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Bulankina, A. Vertebrate Ferlins. Encyclopedia. Available online: https://encyclopedia.pub/entry/9665 (accessed on 26 June 2024).
Bulankina A. Vertebrate Ferlins. Encyclopedia. Available at: https://encyclopedia.pub/entry/9665. Accessed June 26, 2024.
Bulankina, Anna. "Vertebrate Ferlins" Encyclopedia, https://encyclopedia.pub/entry/9665 (accessed June 26, 2024).
Bulankina, A. (2021, May 15). Vertebrate Ferlins. In Encyclopedia. https://encyclopedia.pub/entry/9665
Bulankina, Anna. "Vertebrate Ferlins." Encyclopedia. Web. 15 May, 2021.
Vertebrate Ferlins
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This entry is adapted from the peer-reviewed paper 10.3390/cells9030534

Ferlins are multiple-C2-domain proteins involved in Ca2+-triggered membrane dynamics within the secretory, endocytic and lysosomal pathways. In bony vertebrates there are six ferlin genes encoding, in humans, dysferlin, otoferlin, myoferlin, Fer1L5 and 6 and the long noncoding RNA Fer1L4. Mutations in DYSF (dysferlin) can cause a range of muscle diseases with various clinical manifestations collectively known as dysferlinopathies, including limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy. A mutation in MYOF (myoferlin) was linked to a muscular dystrophy accompanied by cardiomyopathy. Mutations in OTOF (otoferlin) can be the cause of nonsyndromic deafness DFNB9. Dysregulated expression of any human ferlin may be associated with development of cancer.

dysferlin myoferlin otoferlin C2 domain calcium-sensor muscular dystrophy dysferlinopathy limb girdle muscular dystrophy type 2B (LGMD2B) membrane repair T-tubule system DFNB9

1. Introduction

Ferlins belong to the superfamily of proteins with multiple C2 domains (MC2D) that share common functions in tethering membrane-bound organelles or recruiting proteins to cellular membranes. Ferlins are described as calcium ions (Ca2+)-sensors for vesicular trafficking capable of sculpturing membranes [1][2][3]. Ferlins of bony vertebrates (humans and the model organisms zebrafish and mice) are among the largest proteins in this superfamily with molecular weights of more than 200 kDa. Their hallmark is the presence of five to seven C2 domains in the cytoplasmic segment and a single transmembrane domain near the C-terminus, defining them as tail-anchored proteins. Phylogenetic analysis of ferlins within bony vertebrates shows variability in both the presence/absence of individual members of the ferlin family and the numbers of predicted C2 domains within the subgroups. Proper function of ferlins, in particular dysferlin, myoferlin and otoferlin is important for human health [4][5][6][7][8].

2. Vertebrate Ferlins: Family Members and Domain Organization

In the following discussion, we focused on the vertebrates—zebrafish (Danio rerio), mice (Mus musculus) and humans (Homo sapiens)—representing important (model) organisms for the study of ferlin functions. Six ferlin genes were present in each of these organisms (Figure 1). The phylogenetic analysis of the corresponding proteins demonstrating the evolutionary relationship between ferlins is shown in Figure 2.
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Figure 1. Domain organization of ferlins of bony vertebrates. Ferlin domain organization from selected species (Dr, Danio rerio; Mm, Mus musculus; Hs; Homo sapiens) using the genome browser Ensembl (Release 96 from April 2019) [9] was drawn according to SMART and Pfam [10][11]. The corresponding phylogenetic tree was produced using Clustal Omega multiple sequence alignment program using default parameters [12]. Translated proteins are from e!Ensembl. Zebrafish has 6 ferlin genes; fer1l5 is absent; however, two related otoferlin genes otofa and b are present. In the mouse, all 6 ferlin genes are present and encode proteins, whereas in humans, FER1L4 represents a pseudogene producing long noncoding RNA. Abbreviations: Chr, chromosome.
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Figure 2. Phylogeny of ferlins in humans, mouse and zebrafish. The phylogenetic tree was produced using Clustal Omega multiple sequence alignment program using default parameters [12] and translated protein sequences from Figure 1. The branch length is indicative of the evolutionary distance between the sequences.
Human ferlin genes include five protein-encoding members, FER1L1/DYSF (dysferlin), FER1L2/OTOF (otoferlin), FER1L3/MYOF (myoferlin), FER1L5 (Fer1L5) and FER1L6 (Fer1L6), and the pseudogene FER1L4 encoding a long non-coding RNA [13][14][15]. The full set of six ferlin proteins (Fer1l1–6) is expressed in the mouse only. The zebrafish genome contains two otoferlin genes, otofa and otofb, on different chromosomes [16], while no fer1l5 ortholog appears to be present [17] (Figure 1 and Figure 2). It is tempting to speculate that the duplication of the otoferlin gene in zebrafish may parallel the development of the lateral line and inner ear, and it is not present in higher vertebrates that have also no lateral line, since both otoferlin a and b are expressed in the otic placode (giving rise to the inner ear), but only otoferlin b transcripts were detected in the lateral line [16].
C2 domain organization of vertebrate ferlins shows variability in the number of predicted domains and the C2 domain layout is conserved in Fer1L5s only (Figure 1). All other subgroups (dysferlins, otoferlins, myoferlins, Fer1L4s and Fer1L6s) show one outlier each, which has lost or gained one C2 domain. In addition to the C2 domains, ferlins of the bony vertebrates possess all or some of the specific homology domains, namely FerI, FerA, FerB and the ‘embedded’ DysF domain (Figure 1). Dysferlin, myoferlin and Fer1L5 contain all of these homology domains. On the basis of the presence of the embedded DysF domain, they are collectively known as type I ferlins. In contrast, otoferlin, Fer1l4 and Fer1L6 lack DysF domains and thus represent type II ferlins [13]. Of note, FerA domains are apparently not conserved in the primary sequence of type II ferlins of bony vertebrates, however, the characteristic to type I ferlins four amphipathic helix bundle fold of FerA domain is present in human otoferlin and such structural element can be predicted in all ferlin proteins [18]. In summary, the most conserved ferlin domains are the C2B-FerI-C2C stretch and the FerB, C2D and C2F domains as summarized in Figure 1.

