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Nuclear positioning in skeletal muscle
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Review
Nuclear positioning in skeletal muscle William Roman, Edgar R. Gomes ∗ Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal
a r t i c l e
i n f o
Article history: Received 26 July 2017 Received in revised form 24 October 2017 Accepted 6 November 2017 Available online xxx Keywords: Nuclear movement Myogenesis Muscle development Cytoskeleton Muscle disorders
a b s t r a c t Skeletal muscle cells possess a unique cellular architecture designed to fulfill their contractile function. Muscle cells (also known as myofibers) result from the fusion of hundreds of myoblasts and grow into a fiber of several centimeters in length. Cellular structures gradually become organized during muscle development to raise a mature contractile cell. A hallmark of this singular cell architecture is the position of nuclei at the periphery of the myofiber, below the plasma membrane. Nuclei in myofibers are evenly distributed except in specialized regions like the neuromuscular or myotendinous junctions. Disruption of nuclear positioning results in hindered muscle contraction and occurs in a multitude of muscle disorders as well as in regenerative myofibers. We will explore in this review the step by step nuclear migrations during myogenesis for nuclei to reach their evenly distributed anchored position at the periphery. © 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Contents 1.
2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.1. Nuclear centration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00 1.2. Nuclear alignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.3. Nuclear spreading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.4. Nuclear movement to the myofiber periphery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.5. Nuclear anchoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Introduction The skeletal muscle is a tissue that allies strength, flexibility and plasticity thanks to a highly ordered cellular structure [1]. This unique architecture is designed to serve the skeletal muscle’s strenuous contractile function. Muscle biology may therefore be investigated through the prism of its cellular organization. The skeletal muscle is usually a tubular shaped organ that is subdivided into fiber shaped muscle fascicles. These are themselves composed of a bundle of muscle cells. The muscle cell, also known as myofiber, is the largest mammalian cell as it can span several centimeters in length. Its capacity to accomplish such size stems from the fusion of several hundreds of myoblasts at the beginning of myogenesis. Myoblasts exit the cell cycle prior to cell fusion to grow into a thick
∗ Corresponding author. E-mail address: [email protected] (E.R. Gomes).
fiber filled with myofibrils. Myofibrils are intracellular contractile fibers built from sarcomeres joint end on end. One sarcomere unit is delineated on both sides by z-lines which serve as anchors for perpendicular actin filaments participating in the contraction process. Mid-way between two adjacent z-lines is the M-line. M standing for myosin, this line is an anchor for perpendicular myosin chains that overlap and intercalate in between actin filaments. Contraction of the sarcomere is therefore ruled by an actomyosin mechanism in which myosin heads pull on actin filaments. Sarcomeres are in the order of 2 m in length and it is their cumulative contraction (from 200 to 250 serial sarcomeres per millimeter of fiber) that accomplishes overall muscle contraction and our ability to move within our environment [2]. To maximize contraction, the cytoplasm of myofibers is almost entirely occupied by myofibrils. The rest of the organelles is squeezed in between myofibrils or between myofibrils and the
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Fig. 1. (A) Nuclear movements during myogenesis. Blue rectangles represent zoomed illustrations of B–F. (B) Centration. Nucleus from newly fused myoblast is pulled toward the center of the myotube by dynein and microtubules. (C) Alignment. Nesprin-1␣ and PCM-1 recruit centrosomal and motor proteins to the NE. (D) Spreading. Kinesin-1 and Map7 attached to microtubules allow use the anti-parallel microtubular network to spread nuclei along the length of the myotube. Kinesin-1 and kinesin light chain (KLC) at the nuclear envelop walk towards the (+) end of surrounding microtubules to induce nuclear rotation. (E) Peripheral migration. Myofibril crosslinking, contraction and nuclear stiffness variations drive nuclear movement to the periphery. Myofibril crosslinking is mediated by desmin organization at the z-lines. (F) Anchoring. Nesprin organizes an astral microtubular network to anchor nuclei juste below the plasma membrane. Anchoring is reinforced by a desmin network.
plasma membrane. With an average diameter of 10 m, nuclei are normally found at the periphery of the myofiber, just below the plasma membrane. Nuclear positioning at the periphery of myofibers is a hallmark of skeletal muscle although the function of this structural characteristic remains elusive. Nevertheless, peripheral anchoring of nuclei is not a straight forward process. Rather, each nucleus embarks on a journey of several hundreds of micrometers to reach its final position at the periphery of the cell [3]. Nuclear movement during myofiber maturation is a step by step process driven by different mechanisms that will be listed in this review. The first movement is termed centration and involves the migration of myonuclei from fused myoblasts to the center of the newly formed cell [4]. Once accumulated at the center, nuclei align on a central axis [5] and move longitudinally as the cell elongates into a fiber [6,7]. Nuclei then migrate from a central position to the cell periphery right below the plasma membrane where they become anchored (Fig. 1A). Thus, so far, 5 types of nuclear events have been described during muscle development: centration, alignment, spreading, peripheral movement and anchoring [3]. Nuclei are uniformly distributed along the myofiber apart from the neuromuscular junction (NMJ) and myotendinous junction (MTJ) where nuclei cluster [8,9]. The interplay between nuclei and their movement within a single cell is a unique feature of skeletal muscle in mammalian systems. The different types of movement sometimes implicate nuclei converging, spreading or moving independently.
