Anat Sci Int (2015) 90:33–39 DOI 10.1007/s12565-014-0266-6
REVIEW ARTICLE
Organization of organelles and VAMP-associated vesicular transport systems in differentiating skeletal muscle cells Yuki Tajika • Maiko Takahashi • Hitoshi Ueno Tohru Murakami • Hiroshi Yorifuji
•
Received: 24 August 2014 / Accepted: 19 November 2014 / Published online: 5 December 2014 Ó Japanese Association of Anatomists 2014
Abstract Vesicular transport plays an important role in the regulation of cellular function and differentiation of the cell, and intracellular vesicles play a role in the delivery of membrane components and in sorting membrane proteins to appropriate domains in organelles and the plasma membrane. Research on vesicular transport in differentiating cells has mostly focused on neurons and epithelial cells, and few such studies have been carried out on skeletal muscle cells. Skeletal muscle cells have specialized organelles and plasma membrane domains, including T-tubules, sarcoplasmic reticulum, neuromuscular junctions, and myotendinous junctions. The differentiation of skeletal muscle cells is achieved by multiple steps, i.e., proliferation of myoblasts, formation of myotubes by cell–cell fusion, and maturation of myotubes into myofibers. Systematic vesicular transport is expected to play a role in the maintenance and development of skeletal muscle cells. Here, we review a map of the vesicular transport system during the differentiation of skeletal muscle cells. The characteristics of organelle arrangement in myotubes are described according to morphological studies. Vesicular transport in myotubes is explained by the expression profiles of soluble Nethylmaleimide-sensitive factor attachment protein receptor proteins. Keywords Muscle Myoblast Myotube SNARE protein VAMP
Y. Tajika (&) M. Takahashi H. Ueno T. Murakami H. Yorifuji Department of Anatomy, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan e-mail: [email protected] H. Yorifuji e-mail: [email protected]
Introduction Skeletal muscle cells are multinuclear cells with a very long cylindrical appearance, with the longest human skeletal muscle cells having a length of up to 14 cm (Paul 2001). Even the smallest human skeletal muscle cells found in the stapedius muscle are 2 mm in length, which is 100-fold longer than the average mononucleated cell (10–20 lm) (Grounds and Shavlakadze 2011). Skeletal muscle cells have contraction ability and are equipped with a specialized plasma membrane and intracellular structures, such as neuromuscular junctions, myotendinous or myo–myo junctions, myofibrils, T-system, and sarcoplasmic reticulum (SR). These specialized structures of skeletal muscle cells develop in a multiple-step process that consists of (1) the proliferation of mononuclear myoblasts, (2) the fusion of myoblasts to form multinuclear myotubes, and (3) the maturation of myotubes. Systematic vesicular transport is expected to play a role in the differentiation of skeletal muscle cells from myoblasts through to myotubes and for the maintenance of the mature skeletal muscle cells (Towler et al. 2004). However, most of the research on vesicular transport in differentiating cells has been performed on neurons and epithelial cells, and few such studies have focused on skeletal muscle cells. Here, we review recent information on the distribution of organelles and the vesicular transport system in myotubes.
Organelles in myoblasts and myotubes In the early 1960s satellite cells were identified as resident myoblasts in adult muscular tissue (Mauro 1961), and subsequent ultrastructural studies in the 1960s and 1970s described the morphological characteristics of these
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satellite cells. Satellite cells in adult animals are less active mitotically and metabolically than those in juvenile animals based on their characteristics of heterochromatic nuclei, poorly developed Golgi apparatus, and low levels of glycogen (Snow 1977). The satellite cells of developing muscle (Ishikawa 1966) and young animals (Snow 1977) are, in contrast, more active based on the presence of euchromatic nuclei and a well-developed rough endoplasmic reticulum (ER). Satellite cells have caveolae and pinocytotic vesicles in their cytoplasm (Ishikawa 1966; Muir et al. 1965). The satellite cells are considered to be myogenic stem cells, and activated satellite cells, referred to as myoblasts, initiate the muscle differentiation process. Research on the differentiation of skeletal muscle cells shifted from morphological studies to molecular biology studies in the 1990s, with the latter revealing a number of transcription factors (Buckingham and Relaix 2007) and adhesion molecules (Krauss 2010) which regulate the differentiation of skeletal muscle cells. However, to date, no serious effort has been made to determine the intracellular features of myotubes. The myotubes, multinucleated muscle fibers that form from the fusion of myoblasts, are longer than typical mononuclear cells, usually growing to a length of 0.1–0.6 mm even in culture (Burattini et al. 2004). In a recent electron microscopy study, we examined the organelles in whole myotubes as a basis for studying membrane traffic in myotubes (Tajika et al. 2014). We found that the perinuclear region of the myotubes contained small-sized Golgi apparatuses and that autolysosomes and mitochondria were abundant in the perinuclear region. The rough ER extended from the perinuclear region toward the periphery of the myotube while the smooth ER was located further from the nuclei. A large number of vesicles were located near the tip of the myotubes. Vesicles were observed in both satellite cells (myoblasts) and myotubes. These vesicles are expected to play a role in the intracellular vesicular transport system for delivery of membrane components and including proteins to the appropriate organelles. To identify the nature of these vesicles in the vesicular transport system, in this review we focused on soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and describe their protein expression profiles in myoblasts and myotubes.