3. Functions of Dysferlin in Muscle

3.1. Dysferlin Functions in Sarcolemma Repair

The best-studied function of dysferlin is its role in repair of lesions in the surface membrane of striated muscle fibers, the sarcolemma [19]. Muscle fiber contraction mechanically stresses the sarcolemma resulting in micro-lesions. These need to be repaired quickly and efficiently to prevent leakage and death of damaged muscle fibers. The repair process is triggered by Ca2+-influx into the sarcoplasm through the lesion and depends on a set of proteins including dysferlin as one of the key players [19][20]. It is likely, that dysferlin exerts its role during membrane repair promoting membrane aggregation and fusion via its Ca2+-triggered interactions with negatively charged phospholipids [21][22][19]. Dysferlin trafficking and dysferlin-dependent membrane repair are supported by partnering proteins. These include:
  • Ca2+- and PS-binding proteins annexins A1, A2 and A6 [23][24];
  • Muscle-specific proteins mitsugumin 53 (MG53) and caveolin 3, which are important for the nucleation of the sarcolemma repair machinery and for regulating the trafficking of dysferlin to and from the PM, respectively [25][26];
  • A giant scaffolding protein AHNAK participating in the regulation of Ca2+ homeostasis, signaling and structure of cytoskeleton [27][28];
  • Myoferlin, another member of the ferlin protein family [29];
  • Affixin (β-parvin), a protein linking integrins and cytoskeleton [30]; and;
  • A focal adhesion protein vinculin, cytoplasmic dynein participating in the retrograde vesicle transport along the microtubules and tubulin A [29][31].
These dysferlin-interacting proteins link its function as a Ca2+-sensitive membrane-binding protein important for vesicular trafficking during sarcolemma repair to cytoskeleton remodeling. It is likely that dysferlin is participating not only in exocytosis of vesicles or organelles dedicated for sarcolemma repair [32], but also in concomitant endocytosis [2][33]. More than that, in vivo function of dysferlin in sarcolemma repair extends to PS sorting to the site of membrane damage leading to the recruitment of macrophages, which removes the patch or plug (see below), as it was shown in zebrafish [34].
A number of cellular mechanisms have been shown to contribute to PM repair: contraction of membrane wounds, plugging (protein-based crosslinking of intracellular vesicles or membranous organelles without their fusion), patching (restoration of PM integrity by fusion of intracellular vesicles), endocytosis and externalization or membrane shedding [20][35]. The mechanisms could coexist and participate in resealing of the same PM lesion depending on the cell type or the stage of myogenic differentiation and on the extent of the PM injury. Most if not all of these mechanisms could contribute to sarcolemma resealing and proceed to a certain degree dependently on dysferlin.
Relatively large (up to 4 µm) sarcolemma lesions of mature myofibers could be resealed by one of the two mechanisms called patching and plugging, while fusion of the membranous organelles within the patch or plug was not proven. Formation of a dysferlin-containing patch or plug on the sites of sarcolemma wounds in zebrafish was paralleled by an increase in a PS-sensor signal and BODIPY-cholesterol fluorescence, confirming the presence of membranous organelles in the patch or plug [34][36]. These data are supported by earlier observations of vesicle accumulation below membrane lesions in non-necrotic muscle fibers from biopsies of dysferlinopathy patients and dysferlin knock-out mice [19][37][38]. These findings point to a defect in vesicle aggregation or fusion in the absence of dysferlin or under