Differentiated muscle cells, or myofibers, are highly organized in order to coordinate the roles of specialized subcellular structures involved in contraction. Myofibril bundles of sarcomeres provide the contractile force. The power of contraction, however, requires synchronous sarcomere function under control of the ‘excitation-contraction coupling’ system that includes two membranous organelles, the sarcoplasmic reticulum (SR) and Transverse (T)-tubules (Al-Qusairi and Laporte, 2011). The T-tubule membrane network is continuous with the muscle cell plasma membrane, with tubulated membranes that invaginate radially inward in a repeated pattern at each sarcomere. With excitation-contraction coupling, neuromuscular action potentials are transmitted along the muscle T-tubule membrane to the SR junction, or dyad/triad, triggering coordinated SR Ca²⁺ release and synchronous sarcomere contractions (Al-Qusairi and Laporte, 2011). Formation of organized T-tubule membranes is thus critical for muscle function (Takeshima et al., 2015). Mechanisms must also remodel the T-tubule membrane network with ongoing myofiber reorganization in response to muscle use, damage, atrophy and aging. However, the extent and mechanisms of T-tubule remodeling remain largely unknown, in part due to challenges with observing T-tubule membrane network dynamics within intact mammalian myofibers.

The T-tubule network includes both transversal and longitudinal tubular membrane elements that form and mature with myofiber differentiation and growth. In mouse skeletal muscle, mostly longitudinal tubular membranes initially present in embryonic muscle are remodeled postnatally with expansion to predominantly transversal tubular elements (Takekura et al., 2001). In contrast, both longitudinal and transversal T-tubule elements are maintained in adult mammalian cardiac muscle (Brette and Orchard, 2003) and in insect muscles (Razzaq et al., 2001). Relatively few molecular factors are known to shape the T-tubule network, and perhaps not surprisingly, all of which so far encode for membrane-associated functions (CAV3, DYSF, BIN1/Amph2, MTM1, DNM2) (Butler et al., 1997; Hnia et al., 2012; Lek et al., 2012; Morlot and Roux, 2013; Tang et al., 1996). Mutations in each also are associated with human myopathy and/or cardiomyopathy with T-tubule disorganization (Bashir et al., 1998; Betz et al., 2001; Bitoun et al., 2005; Laporte et al., 1996; Liu et al., 1998; Minetti et al., 1998; Nicot et al., 2007), pointing to the critical importance of membrane-mediated mechanisms to maintain the T-tubule membrane network.

Drosophila is a powerful system for insights into the functional requirements for T-tubule formation and remodeling. The BIN1 BAR-domain protein has a conserved function involved in membrane tubulation required for T-tubule formation that was first described for the single Drosophila homolog, Amphiphysin (Lee et al., 2002b; Razzaq et al., 2001). The amph null mutant flies lack transversal T-tubule element membranes in myofibers at all developmental stages, corresponding with both larval and adult mobility defects (Razzaq et al., 2001). In contrast, the myotubularin (mtm) fly homolog of mammalian MTM1/MTMR2/MTMR1 subfamily of phosphatidylinositol 3-phosphate phosphatases is required only at later stages in development for T-tubule remodeling. While mtm loss of function has no obvious effects on larval muscle T-tubule organization or function, mtm-depleted post-larval stage muscles lack transversal T-tubule membranes with adult mobility defects in eclosion and flight (Ribeiro et al., 2011). Together, the amph and mtm mutant conditions that both lack transversal T-tubule elements in post-larval stage muscle yet different early development requirements underscores that distinct mechanisms are involved in T-tubule formation (amph-dependent) versus maintenance/remodeling (amph- and mtm-dependent).