Such variation in the type of nuclear movements makes skeletal muscle a rich system to study nuclear migrations. Nuclear movement in muscle involves the usual suspects. Forces on the nucleus must be generated to induce movement which is achieved by motor proteins that bind to the cytoskeleton and either push or pull the nucleus [8]. Certain nuclear migrations require the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex although the full extent of the complex’s role in all the 5 types of nuclear migrations remains to be elucidated. This complex is composed of KASH and SUN proteins and spans the nuclear envelope to link the nuclear lamina with the cytoskeleton in the cytoplasm [9]. KASH proteins (also known as Nesprins) exist in different isoforms capable of binding the various cytoskeletal families as well as motor proteins. Nuclear mispositioning has previously been linked to muscle dysfunction [6,10]. Centrally located nuclei are routinely found in certain muscle disorders as well as muscle regeneration [11]. Most diseases exhibiting centrally located nuclei are caused by muscle wasting, a constant state of muscle degeneration/regeneration. However, certain myopathies are characterized by an accumulation of centrally located nuclei independent of muscle regeneration. These are found in diseases that affect key structural proteins such as plectin resulting in Epidermolysis Bullosa Simplex with Muscular Dystrophy EBS-MD [12] or the intermediate filament desmin which cause desminopathies [13]. The disease that epitomizes
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the importance of nuclear positioning is termed Centronuclear Myopathy (CNM). This congenital disorder arises from mutations in membrane-related genes (DNM2, BIN1 or MTM1) and is characterized, as the name of the disease indicates, by an accumulation of centrally located nuclei [14]. Onset and severity of symptoms vary greatly based on the mutated gene but all patients suffer from some degree of muscle weakness. Although in vivo work in drosophila shows the importance of nuclear positioning for muscle function, the correlation still remains to be strengthened in a diseased phenotype [6,10]. Mammalian cells and drosophila are the main model systems used to study nuclear movement during myogenesis. Although overlaps exist between these two systems, some chronological characteristics differ. After centration of nuclei in the newly formed cell resulting from the fusion of myoblasts, two groups of nuclei in the drosophila embryo segregate at each extreme of the growing myotube [15]. In contrast, nuclei in mammalian cells align on the same plane without a strict two group segregation [5]. Moreover, nuclear movement to the periphery of the muscle cell in mammalian occurs after the spreading process whereas it remains unclear when nuclei migrate to the periphery in drosophila with relations to nuclear spreading. We will chronologically detail the step by step mechanisms involved in nuclear movement of mammalian and drosophila myofibers. 1.1. Nuclear centration Most nuclear movements during skeletal myogenesis are microtubule (MT) dependent. However, before we describe these movements, it is important to note that the microtubule organizing center (MTOC) normally found at the centrosome is localized at the nuclear envelope in muscle cells [16,17]. This shift in MTOC from a single point in the cytoplasm to being reorganized around the nucleus is triggered even before individual myoblasts fuse into a myotube. This shift drastically changes the paradigm of nuclear movement since it allows a direct nucleation of microtubules from the NE, thus allowing novel mechanisms for nuclear movement involving pushing or pulling of anchored MTs. Nevertheless, MT nucleation can also occur in other cellular localization such as the Golgi [18]. The new MTOC around the NE is rapidly solicited when a myoblast fuses with a myotube. The nucleus migrates to the center of the newly formed cell where it aggregates with already centered myonuclei [4]. The mechanism underlying this gathering of nuclei at the center of the cell is microtubule and dynein dependent. In mammal, centration is regulated by Cdc42, Par6 and Par3. Par6 and Par3 are proteins that form a complex recruited for mitotic spindle positioning, apical–basal epithelia formation and neuronal polarization [19]. For nuclear movement in muscle, this complex was shown to recruit the dynein/dynactin complex at the NE. The mechanism of centration in mammalian cells was therefore stipulated to rely on already centrated nuclei pulling the MTs of the myonucleus newcomer towards the center of the myotube. The myoblast nucleus may also pull on MTs from previously centered nuclei to reach the center (Fig. 1B). 1.2. Nuclear alignment After aggregating in the middle of myotubes, the behavior of nuclei defers between mammalia and drosophila. Within mammalian myotubes, nuclei align on a single plane. This is, chronologically, the first type of nuclear movement in skeletal muscle that is LINC complex dependent. However, the role of the LINC complex and more precisely Nesprin-1␣ is surprisingly different to usual. It was recently shown that Nesprin-1␣ is required to recruit pericentriolar proteins to the NE at the early stages of mus-
3
cle differentiation [5]. The LINC complex is therefore used here as an anchor to complete the transition of certain centrosomal proteins from the centrosome to the NE. The mislocalization of these proteins was also observed in myopathic patients with SUN1 mutations and myotubes generated from patients’ samples with Nesprin-1 mutations [20]. Knockdown studies in myotubes showed that Nesprin-1␣ and PCM-1 are important for the alignment of nuclei. Both proteins are required for the recruitment of centrosomal protein to the NE such as pericentrin or Cep135 as well as microtubule motor proteins such as the dynein/dynactin complex and kinesin motors. PCM-1’s role in nuclear alignment might therefore be similar to Nesprin-1␣ in anchoring motor proteins to the NE [7] (Fig. 1C). Myonuclei in the drosophila embryo do not align but are segregated in two groups at the extremes of the myotubes. This grouped nuclear movement to the tip of the cell is driven by two independent mechanisms that both rely on dynein and kinesins [21,22]. The first mechanism involves the transport of dynein to the cell cortex where it is anchored by a protein called Pins. From there, the dynein/dynactin complex pulls on MTs attached to the NE to translocate myonuclei to the tips of the myotube. The interaction between dynein and MTs is promoted by the cytolinker CLIP190. Thus dynein works from the cell cortex in the drosophila embryo whereas in mammalian dynein seems to exerts its motor activity from the NE [22]. This explains why nuclei in Mammalia align at the center of the myotube whereas those in drosophila are segregated at each end of the myotube. As myonuclei migrate from the center to the tips of the myotubes, myonuclei are affected by another mechanism involving kinesins and dynein. It was observed that kinesins occupied the leading edge of nuclei whereas dynein was localized at the rear end [22]. The kinesins exert a force that deforms the nucleus forward in the direction of the movement whereas dynein retracts the back of the nucleus. As such, as nuclei are being translocated, their sphericity varies due to an interplay between the stretching at the leading edge and the retraction at the rear. This polarization of nuclei created by kinesins and dynein is believed to provide directionality to nuclear movement towards the extremes of the myotubes. Interestingly, it was recently found that genes mutated in two muscle disorders (Emerin: EmeryDreifuss muscular dystrophy (EDMD) and amphiphysin: CNMs) were involved in the proper segregation of the grouped nuclei at the tip of myofibers [23]. Bocksbeutel (drosophila emerin) knock down hampered the formation of two distinct myonuclear populations whereas amphiphysin depletion resulted in the separation of myonuclei within a segregated group. Overall this confirms in drosophila that genes mutated in EDMD and CNMs contribute in mispositioning myonuclei but with different mechanisms. 1.3. Nuclear spreading After nuclear alignment, nuclei spread along the axis of the mammalian myotubes. Similarly to the previous movements, these migrations are MT dependent and involve kinesin and dynein motors. Furthermore these movements are also not dependent on actin [24]. Two mechanisms were observed to underlie this movement. One mechanism revolves around the interaction between kinesin-1/kif5b/khc-1 and the Microtubule Associated Protein 7 (Map7) [6]. Kinesin-1 and Map7 bind MTs, therefore this complex can cross-link MTs. MTs nucleated from the NE of aligned nuclei result in the formation of anti-parallel MTs between nuclei. Map7 will fix the complex on one MT while Kinesin-1 will exert force towards the (+) end of the other anti-parallel MT. Together, these results in a sliding apart mechanism of MTs leading to nuclei spreading from one another. To support such mechanism, it was recently identified that Akap450, a centrosomal protein, is recruited to the NE of myotubes via Nesprin-1␣ and is required
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for MT nucleation from the nuclear envelope [20]. Furthermore Akap450 is required for the spreading of nuclei in myotube. In silico modeling of nuclei positioning in myotubes also demonstrate a role for MT nucleation on nuclear spreading. The second mechanism proposes a role for the LINC complex on recruiting motor proteins to the NE. Nesprin 1 or 2 was found to anchor kinesin-1 at the NE through Kinesin Light Chain (KLC) [25,26]. A conserved LEWD domain on the cytoplasmic portion of Nesprins allows the binding with KLC. This Nesprin/KLC/kinesin1 complex transforms the nucleus into a kinesin-1 cargo capable of translocating throughout the myotubes on the anti-parallel MT network set up by the MTOC of the other numerous nuclei (Fig. 1D). These two mechanisms are not mutually exclusive but the predominating concept is the omnipresence of kinesin-1 in nuclear spreading. Drosophila larvae knocked down for Ens (ensconsin, a Map7 ortholog) or Kinesin-1 (kinesin heavy chain, a kinesin-1 ortholog) have a nuclear phenotype and locomotion issues that can be rescued by the re-expression of Ens. Muscle conditional knock out mice of kinesin-1 die at birth due to a severe muscle dystrophy displaying an accumulation of centrally and aggregated nuclei [27]. To complement these findings, it was found by isolating individual myofibers from mouse embryos that Nesprin 1␣2 knock out mice display aligned but aggregated nuclei due to an incapacity to recruit kinesin-1 to the nuclear envelop [28]. Nesprin-1␣2 is a shorter version of Nesprin-1 giant that lacks actin binding domains. Interestingly, it was shown that the actin binding domains were unnecessary for proper nuclear positioning re-emphazing the role of Nesprin in recruiting kinesin-1 to the nuclear envelop for proper nuclear positioning [28]. Another interesting type of nuclear movement occurs during nuclear spreading which involves the rotation of nuclei. By analyzing chromocenters, the nuclear lamina, emerin proteins in the INM, as well as golgi markers, it was found that the nuclear interior and nuclear envelope rotate together [26,29]. This rotation of nuclei is favored in myotubes due to a shift towards greater sphericity of nuclei when compared with myonuclei in myoblasts. Rotation is achieved, like nuclear spreading, by MTs and kinesin-1 linked to the NE but with MTs that do not adopt and anti-parallel arrangement. As such, it was proposed that number and distribution of NE motors as well as the local MT network determine rotation speed and direction. It was noted that nuclei rotate independently from one another in any direction although at least one nucleus rotates every time nuclei cross each other. As such, nuclear rotation may serve to facilitate nuclear translocation by brushing cytoplasmic elements that arise in nuclei’s paths. 1.4. Nuclear movement to the myofiber periphery A hallmark of the skeletal muscle cell is the position of nuclei at the periphery. After spreading, nuclei migrate from a central position within the myotube to the periphery. In the mammalian system, nuclear migration to the periphery occurs after the formation of myofibrils, the contractile fibers filling the cell. It was recently found that centrally-located nuclei are surrounded by myofibrils that span the length of the myotube before nuclear movement to the periphery [30]. 3D time-lapse microscopy showed that nuclei squeeze through a narrow gap in between myofibrils to reach the periphery of the myofiber. Three main parameters were found to drive the nucleus to squeeze to the periphery: myofibril cross-linking, myofibril contraction and nuclear stiffness variations (Fig. 1E). Myofibril crosslinking is mediated by the intermediate filament desmin. Myofibrils become linked to one another at their z-lines and function as a closing zipper on both sides of the nucleus resulting in the creation of growing forces on the nucleus. Such centripetal forces decrease the sphericity and volume of nuclei surrounded by myofibrils. The
deformation of the nucleus is enhanced by myofibril contraction which contributes in applying even more force on the nucleus. Finally, it was found that local changes in lamin A/C levels could weaken nuclear stiffness making the nucleus more malleable to squeeze in between myofibrils. The uneven distribution of lamin A/C creates local weak points that provide the direction of nuclear movement although it is still not clear if these are stochastically formed. Furthermore stochastic changes in the forces applied by the myofibrils due to contraction and cross-linking can also provide direction to the nuclear movement. In contrast to preceding mechanisms, this nuclear movement does not rely on MT but rather on the intermediate filament desmin as well as actin which is shown to organize the desmin network. Actin had previously been implicated in nuclear movement to the periphery. Amphiphysin-2, encoded by BIN1, a gene mutated in CNM [31] was shown to interact with N-Wasp, a protein involved in actin dynamics [32]. N-Wasp then activates the Arp2/3 complex to nucleate actin. Actin polymerization by the Arp2/3 complex contributes in organizing the desmin network necessary for myofibril crosslinking. Knockout studies and biochemistry revealed that desmin organization, and therefore nuclear movement, relied on specific isoforms of the Arp2/3 complex and actin. Arpc5L containing Arp2/3 complexes and ␥-actin are necessary for nuclear movement whereas Arpc5-containing Arp2/3 complexes and -actin are required for transversal triad formation which follows nuclear movement to the periphery. This is in tune with in vivo data demonstrating that sarcoplasmic reticulum maturation and T-Tubule transversal organization occurs within the first 3 weeks post birth [33] in contrast to peripheral movement which occurs at birth. How nuclei reach the periphery in drosophila is still unclear but the mechanism appears to be different to that in mammalian myofibers. It was recently shown that nuclei reach their final positions in myofibers of the drosophila embryo before myofibril formation which contrasts with the mammalian system in which peripheral movement is myofibril dependent [10]. More importantly, it was postulated that sarcomeres stem from nuclei by the recruitment through the LINC complex of key proteins for sarcomere assembly at the NE. 1.5. Nuclear anchoring The journey of nuclei during skeletal muscle development comes to an end when these nuclei become anchored at the periphery of the cell. Myonuclei can be separated into two groups: those aggregated at the myotendinous junction (MTJ) and neuromuscular junction (NMJ) [34,35] and the rest of the myonuclei that are evenly distributed along the myofiber [32,34]. These two subtypes of nuclei have their own anchoring mechanisms and seem to have play different functions as attests their different expression profiles [36]. NMJ and MTJ nuclei may be particularly important to monitor muscle excitation and stretching respectively. The equal distribution of the rest of the nuclei may be important for each nucleus to house keep his share of the myofiber’s cytoplasm, known as the myonuclear domain theory [15,37]. These myonuclear domains have never been directly demonstrated in fully matured myofibers of non-synaptic myonuclei but nuclear distribution appears to obey these laws as a linear correlation was observed between myofiber size and nuclear distance [38]. The full characterization of nuclear anchoring has never been fully established. An important limitation in studying this process is the lack of a mammalian in vitro muscle system in which myofibers mature to the extent to observe such event. Most work therefore relies on in vivo models and knock outs studies. Anchoring of aggregated nuclei of the MTJ and NMJ differs from the rest of the nuclei along the myofiber. The aggregation of nuclei at the NMJ appears to be correlated with a positive maturation loop between neuron and muscle [39]. This involves the secretion