SNARE proteins Vesicular transport consists of multiple steps regulated by a number of molecules. In this multi-step process, coat proteins help to generate transport vesicles through vesicle
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budding from the membrane (Cai et al. 2007), motor proteins move vesicles along the cytoskeleton (Hirokawa et al. 2010), small GTPases tether the vesicles at the specific membrane compartment (Mizuno-Yamasaki et al. 2012), and SNARE proteins tether and fuse the vesicle to the target membrane (Hong 2005). Small GTPases are recruited from the cytoplasm to the target membrane depending on the GTPase cycle, whereas SNARE proteins are anchored to the membrane. Thus, we have focused on SNARE proteins to represent the nature of the vesicles in myoblasts and myotubes. More than 30 SNARE proteins have been identified in mammals. SNARE proteins are functionally categorized into vesicle-anchored SNAREs (v-SNAREs) and target membrane-anchored SNAREs (t-SNAREs). Each SNARE molecule has one or two coiled–coil domains (the SNARE motif). v-SNARE and t-SNARE assemble into a SNARE complex through the interaction of the SNARE motif, resulting in membrane fusion between vesicles and the target membrane. Restricted intracellular localization of each SNARE and specific combinations of SNAREs to form the SNARE complex ensure the direction of transport vesicles and specify the target membrane site. VAMP family proteins in skeletal muscle Seven v-SNAREs, i.e., VAMPs (vesicle-associated membrane proteins), are believed to reside on transport vesicles (Hong 2005). VAMPs are distributed in post-Golgi transport vesicles in a restricted manner (Table 1). Here, we describe the expression profiles of the VAMPs using data from mouse and rat models to compose a map of postGolgi transport systems within myotubes.
VAMP1/synaptobrevin VAMP1 was originally isolated from synaptic vesicles, leading to it also being called synaptobrevin. VAMP1 mediates exocytosis, i.e., neurotransmitter release (Baumert et al. 1989; Trimble et al. 1988). VAMP1-null mice die by postnatal day 15 due to neurological defects (Nystuen et al. 2006). Analyses using VAMP1-heterozygous mice revealed that VAMP1 plays an essential, non-redundant role in Ca2?-triggered vesicle exocytosis at mouse neuromuscular junctions (Liu et al. 2011). In addition to being present in the neuronal system, VAMP1 has been detected in the pancreas, kidney, and cardiac myocytes (Ferlito et al. 2010; Peters et al. 2006; Rossetto et al. 1996). VAMP1 has been found at the nerve terminals in skeletal muscles, but not in skeletal muscle cells (Tajika et al. 2007) or in developing myotubes (Tajika et al. 2014).
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Table 1 Expression of vesicle-associated membrane proteins during muscle differentiation VAMPsa
Intracellular localizations in non-muscle cells
VAMP expression during muscle differentiation Satellite cell (quiescent)
Myoblasts (proliferating)
Myotubes
Skeletal muscle cells (matured)
VAMP1
SV
-
-
-
-
VAMP2
SV, etc.
?
-
?
?
VAMP3 VAMP4
EE, RE TGN
NR
? ?
? ?
? NR
VAMP5
PM
-
?
?
?
VAMP7
LE, Ly, PM
NR
?
-
-
VAMP8
EE, LE
NR
?
?
NR
SV Synaptic vesicles, EE early endosome, RE recycling endosomes, TGN trans-Golgi network, PM plasma membrane, LE late endosome, Ly lysosome, NR not reported a
VAMPs, Family of vesicle-associated membrane proteins belonging to the category of v-SNAREs (N-ethylmaleimide-sensitive factor attachment protein receptors). For details on each VAMP described in Table 1, see section VAMP family proteins in skeletal muscle
VAMP2/synaptobrevin-2 VAMP2 was originally isolated from synaptic vesicles, leading to it being referred to as synaptobrevin-2 (Baumert et al. 1989; Trimble et al. 1988). In neurons, VAMP2 plays critical roles in Ca2?-triggered neurotransmitter release (Schoch et al. 2001). VAMP2 has also been detected in non-neuronal tissues, i.e., the kidney (Mendez et al. 2011; Procino et al. 2008), lung (Wang et al. 2012), pancreas (Regazzi et al. 1995; Weng et al. 2007), stomach (Karvar 2002), lymphocytes (Matti et al. 2013), adipose tissue (Martin et al. 1998; Zhao et al. 2009), and skeletal muscle (Rose et al. 2009). In the skeletal muscle, VAMP2 is preferentially expressed in the slow-twitch fibers and is localized mainly at the perinuclear cytoplasm (Tajika et al. 2008). It is also found in the cytoplasm of quiescent satellite cells (Fig. 1a) (Tajika et al. 2008), but disappears in the proliferating myoblasts during the muscle differentiation process (Tajika et al. 2014). In the myotubes, VAMP2 has been found to be distributed abundantly near the tip of the cell (Fig. 1b) (Tajika et al. 2010) . Knockdown of VAMP2 was performed using C2C12 culture myotubes, but it did not affect the fusion of myoblasts or the expression level of desmin, a muscle differentiation marker protein. Rudich and Klip (2003) proposed that VAMP2 is involved in the translocation of glucose transporter-4 (GLUT4) in mature skeletal muscle cells. However, to date, the functions of VAMP2 in satellite cells and myotubes remain to be elucidated. VAMP3/cellubrevin VAMP3/cellubrevin is expressed in a variety of tissues and plays a role in endocytosis in various types of cells (McMahon et al. 1993). VAMP3 protein was originally
detected in the skeletal muscle (Volchuk et al. 1994), and immunohistological analysis showed that VAMP3 is expressed in the capillaries. Skeletal muscle cells express VAMP3 at a low level (Tajika et al. 2007). During muscle differentiation, VAMP3 is found in both myoblasts and myotubes (Tajika et al. 2014). In myotubes VAMP3 is localized at the perinuclear region and the tips of protrusions in myoblasts, and in myotubes, it is localized mainly in the periphery of the cell and is colocalized with VAMP2. VAMP4 VAMP4 has been shown to regulate trafficking events in the trans-Golgi network (TGN) (Steegmaier et al. 1999). VAMP4 transcripts were detected in various tissues (Advani et al. 1998), but neither VAMP4 transcripts nor proteins have yet been reported in mature skeletal muscle. During the muscle differentiation process, VAMP4 is localized in the perinuclear region in both myoblasts and myotubes (Tajika et al. 2014). The Golgi apparatus in myotubes is fragmented and also localized in the perinuclear region (Lu et al. 2001; Tajika et al. 2014). The TGN in myotubes is localized in the vicinity of fragmented Golgi apparatus (Tajika et al. 2010). Thus, perinuclear VAMP4 is an indicator of this localization of the Golgi apparatus, especially the TGN, in myoblasts and myotubes. VAMP5 VAMP5 was originally cloned as a muscle-specific VAMP isoform and is believed to regulate the trafficking events between the cytoplasm and the sarcolemma (Takahashi et al. 2013; Zeng et al. 1998). VAMP5 protein has been found in various tissues except the brain (Schwenk et al. 2010; Takahashi et al. 2013). In the skeletal muscle, VAMP5 is
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Fig. 1 a Localization of vesicle-associated membrane protein 2 (VAMP2) in isolated skeletal muscle cells. Skeletal muscle cells were isolated from extensor digitorum longus muscles of 4-week-old mice by collagenase digestion for 2 h. Fixed skeletal muscle cells were immunolabeled for VAMP2 (green) and Pax3/7 (red). Nuclei were stained with DAPI (blue). VAMP2 was detected mainly around the nuclei of skeletal muscle cells and Pax3/7positive satellite cells (arrow). b Localization of VAMP2 and VAMP5 in differentiating myotubes. C2C12 myoblasts were differentiated into multinuclear myotubes and labeled for VAMP2 (green), VAMP5 (red), and nuclei (blue). Both VAMP2 and VAMP5 were detected in the cytoplasm of myotubes, localized mainly near the tips of the myotubes. Images were obtained by confocal microscopy. Bars 20 lm. (Color figure online)
preferentially expressed in fast-twitch (type IIa) fibers (Takahashi et al. 2013). During the muscle differentiation process, VAMP5 is found in myotubes (Fig. 1b) and is localized mainly at the periphery of the cell. VAMP2 and VAMP3 show similar localization at the periphery of myotubes, but their localization is different from that of VAMP5, which is closer to the plasma membrane (Tajika et al. 2014). The precise roles of VAMP5 remain to be elucidated. Knockdown of VAMP5 using C2C12 myotubes has been found to have no effect on the fusion of myoblasts or the expression level of desmin, a muscle differentiation marker protein, nor on muscle differentiation (Takahashi et al. 2013). VAMP7/TI-VAMP VAMP7/TI-VAMP is generally known to regulate vesicular transport to late endosomes and lysosomes (Advani
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et al. 1999). VAMP7 is also distributed in various organelles, such as the Golgi apparatus, TGN, and early endosomes, depending on the cell type (Chaineau et al. 2009). VAMP7 protein is not expressed in mature skeletal muscle (Advani et al. 1999; Sato et al. 2011), but it is expressed in myoblasts, with its expression decreasing as muscle differentiation progresses (Tajika et al. 2014). VAMP8/endobrevin VAMP8/endobrevin has been shown to be distributed in the endosomal systems (Wang et al. 2010; Wong et al. 1998), but its transcripts or proteins have not been reported in mature skeletal muscle. During the process of muscle differentiation, VAMP8 is found in myoblasts as endosome-like dots (Tajika et al. 2014), with subsequent diffuse localization in myotubes. VAMP8 and VAMP7 are both
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Fig. 2 Organelles and VAMPs in myotubes. To show the organelles and VAMPs clearly, we omitted differentiating myofibrils in this figure. Mitochondria and autolysosomes are abundant around the center of the cell. The Golgi apparatus and trans-Golgi network labeled with VAMP4 are localized in the perinuclear region. The
endoplasmic reticulum (ER) expands from the perinuclear region toward the periphery. VAMP2, 3, and 5 are localized at the periphery of the myotubes, with VAMP2 and 3 localized similarly and VAMP5 localized closer to the sarcolemma. Portions of VAMP3 and 5 are localized at the developing T-tubules
involved in the fusion of lysosomes to autophagosomes (Furuta et al. 2010). Autolysosomes are abundant in myotubes, but they are not associated with VAMP7 or VAMP8 (Tajika et al. 2014).
Rab13 are involved in insulin-dependent GLUT4 translocation in skeletal muscle cells (Klip et al. 2014). However, the interactions between VAMPs and other molecules have not been identified in myoblasts or myotubes. Future studies on the molecular interactions and molecular dynamics of VAMPs will clarify the route and target of the vesicles in myotubes. Further studies are required to address how the VAMPbearing vesicles contribute to the differentiation of skeletal muscle cells. We observed that VAMP3 and VAMP5 are colocalized with caveolin-3, a marker of developing T-tubules, leading us to suggest that VAMP3 and VAMP5 may be involved in T-tubule development (Tajika et al. 2014). In addition to T-tubules, characteristic structures, such as neuromuscular junctions (Sanes and Lichtman 2001) and myotendinous junctions (Burkin and Kaufman 1999), should be investigated in future studies, although many difficulties are encountered when attempting to reproduce a whole differentiation process of the skeletal muscle in experimental model systems. Myoblasts in culture are available as cell lines (C2C12, BC3H1, and MM14 from mouse and L6 from rat) or can be isolated from rodent and avian muscle tissues (Neville et al. 1997). These cells do not differentiate to show the full contractile function and the generation of different fiber types. Animal models can be used to study muscle differentiation and do show the terminal differentiation, but it is hard to analyze the time-dependent changes of a single skeletal muscle cell. Research on vesicular transport in myotubes has just marked its beginning. Further expansion of this field will yield insight into not only the nature of skeletal muscle cells but also muscular diseases.
Discussion Expression profiles of the VAMPs during muscle differentiation are summarized in Table 1. Proliferating myoblasts (C2C12 mouse myoblast and/or primary culture myoblasts) express VAMP3, 4, and 8. VAMP3 and 8 may play roles in endosomal trafficking, and VAMP4 may be involved in TGN trafficking. Myotubes express VAMP2, 3, 4, 5, and 8 (Fig. 2). VAMP2, 3, and 5 may regulate endosomal trafficking at the periphery of the myotubes, with VAMP2 and VAMP3 showing similar localization and VAMP5 localized solely near the plasma membrane. These observations may reflect the multiple steps of endosomal trafficking between the cytoplasm and plasma membrane. VAMP4 in myotubes is involved in TGN trafficking at the perinuclear region, while VAMP8 in myotubes shows diffuse signals and therefore may not play significant roles in myotubes. These data were obtained by static morphological analyses and, therefore, are not supported by information on time-dependent changes in the localization of VAMPs or the molecular interactions of VAMPs with other molecules. VAMPs interact with t-SNAREs to form the SNARE complex and function to tether and fuse vesicles to the target membrane (Hong 2005). The formation of the SNARE complex is also regulated by other molecules, such as small GTPases (Grosshans et al. 2006). Only a few studies have reported the expression and the distribution of small GTPases in differentiating skeletal muscle cells. ADP ribosylation factor (ARF) 1 regulates vesicle budding from the ER to the SR (Nori et al. 2004). ARF6 is distributed at the plasma membrane and influences myoblast fusion (Bach et al. 2010; Chen et al. 2003). Rab8A and
Acknowledgments We thank Ms. Harumi Matsuda and Mr. Yoshihiro Morimura (Department of Anatomy, Gunma University Graduate School of Medicine) for secretarial assistance. This work was supported by MEXT KAKENHI Grant Number 25860138. Conflict of interest
None.