the conditions of severe reduction of its level. Resealing of smaller lesions (≥120 nm) also requires dysferlin, but without the formation of a dysferlin-containing patch [24]. It is likely that in such cases the repair of sarcolemma wounds requires formation of a proteinaceous plug or repair cap made up of several annexins. Indeed, when fluorescently labeled, dysferlin was not found in the repair cap, which was also devoid of the negatively charged lipids PS and PIP2, questioning the presence of the membranous organelles in the cap. During the repair process, dysferlin accumulates around the repair cap in a ‘shoulder’ area, possibly via lateral diffusion within the sarcolemma [34][33][24] and its interactions with the cytoskeleton, recruiting PS and hence macrophages to the injury sites [34]. The fusion of dysferlin-containing vesicles with the shoulder regions in this repair process was not demonstrated yet, but could not be excluded.
Nevertheless, the function of dysferlin in vesicular trafficking, which could underlie its role in PM repair, is supported by the observed defects in the injury triggered lysosome exocytosis across the surface of dysferlin-deficient myotubes and myoblasts [23][32]. Of note, dysferlin does not localize to lysosomes in intact myotubes, but dysferlin-containing vesicles fuse with lysosomes upon sarcolemma damage [39]. The lysosomal exocytosis could serve at least two functions: (i) acid sphingomyelinase secretion, which promotes membrane invagination and endocytosis, e.g. of caveolae [40][41][42] and (ii) it is likely that rather uniform secretion of lysosomal enzymes along the surface of the damaged muscle fiber could digest the basal lamina surrounding it and thereby reduce the mechanical stress on the fiber. The origin of the organelles that form the repair patch or fuse next to the site of sarcolemma injury has not been identified yet. Candidate compartments are T-tubule derived vesicles and vesicles originating from the sarcolemma or its subcompartments caveolae as well as enlargosomes [41][43][44].
Another mechanism of sarcolemma repair, which could depend on the function of dysferlin, is the contraction of the membrane wounds. This idea is supported by several observations: (i) dysferlin is accumulating on the rims of the lesions likely by lateral diffusion [34][33][24][45], (ii) the process of lesion contraction is Ca2+-dependent [45], (iii) dysferlin C2-domains are Ca2+-sensitive [21], (iv) dysferlin directly or indirectly interacts with cytoskeleton [27][29][30][31][46] and (vi) dysferlin recruitment to a wound site is dependent on annexin A6, a protein that previously has been shown to be involved in membrane lesion constriction in another cell type [24][47].
In summary, dysferlin bears a potential to participate in sarcolemma repair by at least four mechanisms (Figure 3):
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Figure 3. Mechanisms of dysferlin function in membrane repair. The model shows four possible and nonexclusive contributions of dysferlin to plasma membrane repair: (1) local formation of membranous patch or plug, triggered by calcium entry and supported, amongst others, by MG53 and annexins; (2) biogenesis and maintenance of the T-tubule system as a possible membrane reservoir; (3) cytoskeleton-dependent sorting of phosphatidylserine (PS) for the recruitment of macrophages, simultaneous contraction and subsequent sealing of the membrane wound and (4) exocytosis of lysosomes.
  • Membranous repair patch or plug formation;
  • T-tubule stabilization (see below) with T-tubule as a possible membrane reservoir;
  • PS-sorting; recruitment of macrophages and contraction of the membrane wound, and;
  • Lysosome exocytosis.