In Drosophila, a set of larval body wall muscles that persist as viable pupal abdominal muscles, called dorsal internal oblique muscles (IOMs), are essential for adult eclosion (Kimura and Truman, 1990). During metamorphosis, changes in IOM cell size and myofibril content have been noted (Kuleesha et al., 2014, 2016). We previously showed that wildtype IOMs undergo dramatic cortical and membrane remodeling with costamere integrin adhesion complex disassembly and reassembly at discrete pupal stages (Ribeiro et al., 2011). In contrast, the mtm-depleted IOMs exhibited persistent disassembly or a block in reassembly of integrin costameres along with the loss of transversal T-tubule membranes at late pupal stages, but without any precocious cell death (Ribeiro et al., 2011). A striking feature in the mtm-depleted IOMs was the accumulation of endosomal-like membranes decorated with integrin and T-tubule markers, Amph and Discs large (Dlg1, a PDZ protein). Altogether, these results suggest that T-tubule membranes may undergo disassembly-reassembly with normal myofiber remodeling, including the delivery of disassembled T-tubule membrane into an endomembrane trafficking pathway. The role for a molecular-cellular program in control of T-tubule remodeling that is at least partially distinct from that involved in initial T-tubule formation raises many questions about possible mechanisms, including the regulation of T-tubule organization and dynamics, the membrane fate(s) and source(s) with disassembly-reassembly, respectively, and the specific membrane trafficking routes and effectors involved. Possible hints may come from studies of other specialized dynamic cell membrane invaginations shown to involve endosomal and Golgi membrane trafficking pathways, such as cellularization of Drosophila syncytial embryos (Lee and Harris, 2013, 2014; Pelissier et al., 2003) and the tubulated demarcation membrane system in megakaryocyte platelet formation (Eckly et al., 2014).

Membrane trafficking relies on the large family of Rab GTPases, with over sixty Rabs in humans and thirty in flies (Klöpper et al., 2012). The different Rabs are under distinct spatiotemporal regulation for recruitment, activation and functions at specific membrane compartments or domains. Guanine nucleotide exchange factors (GEFs) convert specific inactive GDP-bound Rabs to an active GTP-bound form. Active Rab-GTP then recruits a range of specific effector proteins to the membrane that mediate key trafficking functions, including cargo selection, vesicle budding, transport, tethering and fusion. Subsequently, GTPase-activating proteins (GAPs) deactivate Rabs by promoting GTP hydrolysis. Many membrane compartments have been defined by well-established localized functions of specific Rabs, for example: ER (Rab1), Golgi (Rab1, Rab6), secretory vesicles (Rab8), early endosomes (Rab5, Rab21), recycling endosomes (Rab11, Rab35), late endosomes (Rab7, Rab9), lysosomes (Rab7) and others (Jean and Kiger, 2012; Stenmark, 2009). Thus, identifying the specific Rabs required for a cellular process can provide clues to potential underlying membrane trafficking mechanisms involved. However, examples exist of Rabs with multiple known sites of function or yet unknown functions, and conversely, certain cellular processes – like T-tubule remodeling – lack defined roles yet for any Rabs.

Here, we utilized the advantages of Drosophila IOMs to screen for Rab GTPases and related membrane trafficking functions required for T-tubule remodeling in intact muscle. Our results show that the entire contractile and excitation-contraction coupling system, including T-tubules, are disassembled and reassembled in IOMs during Drosophila metamorphosis. We found that autophagy, the membrane trafficking process for degradation of cytoplasmic contents by delivery to lysosomes, is upregulated with IOM remodeling where it plays an indispensable role for progression through T-tubule disassembly to reassembly. Our genetic analysis of IOM remodeling also reveals an unexpected and broad role for Rab2 in autophagy in flies and mammals. From our data, we propose that Rab2 localizes to autophagosomes where it interacts with the HOPS complex, which in turn, mediates tethering and trans-SNARE complex formation with Rab7-marked lysosomes to promote autophagosome-lysosome fusion. Together, these results show that Drosophila IOM remodeling provides an unprecedented in vivo context for discovery and analysis of T-tubule dynamics with relevance to human myopathy, as well as an ideal system due to high membrane flux to study fundamental trafficking pathways.