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REVIEW ARTICLE
Organization of organelles and VAMP-associated vesicular transport systems in differentiating skeletal muscle cells Yuki Tajika • Maiko Takahashi • Hitoshi Ueno Tohru Murakami • Hiroshi Yorifuji
•
Received: 24 August 2014 / Accepted: 19 November 2014 / Published online: 5 December 2014 Ó Japanese Association of Anatomists 2014
Abstract Vesicular transport plays an important role in the regulation of cellular function and differentiation of the cell, and intracellular vesicles play a role in the delivery of membrane components and in sorting membrane proteins to appropriate domains in organelles and the plasma membrane. Research on vesicular transport in differentiating cells has mostly focused on neurons and epithelial cells, and few such studies have been carried out on skeletal muscle cells. Skeletal muscle cells have specialized organelles and plasma membrane domains, including T-tubules, sarcoplasmic reticulum, neuromuscular junctions, and myotendinous junctions. The differentiation of skeletal muscle cells is achieved by multiple steps, i.e., proliferation of myoblasts, formation of myotubes by cell–cell fusion, and maturation of myotubes into myofibers. Systematic vesicular transport is expected to play a role in the maintenance and development of skeletal muscle cells. Here, we review a map of the vesicular transport system during the differentiation of skeletal muscle cells. The characteristics of organelle arrangement in myotubes are described according to morphological studies. Vesicular transport in myotubes is explained by the expression profiles of soluble Nethylmaleimide-sensitive factor attachment protein receptor proteins. Keywords Muscle Myoblast Myotube SNARE protein VAMP
Y. Tajika (&) M. Takahashi H. Ueno T. Murakami H. Yorifuji Department of Anatomy, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan e-mail: [email protected] H. Yorifuji e-mail: [email protected]
Introduction Skeletal muscle cells are multinuclear cells with a very long cylindrical appearance, with the longest human skeletal muscle cells having a length of up to 14 cm (Paul 2001). Even the smallest human skeletal muscle cells found in the stapedius muscle are 2 mm in length, which is 100-fold longer than the average mononucleated cell (10–20 lm) (Grounds and Shavlakadze 2011). Skeletal muscle cells have contraction ability and are equipped with a specialized plasma membrane and intracellular structures, such as neuromuscular junctions, myotendinous or myo–myo junctions, myofibrils, T-system, and sarcoplasmic reticulum (SR). These specialized structures of skeletal muscle cells develop in a multiple-step process that consists of (1) the proliferation of mononuclear myoblasts, (2) the fusion of myoblasts to form multinuclear myotubes, and (3) the maturation of myotubes. Systematic vesicular transport is expected to play a role in the differentiation of skeletal muscle cells from myoblasts through to myotubes and for the maintenance of the mature skeletal muscle cells (Towler et al. 2004). However, most of the research on vesicular transport in differentiating cells has been performed on neurons and epithelial cells, and few such studies have focused on skeletal muscle cells. Here, we review recent information on the distribution of organelles and the vesicular transport system in myotubes.
Organelles in myoblasts and myotubes In the early 1960s satellite cells were identified as resident myoblasts in adult muscular tissue (Mauro 1961), and subsequent ultrastructural studies in the 1960s and 1970s described the morphological characteristics of these
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satellite cells. Satellite cells in adult animals are less active mitotically and metabolically than those in juvenile animals based on their characteristics of heterochromatic nuclei, poorly developed Golgi apparatus, and low levels of glycogen (Snow 1977). The satellite cells of developing muscle (Ishikawa 1966) and young animals (Snow 1977) are, in contrast, more active based on the presence of euchromatic nuclei and a well-developed rough endoplasmic reticulum (ER). Satellite cells have caveolae and pinocytotic vesicles in their cytoplasm (Ishikawa 1966; Muir et al. 1965). The satellite cells are considered to be myogenic stem cells, and activated satellite cells, referred to as myoblasts, initiate the muscle differentiation process. Research on the differentiation of skeletal muscle cells shifted from morphological studies to molecular biology studies in the 1990s, with the latter revealing a number of transcription factors (Buckingham and Relaix 2007) and adhesion molecules (Krauss 2010) which regulate the differentiation of skeletal muscle cells. However, to date, no serious effort has been made to determine the intracellular features of myotubes. The myotubes, multinucleated muscle fibers that form from the fusion of myoblasts, are longer than typical mononuclear cells, usually growing to a length of 0.1–0.6 mm even in culture (Burattini et al. 2004). In a recent electron microscopy study, we examined the organelles in whole myotubes as a basis for studying membrane traffic in myotubes (Tajika et al. 2014). We found that the perinuclear region of the myotubes contained small-sized Golgi apparatuses and that autolysosomes and mitochondria were abundant in the perinuclear region. The rough ER extended from the perinuclear region toward the periphery of the myotube while the smooth ER was located further from the nuclei. A large number of vesicles were located near the tip of the myotubes. Vesicles were observed in both satellite cells (myoblasts) and myotubes. These vesicles are expected to play a role in the intracellular vesicular transport system for delivery of membrane components and including proteins to the appropriate organelles. To identify the nature of these vesicles in the vesicular transport system, in this review we focused on soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and describe their protein expression profiles in myoblasts and myotubes.