3.2. Dysferlin Functions in Triad Biology

Besides its function in the repair of sarcolemma of striated muscle fibers, dysferlin plays a role in T-tubule system development and in triad function upon injury. It participates in sculpturing the membranes during T-tubule biogenesis, especially in regenerating muscles and possibly also during repair of the system upon injury [1][48]. More than that, dysferlin takes part in the regulation of Ca2+-metabolism of injured muscle fibers via mechanochemical stabilization of the triad junction and its Ca2+-release and thus decreasing triad and, in particular, T-tubule sensitivity to stress [49][50][51][52].
Anatomically, the triad is defined by three membrane compartments: one T-tubule in the center, surrounded by two terminal cisternae of the sarcoplasmic reticulum. The main function of the triad is excitation–contraction coupling of the striated muscle fibers, which is achieved by physical binding of voltage-gated Ca2+ channels (Cav1.1), also known as L-type Ca2+-channels (LTCC) or dihydropyridine receptors (DHPRs) localized to T-tubules, and the ryanodine receptors (RyRs), calcium channels mediating calcium-induced calcium release from terminal cisternae of sarcoplasmic reticulum.
Dysferlin was found in a complex with DHPRs and caveolin 3, and also with RyRs [53][31]. Dysferlin possibly stabilizes the Ca2+-metabolism of the injured muscle fibers inhibiting DHPRs and preventing injury-induced Ca2+-leak into the sarcoplasm through RyRs, model supported by sustained Ca2+ influxes in dysferlin-deficient muscle fibers sensitive to the DHPR inhibitor diltiazem and reduction of the extracellular Ca2+ concentration [50]. However, later the sarcoplasmic reticulum and RyRs were identified as the primary source of the Ca2+ leak in injured muscle fibers in the absence of dysferlin [52]. Thus, dysferlin localized to T-tubules forms a complex with both DHPRs and RyRs and modulates their function in the case of injury.
Dysferlin-deficient muscles also show T-tubule system abnormalities upon regeneration [1]. Dysferlin interacts with the T-tubule proteins caveolin 3 and amphiphysin 2 as well as with negatively charged lipid PIP2 required for T-tubule biogenesis [1][22][54][55]. It was shown that dysferlin induces the formation of tubular structures upon expression in non-muscle cells [1]. Otoferlin and myoferlin did not induce such intracellular membranes when overexpressed under similar conditions. When truncation mutations and pathogenetic point mutations in dysferlin were analyzed, all except one (L1341P located in C2E) failed to induce membrane tubulation in non-muscle cells. In C2C12 myoblasts, dysferlin colocalizes with PIP2 at the PM and at the T-tubule system. Dysferlin also binds to PIP2-rich vacuoles that were generated by expression of phosphatidylinositol phosphate kinase or a constitutively active Arf6 mutant [1]. Interestingly, most analyzed dysferlin deletions and truncations were not recruited to PIP2-vacuoles, indicating that PIP2 binding is a critical feature of dysferlin. Moreover, when cellular PIP2 have been degraded, dysferlin was lost from the T-tubule system, the T-tubule system was altered and, in non-muscle cells, dysferlin overexpression, could no longer induce formation of T-tubule-like intracellular membrane structures [1]. These data suggest that dysferlin together with PIP2 is critical for the biogenesis of the T-tubule system. In addition, the repair of the T-tubule system could be mediated by sarcolemma resealing complex of dysferlin, MG53 and annexin A1, as these proteins are enriched at longitudinal tubules of the system under overstretch conditions [48].

3.3. Dysferlin in the Differentiation, Growth and Regeneration of Skeletal Muscle

Skeletal muscles develop normally in pre-symptomatic dysferlinopathy patients and dysferlin-deficient mice. However, after reaching a certain age, several muscle groups begin to show initial signs of pathology: centrally nucleated fibers and variability in fiber size, which deteriorate with time. So, if dysferlin plays a role in muscle growth, myoblast differentiation and fusion, then it, likely, takes place after a defined developmental stage. There are contradicting reports concerning dysferlin role in skeletal muscle differentiation, grow and regeneration. Some authors present evidence for the absence of an effect of dysferlin-deficiency on myoblast differentiation in vitro [32][56][57]. However, none of them presented fusion indices or the numbers of nuclei per myotube differentiated in culture. There are also reports about higher regeneration capacity upon injury in mice bearing a mutation in Dysf [58][59][60]. Other authors argue for a role of dysferlin in myoblast differentiation and cytokine secretion so that myoblast fusion is affected indirectly only. In their studies, dysferlin-deficiency leads to decreased levels of myogenesis regulatory factors like MyoD and myogenin and delays myogenic differentiation in vitro [61][62]. Accordingly, induction of dysferlin expression in myoblasts was shown to promote their myogenic differentiation [63]. Myoblasts isolated from dysferlinopathy patients or derived from dysferlin-deficient mice proliferated with the normal rate [61][62], but showed decreased fusion efficiency in vitro as a result of activated signaling of the pro-inflammatory network inhibiting myogenesis [62]. In this context it is important to mention that dysferlin has been found in a protein complex with minion/myomerger, a fusogenic protein, which together with myomaker conveys the ability to form syncytia to myogenic and non-myogenic cells [64].
Impaired adult satellite cell differentiation, myoblast-to-myotube fusion and muscle growth in the absence of dysferlin can be attributed to a defect in insulin-like growth factor-1 receptor (IGF1R) trafficking, since IGFs are known to promote muscle cell differentiation [65][66]. