-term aerobic exercise, the proportion of slow-twitch fiber has increased, which subsequently causes an increase in the activity and number of MitoIMF [39][40], but the mechanism is still unclear.

In the human melanoma cell, Kiss1 inhibits the acetyl-CoA carboxylase phosphorylation by AMPK directly or upregulates PGC1α mRNA to activate the AMPK expression [41][42], which enhances mitochondrial β-oxidation and thus reverses the Warburg effect [43][44][45]. Kiss1 can also directly promote mitochondrial biogenesis by regulating the expression of PGC1α [41]. Our previous study has shown that Kiss1 and GPR54 mRNAs can be detected in the skeletal muscles of C57Bl6 mice. The concentration of kisspeptin is stabilized at low-p mol levels in the plasma [46]. Given that the enhancement of mitochondrial activity in the skeletal muscle is reflected by the ability to oxidize fatty acids and substrates [47], which is consistent with the promotion of mitochondrial biogenesis by Kiss1 in human melanoma cells, we speculate that the role of Kiss1 in promoting mitochondrial β-oxidation may be present in the skeletal muscle.

During high-intensity exercise, the phosphagen system provides approximately 50% of the ATP in the first 6 s, and the predominant ATP producer is the glycolysis system in the next 10 s [48]. Increased levels of Ca2+ and inorganic phosphate released from the sarcoplasmic reticulum lead to a high level of pyruvate production through glycogen breakdown. Pyruvate can either be metabolized in the cytoplasm to produce lactate or enter the mitochondria for oxidation [49]. This process requires both the stability of Ca2+ levels and the adequacy of mitochondrial capacity[47][29]. Therefore, combined with the fact that Kiss1 can affect Ca2+ signaling and mitochondrial β-oxidation in tumor biology, we propose that the Kiss1/GPR54 system in the skeletal muscle might have an implication for energy metabolism during exercise (Figure 2)

Figure 2. The hypothesis between the Kiss1/GPR54 system in skeletal muscle and exercise capacity. (a) Kisspeptin regulates Ca2+ concentration in skeletal muscle to promote proliferation and differentiation via the PLC-MAPK/IP-3 pathway. (b) Kisspeptin inhibits ACC in skeletal muscle to promote mitochondrial activity by APMK and PGC1α.

This entry is adapted from the peer-reviewed paper 10.3390/cells11193148

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