SNARE proteins Vesicular transport consists of multiple steps regulated by a number of molecules. In this multi-step process, coat proteins help to generate transport vesicles through vesicle
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budding from the membrane (Cai et al. 2007), motor proteins move vesicles along the cytoskeleton (Hirokawa et al. 2010), small GTPases tether the vesicles at the specific membrane compartment (Mizuno-Yamasaki et al. 2012), and SNARE proteins tether and fuse the vesicle to the target membrane (Hong 2005). Small GTPases are recruited from the cytoplasm to the target membrane depending on the GTPase cycle, whereas SNARE proteins are anchored to the membrane. Thus, we have focused on SNARE proteins to represent the nature of the vesicles in myoblasts and myotubes. More than 30 SNARE proteins have been identified in mammals. SNARE proteins are functionally categorized into vesicle-anchored SNAREs (v-SNAREs) and target membrane-anchored SNAREs (t-SNAREs). Each SNARE molecule has one or two coiled–coil domains (the SNARE motif). v-SNARE and t-SNARE assemble into a SNARE complex through the interaction of the SNARE motif, resulting in membrane fusion between vesicles and the target membrane. Restricted intracellular localization of each SNARE and specific combinations of SNAREs to form the SNARE complex ensure the direction of transport vesicles and specify the target membrane site. VAMP family proteins in skeletal muscle Seven v-SNAREs, i.e., VAMPs (vesicle-associated membrane proteins), are believed to reside on transport vesicles (Hong 2005). VAMPs are distributed in post-Golgi transport vesicles in a restricted manner (Table 1). Here, we describe the expression profiles of the VAMPs using data from mouse and rat models to compose a map of postGolgi transport systems within myotubes.
VAMP1/synaptobrevin VAMP1 was originally isolated from synaptic vesicles, leading to it also being called synaptobrevin. VAMP1 mediates exocytosis, i.e., neurotransmitter release (Baumert et al. 1989; Trimble et al. 1988). VAMP1-null mice die by postnatal day 15 due to neurological defects (Nystuen et al. 2006). Analyses using VAMP1-heterozygous mice revealed that VAMP1 plays an essential, non-redundant role in Ca2?-triggered vesicle exocytosis at mouse neuromuscular junctions (Liu et al. 2011). In addition to being present in the neuronal system, VAMP1 has been detected in the pancreas, kidney, and cardiac myocytes (Ferlito et al. 2010; Peters et al. 2006; Rossetto et al. 1996). VAMP1 has been found at the nerve terminals in skeletal muscles, but not in skeletal muscle cells (Tajika et al. 2007) or in developing myotubes (Tajika et al. 2014).
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Table 1 Expression of vesicle-associated membrane proteins during muscle differentiation VAMPsa
Intracellular localizations in non-muscle cells
VAMP expression during muscle differentiation Satellite cell (quiescent)
Myoblasts (proliferating)
Myotubes
Skeletal muscle cells (matured)
VAMP1
SV
-
-
-
-
VAMP2
SV, etc.
?
-
?
?
VAMP3 VAMP4
EE, RE TGN
NR
? ?
? ?
? NR
VAMP5
PM
-
?
?
?
VAMP7
LE, Ly, PM
NR
?
-
-
VAMP8
EE, LE
NR
?
?
NR
SV Synaptic vesicles, EE early endosome, RE recycling endosomes, TGN trans-Golgi network, PM plasma membrane, LE late endosome, Ly lysosome, NR not reported a
VAMPs, Family of vesicle-associated membrane proteins belonging to the category of v-SNAREs (N-ethylmaleimide-sensitive factor attachment protein receptors). For details on each VAMP described in Table 1, see section VAMP family proteins in skeletal muscle
VAMP2/synaptobrevin-2 VAMP2 was originally isolated from synaptic vesicles, leading to it being referred to as synaptobrevin-2 (Baumert et al. 1989; Trimble et al. 1988). In neurons, VAMP2 plays critical roles in Ca2?-triggered neurotransmitter release (Schoch et al. 2001). VAMP2 has also been detected in non-neuronal tissues, i.e., the kidney (Mendez et al. 2011; Procino et al. 2008), lung (Wang et al. 2012), pancreas (Regazzi et al. 1995; Weng et al. 2007), stomach (Karvar 2002), lymphocytes (Matti et al. 2013), adipose tissue (Martin et al. 1998; Zhao et al. 2009), and skeletal muscle (Rose et al. 2009). In the skeletal muscle, VAMP2 is preferentially expressed in the slow-twitch fibers and is localized mainly at the perinuclear cytoplasm (Tajika et al. 2008). It is also found in the cytoplasm of quiescent satellite cells (Fig. 1a) (Tajika et al. 2008), but disappears in the proliferating myoblasts during the muscle differentiation process (Tajika et al. 2014). In the myotubes, VAMP2 has been found to be distributed abundantly near the tip of the cell (Fig. 1b) (Tajika et al. 2010) . Knockdown of VAMP2 was performed using C2C12 culture myotubes, but it did not affect the fusion of myoblasts or the expression level of desmin, a muscle differentiation marker protein. Rudich and Klip (2003) proposed that VAMP2 is involved in the translocation of glucose transporter-4 (GLUT4) in mature skeletal muscle cells. However, to date, the functions of VAMP2 in satellite cells and myotubes remain to be elucidated. VAMP3/cellubrevin VAMP3/cellubrevin is expressed in a variety of tissues and plays a role in endocytosis in various types of cells (McMahon et al. 1993). VAMP3 protein was originally
detected in the skeletal muscle (Volchuk et al. 1994), and immunohistological analysis showed that VAMP3 is expressed in the capillaries. Skeletal muscle cells express VAMP3 at a low level (Tajika et al. 2007). During muscle differentiation, VAMP3 is found in both myoblasts and myotubes (Tajika et al. 2014). In myotubes VAMP3 is localized at the perinuclear region and the tips of protrusions in myoblasts, and in myotubes, it is localized mainly in the periphery of the cell and is colocalized with VAMP2. VAMP4 VAMP4 has been shown to regulate trafficking events in the trans-Golgi network (TGN) (Steegmaier et al. 1999). VAMP4 transcripts were detected in various tissues (Advani et al. 1998), but neither VAMP4 transcripts nor proteins have yet been reported in mature skeletal muscle. During the muscle differentiation process, VAMP4 is localized in the perinuclear region in both myoblasts and myotubes (Tajika et al. 2014). The Golgi apparatus in myotubes is fragmented and also localized in the perinuclear region (Lu et al. 2001; Tajika et al. 2014). The TGN in myotubes is localized in the vicinity of fragmented Golgi apparatus (Tajika et al. 2010). Thus, perinuclear VAMP4 is an indicator of this localization of the Golgi apparatus, especially the TGN, in myoblasts and myotubes. VAMP5 VAMP5 was originally cloned as a muscle-specific VAMP isoform and is believed to regulate the trafficking events between the cytoplasm and the sarcolemma (Takahashi et al. 2013; Zeng et al. 1998). VAMP5 protein has been found in various tissues except the brain (Schwenk et al. 2010; Takahashi et al. 2013). In the skeletal muscle, VAMP5 is
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Fig. 1 a Localization of vesicle-associated membrane protein 2 (VAMP2) in isolated skeletal muscle cells. Skeletal muscle cells were isolated from extensor digitorum longus muscles of 4-week-old mice by collagenase digestion for 2 h. Fixed skeletal muscle cells were immunolabeled for VAMP2 (green) and Pax3/7 (red). Nuclei were stained with DAPI (blue). VAMP2 was detected mainly around the nuclei of skeletal muscle cells and Pax3/7positive satellite cells (arrow). b Localization of VAMP2 and VAMP5 in differentiating myotubes. C2C12 myoblasts were differentiated into multinuclear myotubes and labeled for VAMP2 (green), VAMP5 (red), and nuclei (blue). Both VAMP2 and VAMP5 were detected in the cytoplasm of myotubes, localized mainly near the tips of the myotubes. Images were obtained by confocal microscopy. Bars 20 lm. (Color figure online)
preferentially expressed in fast-twitch (type IIa) fibers (Takahashi et al. 2013). During the muscle differentiation process, VAMP5 is found in myotubes (Fig. 1b) and is localized mainly at the periphery of the cell. VAMP2 and VAMP3 show similar localization at the periphery of myotubes, but their localization is different from that of VAMP5, which is closer to the plasma membrane (Tajika et al. 2014). The precise roles of VAMP5 remain to be elucidated. Knockdown of VAMP5 using C2C12 myotubes has been found to have no effect on the fusion of myoblasts or the expression level of desmin, a muscle differentiation marker protein, nor on muscle differentiation (Takahashi et al. 2013). VAMP7/TI-VAMP VAMP7/TI-VAMP is generally known to regulate vesicular transport to late endosomes and lysosomes (Advani
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et al. 1999). VAMP7 is also distributed in various organelles, such as the Golgi apparatus, TGN, and early endosomes, depending on the cell type (Chaineau et al. 2009). VAMP7 protein is not expressed in mature skeletal muscle (Advani et al. 1999; Sato et al. 2011), but it is expressed in myoblasts, with its expression decreasing as muscle differentiation progresses (Tajika et al. 2014). VAMP8/endobrevin VAMP8/endobrevin has been shown to be distributed in the endosomal systems (Wang et al. 2010; Wong et al. 1998), but its transcripts or proteins have not been reported in mature skeletal muscle. During the process of muscle differentiation, VAMP8 is found in myoblasts as endosome-like dots (Tajika et al. 2014), with subsequent diffuse localization in myotubes. VAMP8 and VAMP7 are both
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Fig. 2 Organelles and VAMPs in myotubes. To show the organelles and VAMPs clearly, we omitted differentiating myofibrils in this figure. Mitochondria and autolysosomes are abundant around the center of the cell. The Golgi apparatus and trans-Golgi network labeled with VAMP4 are localized in the perinuclear region. The
endoplasmic reticulum (ER) expands from the perinuclear region toward the periphery. VAMP2, 3, and 5 are localized at the periphery of the myotubes, with VAMP2 and 3 localized similarly and VAMP5 localized closer to the sarcolemma. Portions of VAMP3 and 5 are localized at the developing T-tubules
involved in the fusion of lysosomes to autophagosomes (Furuta et al. 2010). Autolysosomes are abundant in myotubes, but they are not associated with VAMP7 or VAMP8 (Tajika et al. 2014).
Rab13 are involved in insulin-dependent GLUT4 translocation in skeletal muscle cells (Klip et al. 2014). However, the interactions between VAMPs and other molecules have not been identified in myoblasts or myotubes. Future studies on the molecular interactions and molecular dynamics of VAMPs will clarify the route and target of the vesicles in myotubes. Further studies are required to address how the VAMPbearing vesicles contribute to the differentiation of skeletal muscle cells. We observed that VAMP3 and VAMP5 are colocalized with caveolin-3, a marker of developing T-tubules, leading us to suggest that VAMP3 and VAMP5 may be involved in T-tubule development (Tajika et al. 2014). In addition to T-tubules, characteristic structures, such as neuromuscular junctions (Sanes and Lichtman 2001) and myotendinous junctions (Burkin and Kaufman 1999), should be investigated in future studies, although many difficulties are encountered when attempting to reproduce a whole differentiation process of the skeletal muscle in experimental model systems. Myoblasts in culture are available as cell lines (C2C12, BC3H1, and MM14 from mouse and L6 from rat) or can be isolated from rodent and avian muscle tissues (Neville et al. 1997). These cells do not differentiate to show the full contractile function and the generation of different fiber types. Animal models can be used to study muscle differentiation and do show the terminal differentiation, but it is hard to analyze the time-dependent changes of a single skeletal muscle cell. Research on vesicular transport in myotubes has just marked its beginning. Further expansion of this field will yield insight into not only the nature of skeletal muscle cells but also muscular diseases.
Discussion Expression profiles of the VAMPs during muscle differentiation are summarized in Table 1. Proliferating myoblasts (C2C12 mouse myoblast and/or primary culture myoblasts) express VAMP3, 4, and 8. VAMP3 and 8 may play roles in endosomal trafficking, and VAMP4 may be involved in TGN trafficking. Myotubes express VAMP2, 3, 4, 5, and 8 (Fig. 2). VAMP2, 3, and 5 may regulate endosomal trafficking at the periphery of the myotubes, with VAMP2 and VAMP3 showing similar localization and VAMP5 localized solely near the plasma membrane. These observations may reflect the multiple steps of endosomal trafficking between the cytoplasm and plasma membrane. VAMP4 in myotubes is involved in TGN trafficking at the perinuclear region, while VAMP8 in myotubes shows diffuse signals and therefore may not play significant roles in myotubes. These data were obtained by static morphological analyses and, therefore, are not supported by information on time-dependent changes in the localization of VAMPs or the molecular interactions of VAMPs with other molecules. VAMPs interact with t-SNAREs to form the SNARE complex and function to tether and fuse vesicles to the target membrane (Hong 2005). The formation of the SNARE complex is also regulated by other molecules, such as small GTPases (Grosshans et al. 2006). Only a few studies have reported the expression and the distribution of small GTPases in differentiating skeletal muscle cells. ADP ribosylation factor (ARF) 1 regulates vesicle budding from the ER to the SR (Nori et al. 2004). ARF6 is distributed at the plasma membrane and influences myoblast fusion (Bach et al. 2010; Chen et al. 2003). Rab8A and
Acknowledgments We thank Ms. Harumi Matsuda and Mr. Yoshihiro Morimura (Department of Anatomy, Gunma University Graduate School of Medicine) for secretarial assistance. This work was supported by MEXT KAKENHI Grant Number 25860138. Conflict of interest
None.
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