The importance of T-tubule organization for muscle function is well established. However, the dynamics and mechanisms that shape the T-tubule membrane network are largely unexplored, in part due to methodological challenges in many systems. In the present study, we characterized a wildtype myofiber remodeling program by confocal and electron microscopy in intact muscles in vivo. In Drosophila IOMs during metamorphosis, the entire contractile and excitation-contraction coupling system, including T-tubules, are disassembled and then reassembled. This process highlights that myofibers harbor distinct programs for initial T-tubule formation versus regulated T-tubule remodeling. This likely includes additional mechanisms for T-tubule membrane disassembly and renovation, features that reflect those seen with mammalian myofiber atrophy and recovery (Piccirillo et al., 2014). We demonstrate that the Drosophila body wall muscles provide an unprecedented system permitting a combination of powerful visualization and systematic perturbation analysis, including the first genetic screens, of T-tubule dynamics and organization. We uncovered both that autophagy is indispensable for the remodeling, and that Rab2 plays an unexpected role at autophagosomes for autophagic clearance in this process and in broader contexts.

Autophagy is upregulated with the onset of IOM remodeling during metamorphosis (Figure 6A–D). Further, disruption of autophagy initiation, autophagosome formation or clearance all induced loss of T-tubules with a block in IOM remodeling at/after T-tubule disassembly (Figure 6E). As far as we know, this is the first report of a non-cell death role of autophagy in Drosophila metamorphosis. The role of autophagy in IOMs that persist and redifferentiate during metamorphosis is clearly different from its roles in pupal midgut and salivary gland cells that undergo autophagic forms of cell death (Berry and Baehrecke, 2007; Chang et al., 2013; Das et al., 2012; Lee et al., 2002a). There are multiple speculative direct or indirect role(s) for autophagy specifically in T-tubule membrane remodeling: (1) a direct role in T-tubule membrane recycling, as a means to deliver disassembled T-tubule membrane via autophagosomes to lysosomes or related organelles for intracellular storage, then later redeployed to contribute to T-tubule reassembly; (2) an indirect role in cell renovation, including T-tubule membrane clearance, to permit cell space for redifferentiation; or (3) an indirect role in cell metabolism, to support cell survival and/or the energy cost of redifferentiation with starvation during metamorphosis. Most likely, autophagy serves some combination of these roles in IOM remodeling.

How could autophagy play a direct role in T-tubule remodeling? It was surprising that mCD8:GFP-positive small vesicles accumulated to a similar degree as autophagosome numbers in IOMs when autophagosome-lysosome fusion was blocked (Figures 3 and 4). This suggests that mCD8:GFP localizes to autophagosomes during IOM remodeling. It is possible that T-tubule membranes are a source of autophagosomal membrane, at least in part: mCD8:GFP labels the muscle plasma membrane and T-tubules in larval muscle precursor cells of IOMs (Figure 1F), and T-tubule disassembly coincides with the upregulation in autophagy early in metamorphosis (Figure 6C–D). Also, disruption of autophagy induction blocked normal progression in disassembly and remodeling of T-tubule-derived mCD8:GFP-marked membranes (Figure 6E and Figure 6—figure supplement 2B). In the absence of autophagy initiation, mCD8:GFP-positive stacked membranes were observed (Figure 6E and Figure 6—figure supplement 2B), likely retained or partially disassembled T-tubules. We propose that T-tubules are remodeled through autophagosomes. It is important to note that T-tubules are not an apparent autophagic cargo, but instead, a possible source of autophagosome membrane. In this scenario, T-tubules are disassembled into autophagosomes and then reassembled from subsequent autolysosome-related structures (Figure 9F), both of which successively increased in numbers during wildtype IOM remodeling (Figure 6A).