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of agrin by the motor neuron which activates the MuSk and LPR4 receptor which in turn upregulates the exposure of acetylcholine receptor at the myofiber surface [40–43]. Whether clustering of synaptic nuclei at the NMJ is correlated with the Agrin/MuSk pathway remains to be elucidated. However, patients with SUN mutations as well as Nesprin-1 and SUN knock out mice display severe synaptic nuclei anchoring defects [44,45]. Blood vessels have also been linked with nuclear anchoring as it was observed that nuclei preferentially anchor near blood vessels [46]. The mechanism behind the interplay between myonuclei and blood vessels remains unknown. KASH proteins are particularly implicated in nuclear anchoring. KASH domain truncations from Syne-1 and Syne-2 lead to anchoring defects of both synaptic and non-synaptic nuclei [47]. Nesprin-1 and SUN1 and 2 double knock out mice have internalized nuclei as well as aligned nuclei that appear not to have spread [44,48]. Nesprin’s role in nuclear anchorage appears to be in part due to its recruitment of microtubules to form an astral structure caging the nucleus in its place [49] (Fig. 1F). Desmin, the intermediate filament was also found involved in nuclear anchorage [50]. Two studies using knock out mice for desmin show that these mice suffer from nuclear anchorage defects with internalized and unevenly distributed nuclei [45,50]. Moreover, nuclei in these mice lose their parallel alignment with the axis of the myofiber demonstrating the importance of desmin on myofiber architecture. Desmin’s action in myonuclear anchorage is dependent on the cytolinker protein plectin-1 [12]. Plectins exist in several isoforms and act as scaffolds for desmin to link several organelles in the muscle [51–53]. Similarly to desmin knockout mice, plectin 1 knockout mice exhibit internalized and unevenly distributed nuclei [54]. CNM genes might also be central in anchoring nuclei. Amphiphysin can interact with MT and Nesprin which is important for anchoring nuclei whereas MTM1 can directly bind desmin to regulate its organization [55]. Nuclear anchorage defects are often accompanied with misorientated and deformed nuclei [45,54,55]. Being part of a myofiber involves extensive stress and strain due to myofibril contraction. Anchoring nuclei at the periphery can alleviate part of the pressure sustained by nuclei during contraction. However, the cytoskeleton and Nesprins also appear to play a protective role. For example, Nesprin-1 cooperates with spectraplakin and EB1 to provide elasticity to anchored nuclei [56]. This was confirmed in Nesprin1 or desmin 1 knockout mice that have decreased deformation capabilities when myofiber length changes [45]. Aberrant nuclear shape and rigidity alters the distribution of nuclear lamins as well as chromatin conformation [45,57,58]. Such alterations may have drastic implication for the expression profile of myonuclei as was suggested by the plectin1 knock out mice showing different mechano-transduction coupling and epigenetic configuration when compared to control [54].
2. Conclusion The importance of nuclear positioning for muscle function remains elusive. Knock out studies and certain muscle disorders displaying centrally located nuclei attest for an influence of nuclear positioning in muscle dynamics but it is still unclear if this is a consequence or cause of the muscle disorders. Nevertheless, nuclear movements in muscle are active biological processes necessitating the contribution of specialized proteins. Different mechanisms underlie sequential nuclear migrations throughout the stages of muscle maturation. Why nuclei transit through these different stages remains mostly unknown although answers are beginning to arise. For example, it was recently found that sarcomere assembly occurred at the proximity of nuclei [10]. This could explain why
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nuclei spread along the myotube, laying down the cell’s foundation as they cover its length. Another interesting event is the lamin polarization observed during nuclear squeezing to the cell periphery which may involve changes in gene expression [30]. Nuclear squeezing would therefore act as a maturation checkpoint to initiate an expression profile adapted to terminal stages of muscle differentiation. The skeletal muscle syncytium also elicits a question with regards to inter-nuclear communication. The communication between myonuclei of the same cell is also poorly studied. In contrast to other cell types which require mechano-transduction strategies to communicate pass the cell membrane, myonuclei may rely on different mechanisms to share information. Even distribution of nuclei may mostly rely on the MT repulsion mechanism as was previously suggested [30]. Aggregation of myonuclei at the NMJ and MTJ as well as lining blood vessels also suggests that external cues are involved in myonuclear distribution. This localization may be necessary for myofibers to probe their environment in contrast to other myonuclei that play a more homeostatic role. But it is unclear if nuclei share information beyond their respective position. Answers will most likely stem from the understanding of muscle regeneration, a process poorly studied due to the lack of a robust in vitro system recapitulating in vivo conditions. It is however speculated that nuclei detach from their peripheral anchorage to migrate back to the cell the center. In parallel, satellite cells proliferate and fuse to pre-existing myotubes or form new myotubes, that might recapitulate myogenesis, giving rise to centrally-located nuclei. Both these models probably co-exist and must involve a drastic reorganization of the myofiber architecture and a shift in gene expression. Acknowledgements We thank the Gomes Laboratory for discussions. This work was supported by the European Research Council, EMBO, LISBOA-010145-FEDER-007391 co-funded by FEDER through POR Lisboa 2020 – Programa Operacional Regional de Lisboa, PORTUGAL 2020, and Fundac¸ão para a Ciência e a Tecnologia. References [1] R.A. Fishman, Myology: basic and clinical, second edition, vols 1 and 2. Edited by Andrew G. Engel and Clara Franzini-Armstrong, New York, McGraw-Hill, 1994, 1937 pp. illustrated. $350.00, Ann. Neurol. 36 (1994), 808–808. [2] B.W. Infantolino, M.J. Ellis, J.H. Challis, Individual sarcomere lengths in whole muscle fibers and optimal fiber length computation, Anat. Rec. Adv. Integr. Anat. Evol. Biol. 293 (2010) 1913–1919. [3] B. Cadot, V. Gache, E.R. Gomes, Moving and positioning the nucleus in skeletal muscle–one step at a time, Nucl. Austin Tex. 6 (2015) 373–381. [4] B. Cadot, et al., Nuclear movement during myotube formation is microtubule and dynein dependent and is regulated by Cdc42, Par6 and Par3, EMBO Rep. 13 (2012) 741–749. [5] A. Espigat-Georger, V. Dyachuk, C. Chemin, L. Emorine, A. Merdes, Nuclear alignment in myotubes requires centrosome proteins recruited by nesprin-1, J. Cell Sci. 129 (2016) 4227–4237. [6] T. Metzger, et al., MAP and kinesin-dependent nuclear positioning is required for skeletal muscle function, Nature 484 (2012) 120–124. [7] M.H. Wilson, E.L.F. Holzbaur, Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells, Dev. Camb. Engl. 142 (2015) 218–228. [8] V. Gache, E.R. Gomes, B. Cadot, Microtubule motors involved in nuclear movement during skeletal muscle differentiation, Mol. Biol. Cell. 28 (7) (2017) 865–874. [9] M. Crisp, et al., Coupling of the nucleus and cytoplasm: role of the LINC complex, J. Cell Biol. 172 (2006) 41–53. [10] A.L. Auld, E.S. Folker, Nucleus-dependent sarcomere assembly is mediated by the LINC complex, Mol. Biol. Cell 27 (2016) 2351–2359. [11] E.S. Folker, M.K. Baylies, Nuclear positioning in muscle development and disease, Front. Physiol. 4 (2013) 363. [12] L. Winter, G. Wiche, The many faces of plectin and plectinopathies: pathology and mechanisms, Acta Neuropathol. (Berl.) 125 (2013) 77–93. [13] C.S. Clemen, H. Herrmann, S.V. Strelkov, R. Schröder, Desminopathies: pathology and mechanisms, Acta Neuropathol. (Berl.) 125 (2013) 47–75.
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Review
Nuclear positioning in skeletal muscle William Roman, Edgar R. Gomes ∗ Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal
a r t i c l e
i n f o
Article history: Received 26 July 2017 Received in revised form 24 October 2017 Accepted 6 November 2017 Available online xxx Keywords: Nuclear movement Myogenesis Muscle development Cytoskeleton Muscle disorders
a b s t r a c t Skeletal muscle cells possess a unique cellular architecture designed to fulfill their contractile function. Muscle cells (also known as myofibers) result from the fusion of hundreds of myoblasts and grow into a fiber of several centimeters in length. Cellular structures gradually become organized during muscle development to raise a mature contractile cell. A hallmark of this singular cell architecture is the position of nuclei at the periphery of the myofiber, below the plasma membrane. Nuclei in myofibers are evenly distributed except in specialized regions like the neuromuscular or myotendinous junctions. Disruption of nuclear positioning results in hindered muscle contraction and occurs in a multitude of muscle disorders as well as in regenerative myofibers. We will explore in this review the step by step nuclear migrations during myogenesis for nuclei to reach their evenly distributed anchored position at the periphery. © 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Contents 1.
2.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.1. Nuclear centration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00 1.2. Nuclear alignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.3. Nuclear spreading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.4. Nuclear movement to the myofiber periphery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.5. Nuclear anchoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Introduction The skeletal muscle is a tissue that allies strength, flexibility and plasticity thanks to a highly ordered cellular structure [1]. This unique architecture is designed to serve the skeletal muscle’s strenuous contractile function. Muscle biology may therefore be investigated through the prism of its cellular organization. The skeletal muscle is usually a tubular shaped organ that is subdivided into fiber shaped muscle fascicles. These are themselves composed of a bundle of muscle cells. The muscle cell, also known as myofiber, is the largest mammalian cell as it can span several centimeters in length. Its capacity to accomplish such size stems from the fusion of several hundreds of myoblasts at the beginning of myogenesis. Myoblasts exit the cell cycle prior to cell fusion to grow into a thick
∗ Corresponding author. E-mail address: [email protected] (E.R. Gomes).
fiber filled with myofibrils. Myofibrils are intracellular contractile fibers built from sarcomeres joint end on end. One sarcomere unit is delineated on both sides by z-lines which serve as anchors for perpendicular actin filaments participating in the contraction process. Mid-way between two adjacent z-lines is the M-line. M standing for myosin, this line is an anchor for perpendicular myosin chains that overlap and intercalate in between actin filaments. Contraction of the sarcomere is therefore ruled by an actomyosin mechanism in which myosin heads pull on actin filaments. Sarcomeres are in the order of 2 m in length and it is their cumulative contraction (from 200 to 250 serial sarcomeres per millimeter of fiber) that accomplishes overall muscle contraction and our ability to move within our environment [2]. To maximize contraction, the cytoplasm of myofibers is almost entirely occupied by myofibrils. The rest of the organelles is squeezed in between myofibrils or between myofibrils and the
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Fig. 1. (A) Nuclear movements during myogenesis. Blue rectangles represent zoomed illustrations of B–F. (B) Centration. Nucleus from newly fused myoblast is pulled toward the center of the myotube by dynein and microtubules. (C) Alignment. Nesprin-1␣ and PCM-1 recruit centrosomal and motor proteins to the NE. (D) Spreading. Kinesin-1 and Map7 attached to microtubules allow use the anti-parallel microtubular network to spread nuclei along the length of the myotube. Kinesin-1 and kinesin light chain (KLC) at the nuclear envelop walk towards the (+) end of surrounding microtubules to induce nuclear rotation. (E) Peripheral migration. Myofibril crosslinking, contraction and nuclear stiffness variations drive nuclear movement to the periphery. Myofibril crosslinking is mediated by desmin organization at the z-lines. (F) Anchoring. Nesprin organizes an astral microtubular network to anchor nuclei juste below the plasma membrane. Anchoring is reinforced by a desmin network.
plasma membrane. With an average diameter of 10 m, nuclei are normally found at the periphery of the myofiber, just below the plasma membrane. Nuclear positioning at the periphery of myofibers is a hallmark of skeletal muscle although the function of this structural characteristic remains elusive. Nevertheless, peripheral anchoring of nuclei is not a straight forward process. Rather, each nucleus embarks on a journey of several hundreds of micrometers to reach its final position at the periphery of the cell [3]. Nuclear movement during myofiber maturation is a step by step process driven by different mechanisms that will be listed in this review. The first movement is termed centration and involves the migration of myonuclei from fused myoblasts to the center of the newly formed cell [4]. Once accumulated at the center, nuclei align on a central axis [5] and move longitudinally as the cell elongates into a fiber [6,7]. Nuclei then migrate from a central position to the cell periphery right below the plasma membrane where they become anchored (Fig. 1A). Thus, so far, 5 types of nuclear events have been described during muscle development: centration, alignment, spreading, peripheral movement and anchoring [3]. Nuclei are uniformly distributed along the myofiber apart from the neuromuscular junction (NMJ) and myotendinous junction (MTJ) where nuclei cluster [8,9]. The interplay between nuclei and their movement within a single cell is a unique feature of skeletal muscle in mammalian systems. The different types of movement sometimes implicate nuclei converging, spreading or moving independently.
Such variation in the type of nuclear movements makes skeletal muscle a rich system to study nuclear migrations. Nuclear movement in muscle involves the usual suspects. Forces on the nucleus must be generated to induce movement which is achieved by motor proteins that bind to the cytoskeleton and either push or pull the nucleus [8]. Certain nuclear migrations require the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex although the full extent of the complex’s role in all the 5 types of nuclear migrations remains to be elucidated. This complex is composed of KASH and SUN proteins and spans the nuclear envelope to link the nuclear lamina with the cytoskeleton in the cytoplasm [9]. KASH proteins (also known as Nesprins) exist in different isoforms capable of binding the various cytoskeletal families as well as motor proteins. Nuclear mispositioning has previously been linked to muscle dysfunction [6,10]. Centrally located nuclei are routinely found in certain muscle disorders as well as muscle regeneration [11]. Most diseases exhibiting centrally located nuclei are caused by muscle wasting, a constant state of muscle degeneration/regeneration. However, certain myopathies are characterized by an accumulation of centrally located nuclei independent of muscle regeneration. These are found in diseases that affect key structural proteins such as plectin resulting in Epidermolysis Bullosa Simplex with Muscular Dystrophy EBS-MD [12] or the intermediate filament desmin which cause desminopathies [13]. The disease that epitomizes
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the importance of nuclear positioning is termed Centronuclear Myopathy (CNM). This congenital disorder arises from mutations in membrane-related genes (DNM2, BIN1 or MTM1) and is characterized, as the name of the disease indicates, by an accumulation of centrally located nuclei [14]. Onset and severity of symptoms vary greatly based on the mutated gene but all patients suffer from some degree of muscle weakness. Although in vivo work in drosophila shows the importance of nuclear positioning for muscle function, the correlation still remains to be strengthened in a diseased phenotype [6,10]. Mammalian cells and drosophila are the main model systems used to study nuclear movement during myogenesis. Although overlaps exist between these two systems, some chronological characteristics differ. After centration of nuclei in the newly formed cell resulting from the fusion of myoblasts, two groups of nuclei in the drosophila embryo segregate at each extreme of the growing myotube [15]. In contrast, nuclei in mammalian cells align on the same plane without a strict two group segregation [5]. Moreover, nuclear movement to the periphery of the muscle cell in mammalian occurs after the spreading process whereas it remains unclear when nuclei migrate to the periphery in drosophila with relations to nuclear spreading. We will chronologically detail the step by step mechanisms involved in nuclear movement of mammalian and drosophila myofibers. 1.1. Nuclear centration Most nuclear movements during skeletal myogenesis are microtubule (MT) dependent. However, before we describe these movements, it is important to note that the microtubule organizing center (MTOC) normally found at the centrosome is localized at the nuclear envelope in muscle cells [16,17]. This shift in MTOC from a single point in the cytoplasm to being reorganized around the nucleus is triggered even before individual myoblasts fuse into a myotube. This shift drastically changes the paradigm of nuclear movement since it allows a direct nucleation of microtubules from the NE, thus allowing novel mechanisms for nuclear movement involving pushing or pulling of anchored MTs. Nevertheless, MT nucleation can also occur in other cellular localization such as the Golgi [18]. The new MTOC around the NE is rapidly solicited when a myoblast fuses with a myotube. The nucleus migrates to the center of the newly formed cell where it aggregates with already centered myonuclei [4]. The mechanism underlying this gathering of nuclei at the center of the cell is microtubule and dynein dependent. In mammal, centration is regulated by Cdc42, Par6 and Par3. Par6 and Par3 are proteins that form a complex recruited for mitotic spindle positioning, apical–basal epithelia formation and neuronal polarization [19]. For nuclear movement in muscle, this complex was shown to recruit the dynein/dynactin complex at the NE. The mechanism of centration in mammalian cells was therefore stipulated to rely on already centrated nuclei pulling the MTs of the myonucleus newcomer towards the center of the myotube. The myoblast nucleus may also pull on MTs from previously centered nuclei to reach the center (Fig. 1B). 1.2. Nuclear alignment After aggregating in the middle of myotubes, the behavior of nuclei defers between mammalia and drosophila. Within mammalian myotubes, nuclei align on a single plane. This is, chronologically, the first type of nuclear movement in skeletal muscle that is LINC complex dependent. However, the role of the LINC complex and more precisely Nesprin-1␣ is surprisingly different to usual. It was recently shown that Nesprin-1␣ is required to recruit pericentriolar proteins to the NE at the early stages of mus-
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cle differentiation [5]. The LINC complex is therefore used here as an anchor to complete the transition of certain centrosomal proteins from the centrosome to the NE. The mislocalization of these proteins was also observed in myopathic patients with SUN1 mutations and myotubes generated from patients’ samples with Nesprin-1 mutations [20]. Knockdown studies in myotubes showed that Nesprin-1␣ and PCM-1 are important for the alignment of nuclei. Both proteins are required for the recruitment of centrosomal protein to the NE such as pericentrin or Cep135 as well as microtubule motor proteins such as the dynein/dynactin complex and kinesin motors. PCM-1’s role in nuclear alignment might therefore be similar to Nesprin-1␣ in anchoring motor proteins to the NE [7] (Fig. 1C). Myonuclei in the drosophila embryo do not align but are segregated in two groups at the extremes of the myotubes. This grouped nuclear movement to the tip of the cell is driven by two independent mechanisms that both rely on dynein and kinesins [21,22]. The first mechanism involves the transport of dynein to the cell cortex where it is anchored by a protein called Pins. From there, the dynein/dynactin complex pulls on MTs attached to the NE to translocate myonuclei to the tips of the myotube. The interaction between dynein and MTs is promoted by the cytolinker CLIP190. Thus dynein works from the cell cortex in the drosophila embryo whereas in mammalian dynein seems to exerts its motor activity from the NE [22]. This explains why nuclei in Mammalia align at the center of the myotube whereas those in drosophila are segregated at each end of the myotube. As myonuclei migrate from the center to the tips of the myotubes, myonuclei are affected by another mechanism involving kinesins and dynein. It was observed that kinesins occupied the leading edge of nuclei whereas dynein was localized at the rear end [22]. The kinesins exert a force that deforms the nucleus forward in the direction of the movement whereas dynein retracts the back of the nucleus. As such, as nuclei are being translocated, their sphericity varies due to an interplay between the stretching at the leading edge and the retraction at the rear. This polarization of nuclei created by kinesins and dynein is believed to provide directionality to nuclear movement towards the extremes of the myotubes. Interestingly, it was recently found that genes mutated in two muscle disorders (Emerin: EmeryDreifuss muscular dystrophy (EDMD) and amphiphysin: CNMs) were involved in the proper segregation of the grouped nuclei at the tip of myofibers [23]. Bocksbeutel (drosophila emerin) knock down hampered the formation of two distinct myonuclear populations whereas amphiphysin depletion resulted in the separation of myonuclei within a segregated group. Overall this confirms in drosophila that genes mutated in EDMD and CNMs contribute in mispositioning myonuclei but with different mechanisms. 1.3. Nuclear spreading After nuclear alignment, nuclei spread along the axis of the mammalian myotubes. Similarly to the previous movements, these migrations are MT dependent and involve kinesin and dynein motors. Furthermore these movements are also not dependent on actin [24]. Two mechanisms were observed to underlie this movement. One mechanism revolves around the interaction between kinesin-1/kif5b/khc-1 and the Microtubule Associated Protein 7 (Map7) [6]. Kinesin-1 and Map7 bind MTs, therefore this complex can cross-link MTs. MTs nucleated from the NE of aligned nuclei result in the formation of anti-parallel MTs between nuclei. Map7 will fix the complex on one MT while Kinesin-1 will exert force towards the (+) end of the other anti-parallel MT. Together, these results in a sliding apart mechanism of MTs leading to nuclei spreading from one another. To support such mechanism, it was recently identified that Akap450, a centrosomal protein, is recruited to the NE of myotubes via Nesprin-1␣ and is required
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for MT nucleation from the nuclear envelope [20]. Furthermore Akap450 is required for the spreading of nuclei in myotube. In silico modeling of nuclei positioning in myotubes also demonstrate a role for MT nucleation on nuclear spreading. The second mechanism proposes a role for the LINC complex on recruiting motor proteins to the NE. Nesprin 1 or 2 was found to anchor kinesin-1 at the NE through Kinesin Light Chain (KLC) [25,26]. A conserved LEWD domain on the cytoplasmic portion of Nesprins allows the binding with KLC. This Nesprin/KLC/kinesin1 complex transforms the nucleus into a kinesin-1 cargo capable of translocating throughout the myotubes on the anti-parallel MT network set up by the MTOC of the other numerous nuclei (Fig. 1D). These two mechanisms are not mutually exclusive but the predominating concept is the omnipresence of kinesin-1 in nuclear spreading. Drosophila larvae knocked down for Ens (ensconsin, a Map7 ortholog) or Kinesin-1 (kinesin heavy chain, a kinesin-1 ortholog) have a nuclear phenotype and locomotion issues that can be rescued by the re-expression of Ens. Muscle conditional knock out mice of kinesin-1 die at birth due to a severe muscle dystrophy displaying an accumulation of centrally and aggregated nuclei [27]. To complement these findings, it was found by isolating individual myofibers from mouse embryos that Nesprin 1␣2 knock out mice display aligned but aggregated nuclei due to an incapacity to recruit kinesin-1 to the nuclear envelop [28]. Nesprin-1␣2 is a shorter version of Nesprin-1 giant that lacks actin binding domains. Interestingly, it was shown that the actin binding domains were unnecessary for proper nuclear positioning re-emphazing the role of Nesprin in recruiting kinesin-1 to the nuclear envelop for proper nuclear positioning [28]. Another interesting type of nuclear movement occurs during nuclear spreading which involves the rotation of nuclei. By analyzing chromocenters, the nuclear lamina, emerin proteins in the INM, as well as golgi markers, it was found that the nuclear interior and nuclear envelope rotate together [26,29]. This rotation of nuclei is favored in myotubes due to a shift towards greater sphericity of nuclei when compared with myonuclei in myoblasts. Rotation is achieved, like nuclear spreading, by MTs and kinesin-1 linked to the NE but with MTs that do not adopt and anti-parallel arrangement. As such, it was proposed that number and distribution of NE motors as well as the local MT network determine rotation speed and direction. It was noted that nuclei rotate independently from one another in any direction although at least one nucleus rotates every time nuclei cross each other. As such, nuclear rotation may serve to facilitate nuclear translocation by brushing cytoplasmic elements that arise in nuclei’s paths. 1.4. Nuclear movement to the myofiber periphery A hallmark of the skeletal muscle cell is the position of nuclei at the periphery. After spreading, nuclei migrate from a central position within the myotube to the periphery. In the mammalian system, nuclear migration to the periphery occurs after the formation of myofibrils, the contractile fibers filling the cell. It was recently found that centrally-located nuclei are surrounded by myofibrils that span the length of the myotube before nuclear movement to the periphery [30]. 3D time-lapse microscopy showed that nuclei squeeze through a narrow gap in between myofibrils to reach the periphery of the myofiber. Three main parameters were found to drive the nucleus to squeeze to the periphery: myofibril cross-linking, myofibril contraction and nuclear stiffness variations (Fig. 1E). Myofibril crosslinking is mediated by the intermediate filament desmin. Myofibrils become linked to one another at their z-lines and function as a closing zipper on both sides of the nucleus resulting in the creation of growing forces on the nucleus. Such centripetal forces decrease the sphericity and volume of nuclei surrounded by myofibrils. The
deformation of the nucleus is enhanced by myofibril contraction which contributes in applying even more force on the nucleus. Finally, it was found that local changes in lamin A/C levels could weaken nuclear stiffness making the nucleus more malleable to squeeze in between myofibrils. The uneven distribution of lamin A/C creates local weak points that provide the direction of nuclear movement although it is still not clear if these are stochastically formed. Furthermore stochastic changes in the forces applied by the myofibrils due to contraction and cross-linking can also provide direction to the nuclear movement. In contrast to preceding mechanisms, this nuclear movement does not rely on MT but rather on the intermediate filament desmin as well as actin which is shown to organize the desmin network. Actin had previously been implicated in nuclear movement to the periphery. Amphiphysin-2, encoded by BIN1, a gene mutated in CNM [31] was shown to interact with N-Wasp, a protein involved in actin dynamics [32]. N-Wasp then activates the Arp2/3 complex to nucleate actin. Actin polymerization by the Arp2/3 complex contributes in organizing the desmin network necessary for myofibril crosslinking. Knockout studies and biochemistry revealed that desmin organization, and therefore nuclear movement, relied on specific isoforms of the Arp2/3 complex and actin. Arpc5L containing Arp2/3 complexes and ␥-actin are necessary for nuclear movement whereas Arpc5-containing Arp2/3 complexes and -actin are required for transversal triad formation which follows nuclear movement to the periphery. This is in tune with in vivo data demonstrating that sarcoplasmic reticulum maturation and T-Tubule transversal organization occurs within the first 3 weeks post birth [33] in contrast to peripheral movement which occurs at birth. How nuclei reach the periphery in drosophila is still unclear but the mechanism appears to be different to that in mammalian myofibers. It was recently shown that nuclei reach their final positions in myofibers of the drosophila embryo before myofibril formation which contrasts with the mammalian system in which peripheral movement is myofibril dependent [10]. More importantly, it was postulated that sarcomeres stem from nuclei by the recruitment through the LINC complex of key proteins for sarcomere assembly at the NE. 1.5. Nuclear anchoring The journey of nuclei during skeletal muscle development comes to an end when these nuclei become anchored at the periphery of the cell. Myonuclei can be separated into two groups: those aggregated at the myotendinous junction (MTJ) and neuromuscular junction (NMJ) [34,35] and the rest of the myonuclei that are evenly distributed along the myofiber [32,34]. These two subtypes of nuclei have their own anchoring mechanisms and seem to have play different functions as attests their different expression profiles [36]. NMJ and MTJ nuclei may be particularly important to monitor muscle excitation and stretching respectively. The equal distribution of the rest of the nuclei may be important for each nucleus to house keep his share of the myofiber’s cytoplasm, known as the myonuclear domain theory [15,37]. These myonuclear domains have never been directly demonstrated in fully matured myofibers of non-synaptic myonuclei but nuclear distribution appears to obey these laws as a linear correlation was observed between myofiber size and nuclear distance [38]. The full characterization of nuclear anchoring has never been fully established. An important limitation in studying this process is the lack of a mammalian in vitro muscle system in which myofibers mature to the extent to observe such event. Most work therefore relies on in vivo models and knock outs studies. Anchoring of aggregated nuclei of the MTJ and NMJ differs from the rest of the nuclei along the myofiber. The aggregation of nuclei at the NMJ appears to be correlated with a positive maturation loop between neuron and muscle [39]. This involves the secretion
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of agrin by the motor neuron which activates the MuSk and LPR4 receptor which in turn upregulates the exposure of acetylcholine receptor at the myofiber surface [40–43]. Whether clustering of synaptic nuclei at the NMJ is correlated with the Agrin/MuSk pathway remains to be elucidated. However, patients with SUN mutations as well as Nesprin-1 and SUN knock out mice display severe synaptic nuclei anchoring defects [44,45]. Blood vessels have also been linked with nuclear anchoring as it was observed that nuclei preferentially anchor near blood vessels [46]. The mechanism behind the interplay between myonuclei and blood vessels remains unknown. KASH proteins are particularly implicated in nuclear anchoring. KASH domain truncations from Syne-1 and Syne-2 lead to anchoring defects of both synaptic and non-synaptic nuclei [47]. Nesprin-1 and SUN1 and 2 double knock out mice have internalized nuclei as well as aligned nuclei that appear not to have spread [44,48]. Nesprin’s role in nuclear anchorage appears to be in part due to its recruitment of microtubules to form an astral structure caging the nucleus in its place [49] (Fig. 1F). Desmin, the intermediate filament was also found involved in nuclear anchorage [50]. Two studies using knock out mice for desmin show that these mice suffer from nuclear anchorage defects with internalized and unevenly distributed nuclei [45,50]. Moreover, nuclei in these mice lose their parallel alignment with the axis of the myofiber demonstrating the importance of desmin on myofiber architecture. Desmin’s action in myonuclear anchorage is dependent on the cytolinker protein plectin-1 [12]. Plectins exist in several isoforms and act as scaffolds for desmin to link several organelles in the muscle [51–53]. Similarly to desmin knockout mice, plectin 1 knockout mice exhibit internalized and unevenly distributed nuclei [54]. CNM genes might also be central in anchoring nuclei. Amphiphysin can interact with MT and Nesprin which is important for anchoring nuclei whereas MTM1 can directly bind desmin to regulate its organization [55]. Nuclear anchorage defects are often accompanied with misorientated and deformed nuclei [45,54,55]. Being part of a myofiber involves extensive stress and strain due to myofibril contraction. Anchoring nuclei at the periphery can alleviate part of the pressure sustained by nuclei during contraction. However, the cytoskeleton and Nesprins also appear to play a protective role. For example, Nesprin-1 cooperates with spectraplakin and EB1 to provide elasticity to anchored nuclei [56]. This was confirmed in Nesprin1 or desmin 1 knockout mice that have decreased deformation capabilities when myofiber length changes [45]. Aberrant nuclear shape and rigidity alters the distribution of nuclear lamins as well as chromatin conformation [45,57,58]. Such alterations may have drastic implication for the expression profile of myonuclei as was suggested by the plectin1 knock out mice showing different mechano-transduction coupling and epigenetic configuration when compared to control [54].
2. Conclusion The importance of nuclear positioning for muscle function remains elusive. Knock out studies and certain muscle disorders displaying centrally located nuclei attest for an influence of nuclear positioning in muscle dynamics but it is still unclear if this is a consequence or cause of the muscle disorders. Nevertheless, nuclear movements in muscle are active biological processes necessitating the contribution of specialized proteins. Different mechanisms underlie sequential nuclear migrations throughout the stages of muscle maturation. Why nuclei transit through these different stages remains mostly unknown although answers are beginning to arise. For example, it was recently found that sarcomere assembly occurred at the proximity of nuclei [10]. This could explain why
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nuclei spread along the myotube, laying down the cell’s foundation as they cover its length. Another interesting event is the lamin polarization observed during nuclear squeezing to the cell periphery which may involve changes in gene expression [30]. Nuclear squeezing would therefore act as a maturation checkpoint to initiate an expression profile adapted to terminal stages of muscle differentiation. The skeletal muscle syncytium also elicits a question with regards to inter-nuclear communication. The communication between myonuclei of the same cell is also poorly studied. In contrast to other cell types which require mechano-transduction strategies to communicate pass the cell membrane, myonuclei may rely on different mechanisms to share information. Even distribution of nuclei may mostly rely on the MT repulsion mechanism as was previously suggested [30]. Aggregation of myonuclei at the NMJ and MTJ as well as lining blood vessels also suggests that external cues are involved in myonuclear distribution. This localization may be necessary for myofibers to probe their environment in contrast to other myonuclei that play a more homeostatic role. But it is unclear if nuclei share information beyond their respective position. Answers will most likely stem from the understanding of muscle regeneration, a process poorly studied due to the lack of a robust in vitro system recapitulating in vivo conditions. It is however speculated that nuclei detach from their peripheral anchorage to migrate back to the cell the center. In parallel, satellite cells proliferate and fuse to pre-existing myotubes or form new myotubes, that might recapitulate myogenesis, giving rise to centrally-located nuclei. Both these models probably co-exist and must involve a drastic reorganization of the myofiber architecture and a shift in gene expression. Acknowledgements We thank the Gomes Laboratory for discussions. This work was supported by the European Research Council, EMBO, LISBOA-010145-FEDER-007391 co-funded by FEDER through POR Lisboa 2020 – Programa Operacional Regional de Lisboa, PORTUGAL 2020, and Fundac¸ão para a Ciência e a Tecnologia. References [1] R.A. Fishman, Myology: basic and clinical, second edition, vols 1 and 2. Edited by Andrew G. Engel and Clara Franzini-Armstrong, New York, McGraw-Hill, 1994, 1937 pp. illustrated. $350.00, Ann. Neurol. 36 (1994), 808–808. [2] B.W. Infantolino, M.J. Ellis, J.H. Challis, Individual sarcomere lengths in whole muscle fibers and optimal fiber length computation, Anat. Rec. Adv. Integr. Anat. Evol. Biol. 293 (2010) 1913–1919. [3] B. Cadot, V. Gache, E.R. Gomes, Moving and positioning the nucleus in skeletal muscle–one step at a time, Nucl. Austin Tex. 6 (2015) 373–381. [4] B. Cadot, et al., Nuclear movement during myotube formation is microtubule and dynein dependent and is regulated by Cdc42, Par6 and Par3, EMBO Rep. 13 (2012) 741–749. [5] A. Espigat-Georger, V. Dyachuk, C. Chemin, L. Emorine, A. Merdes, Nuclear alignment in myotubes requires centrosome proteins recruited by nesprin-1, J. Cell Sci. 129 (2016) 4227–4237. [6] T. Metzger, et al., MAP and kinesin-dependent nuclear positioning is required for skeletal muscle function, Nature 484 (2012) 120–124. [7] M.H. Wilson, E.L.F. Holzbaur, Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells, Dev. Camb. Engl. 142 (2015) 218–228. [8] V. Gache, E.R. Gomes, B. Cadot, Microtubule motors involved in nuclear movement during skeletal muscle differentiation, Mol. Biol. Cell. 28 (7) (2017) 865–874. [9] M. Crisp, et al., Coupling of the nucleus and cytoplasm: role of the LINC complex, J. Cell Biol. 172 (2006) 41–53. [10] A.L. Auld, E.S. Folker, Nucleus-dependent sarcomere assembly is mediated by the LINC complex, Mol. Biol. Cell 27 (2016) 2351–2359. [11] E.S. Folker, M.K. Baylies, Nuclear positioning in muscle development and disease, Front. Physiol. 4 (2013) 363. [12] L. Winter, G. Wiche, The many faces of plectin and plectinopathies: pathology and mechanisms, Acta Neuropathol. (Berl.) 125 (2013) 77–93. [13] C.S. Clemen, H. Herrmann, S.V. Strelkov, R. Schröder, Desminopathies: pathology and mechanisms, Acta Neuropathol. (Berl.) 125 (2013) 47–75.
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