Alternatively or additionally, other roles for autophagy could indirectly impact T-tubule remodeling. Extensive IOM atrophy with nearly complete disassembly of the contractile and excitation-contraction systems by 1d APF is followed by a rapid re-differentiation within hours after 3.5d APF. Autophagy could be required to simply clear away and degrade the old contraction systems in order to make space to rebuild and realign new systems, as well as permit the normal central repositioning of nuclei away from the myofiber cortex. However, the persistent block in early IOM remodeling with autophagy disruption suggests that the remodeling normally proceeds through a progression of interrelated steps rather than independent programs for disassembly and reassembly. Autophagy also has a well-established role in metabolic homeostasis through the recycling of amino acids and turnover of damaged mitochondria in the lysosome. Our data suggests that mitochondria are a major autophagic cargo with IOM remodeling. In conditions that disrupted autophagy initiation (Atg1, Atg18 RNAi), the cytoplasm was abnormally filled with mitochondria in IOMs at 4d APF (Figure 5C). Consistent with that, a significant portion of autophagosomes harbored intact mitochondria when autophagosome-lysosome fusion was blocked (Rab2, Rab7 or Stx17 RNAi; Figure 4E). This is different from observations in larval muscle, in which mitochondria were notably absent in autophagosomes that accumulated with a block in autophagy (Zirin et al., 2013). It is possible that mitophagy, a selective form of autophagy for mitochondrial turnover, is upregulated and could play both metabolic and cell renovation roles in IOM remodeling. Interestingly, the autophagy-blocked IOMs remained viable throughout metamorphosis, suggesting that autophagy is not absolutely required for cell survival through the starvation with metamorphosis.

Through a systemic screen of all Drosophila Rab GTPases, we uncovered an unexpected role for Rab2 in autophagy. The striking Rab2 RNAi IOM phenotype was shared with RNAi of other functions known to be specifically required for autophagosome-lysosome fusion. Genetic blockade of autophagosome-lysosome fusion resulted in a dramatic phenotype, with massive accumulations of autophagosomes within IOMs (Figure 4). Previously, autophagosome-lysosome fusion was shown to involve the cooperative functions of Rab7, the HOPS tethering complex, and a trans-SNARE complex between Stx17, SNAP29 and VAMP7/8 (Shen and Mizushima, 2014). Among these tethering and fusion functions, it has been shown that Stx17 (a hairpin SNARE) is recruited to autophagosomal membranes, while Rab7 and VAMP7/8 localize to endolysosomal membranes. Stx17 localizes to autophagosomes as well as to the ER and mitochondria (Itakura et al., 2012), but the HOPS complex directly associates and colocalizes with Stx17 only at autophagosomes (Jiang et al., 2014; Takáts et al., 2014). This suggests that Stx17 is not a sole determinant for HOPS complex recruitment.

We propose that Rab2 is required for the autophagosomal recruitment of the HOPS complex. Rab2 specifically localized to completed autophagosomes (Figures 8–9), and Rab2 had an affinity with the HOPS complex (Figure 8A), as does Stx17 (Gillingham et al., 2014). We envision that upon completion of autophagosome biogenesis/maturation, Rab2 and Stx17 are recruited to the outer autophagosomal membrane. Then, the HOPS complex is subsequently recruited to autophagosomes in a Rab2-depedent manner through coincident interactions with both Stx17 and Rab2 (Figure 9D–E). At the same time, the HOPS complex binds Rab7 on lysosomes. In turn, the HOPS complex tethers autophagosomes and lysosomes to promote trans-SNARE complex formation between Stx17, SNAP29 and Vamp7/8 and ultimately autophagosome-lysosome fusion (Figure 9F).

We found that the Rab2 role in autophagy discovered in fly muscle relates to a broader autophagy requirement in other cell types and across species. The localization of Rab2 on autophagosomes in Drosophila IOMs was conserved for both Rab2A and Rab2B in mouse embryonic fibroblasts (MEFs). As in flies, the Rab2A/2B double knockout led to a delay or block in autophagy clearance as indicated by accumulation of LC3/Atg8. However, the specific Rab2 loss-of-function phenotypes were not identical. While Rab2 was required for autophagosome-lysosome fusion in fly IOMs, the Rab2A/2B double knockouts in MEFs indicated a requirement at a later step in autophagic clearance. Interestingly, this disparity in autophagy phenotypes across species is also seen with Rab7. In flies and yeast, Rab7/Ypt7 is essential for autophagosome-lyososome/vacuole fusion (Kirisako et al., 1999; Hegedűs et al., 2016), while mammalian Rab7 knockdowns more clearly indicate a required role in autolysosome maturation (Gutierrez et al., 2004; Jäger et al., 2004). Other examples indicate that the autophagosome-lysosome fusion machinery is not highly evolutionarily conserved. The Stx17-SNAP29-VAMP7/8 trans-SNARE complex is conserved in Drosophila and mammals, but not in yeast (Shen and Mizushima, 2014), where no autophagosomal SNARE has been reported so far. Moreover, budding yeast do not encode for Rab2 (Klöpper et al., 2012).

Altogether, it is plausible that Rab2 is required for autophagosome-lysosome fusion efficiency, and Rab2-dependency is variable across different tissues or species. Two possible models could explain the different Rab2 autophagy requirements in flies and mouse cells. First, it is suggested that autophagosomes sequentially fuse with endosomes then lysosomes to become amphisomes and autolysosomes, respectively. If either of the steps requires Rab2A/2B, then intermediates with partially degraded contents could accumulate in double knockout MEFs. Alternatively, an autophagosome may normally fuse with multiple lysosomes to ensure full degradation of its contents (Tsuboyama et al., 2016). In the absence of Rab2A/2B in MEFs, autophagosomes could still fuse but not with a sufficient number of lysosomes, resulting in an accumulation of partially digested autolysosomes.

Rab2 has been previously associated with transport events at the Golgi apparatus, ER-to-Golgi traffic and secretory granule formation (Ailion et al., 2014; Edwards et al., 2009; Saraste, 2016), as well as in a C. elegans endocytic/phagocytic pathway (Chun et al., 2008; Mangahas et al., 2008). Gillingham et al. systematically explored Rab effectors in Drosophila cultured cells, and found that Rab2 interacts with the HOPS complex besides known Golgi-resident effectors (Gillingham et al., 2014). The interaction between Rab2 and HOPS complex is also conserved in mammals (Kajiho et al., 2016) (Figure 8A), and we found the unexpected Rab2 localization to autophagosomes (Figure 8B–H and Figure 8—figure supplement 1). Thus, it is likely that Rab2 exerts multiple functions through interaction with different effectors at different places. We do not exclude a possible Rab2 function in the endosome-lysosome system that affects autophagic flux, although we did not detect clear lysosomal defects in Rab2A/B knockout MEFs (Figure 7H–I and Figure 7—figure supplement 2F–I). Several other factors that localize to autophagosomes or late endosomes-lysosomes, including Atg14, PLEKHM1 and EPG5 (Tian et al., 2010; Tabata et al., 2010; Carlsson and Simonsen, 2015), have been shown to control autophagosome maturation. It is plausible that Rab2 contributes to autophagosome maturation through both a direct role in the fusion mechanism and an indirect role in endo-lysosome maturation, the same as Rab7 and the HOPS complex.

How Rab2 localizes to autophagosomes remains unclear. Localization of Rab2 on autophagosomes in IOMs did not depend on HOPS complex subunits, Vps39 and Vps41, or on Stx17 (Figure 9B–C). Further studies will be needed to determine the identities of the Rab2 guanine nucleotide exchange factor (GEF) and GTPase-activating protein (GAP) that regulate Rab2 GTPase activity in autophagosome-lysosome fusion. A conserved TBC domain protein, OATL1/TBC1D25, is a strong candidate for a Rab2 GAP, given OATL1 localization to autophagosomes and involvement in autophagosome-lysosome fusion (Itoh et al., 2011). Further, it was reported that OATL1 directly bound to and showed GAP activity for Rab2A (Itoh et al., 2006).

Autophagy is critical for the maintenance of myofiber homeostasis in mammalian skeletal muscle. It is known that several myopathies are associated with excess accumulation of autophagic structures in muscle (Malicdan et al., 2008). Further, loss of autophagy in mouse skeletal muscle shows anomalies, including abnormal mitochondria, disassembled sarcomeres and disorganized triads (Masiero et al., 2009), as also seen in aged muscle (Demontis et al., 2013; Weisleder et al., 2006). It is established that autophagy is down-regulated during the course of aging (Rubinsztein et al., 2011). This evidence points to a possible significance of autophagy in myofiber remodeling and in T-tubule maintenance. Jumpy/MTMR14 PI3-phosphatase and Dynamin-2 (DNM2) GTPase, two causative genes of human centronuclear myopathy, are required for not only T-tubule maintenance but also proper progression of autophagy (Dowling et al., 2010; Durieux et al., 2012). Based on these reports and our findings, we speculate that their roles in T-tubule maintenance are mediated, at least in part, through autophagy.

Signaling pathways that regulate atrophy and hypertrophy in Drosophila have been identified (Piccirillo et al., 2014), however, the mechanisms and direct mediators of muscle remodeling remain largely unknown. IOM remodeling is a good model to study the mechanisms of muscle remodeling, given that the signaling pathways that control muscle remodeling are conserved between Drosophila and mammals (Piccirillo et al., 2014). Advantages of the IOM system are not only its genetic tractability, but also its reproducibility and structure. As a relatively giant single cell along the body wall, IOMs enable tracking of a single cell and its subcellular organization during metamorphosis. Our results show that studies in IOMs can provide new insights into the mechanisms of muscle remodeling as well as regulation of fundamental membrane trafficking pathways, such as autophagy and endocytosis.

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Author details

1. Naonobu Fujita

   1. Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States
   2. Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan

   Contribution

   NF, Designed the research, performed the experiments, analyzed and interpreted data, and wrote the manuscript with input from all authors

   For correspondence

   naonobu.fujita.b8@tohoku.ac.jp

   Competing interests

   No competing interests declared.

2. Wilson Huang

   Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States

   Contribution

   WH, Performed the experiments and analyzed and interpreted data

   Competing interests

   No competing interests declared.

3. Tzu-han Lin

   Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States

   Contribution

   T-hL, Performed the experiments and analyzed and interpreted data

   Competing interests

   No competing interests declared.

4. Jean-Francois Groulx

   Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States

   Contribution

   J-FG, Performed the experiments and analyzed and interpreted data

   Competing interests

   No competing interests declared.

5. Steve Jean

   Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States

   Contribution

   SJ, Performed the experiments and analyzed and interpreted data

   Competing interests

   No competing interests declared.

6. Jen Nguyen

   Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States

   Contribution

   JN, Performed the experiments and analyzed and interpreted data

   Competing interests

   No competing interests declared.

7. Yoshihiko Kuchitsu

   Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan

   Contribution

   YK, Analyzed and interpreted data

   Competing interests

   No competing interests declared.

8. Ikuko Koyama-Honda

   Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan

   Contribution

   IK-H, Analyzed and interpreted data

   Competing interests

   IK-H: Reviewing editor, eLife

9. Noboru Mizushima

   Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan

   Contribution

   NM, Analyzed and interpreted data

   Competing interests

   No competing interests declared.

   "This ORCID iD identifies the author of this article:" 0000-0002-6258-6444

10. Mitsunori Fukuda

    Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan

    Contribution

    MF, Generated reagents and analyzed and interpreted data.

    Competing interests

    No competing interests declared.

    "This ORCID iD identifies the author of this article:" 0000-0002-8620-5853

11. Amy A Kiger

    Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States

    Contribution

    AAK, Designed the research, analyzed and interpreted data, and wrote the manuscript with input from all authors.

    For correspondence

    akiger@ucsd.edu

    Competing interests

    No competing interests declared.

    "This ORCID iD identifies the author of this article:" 0000-0003-4300-176X

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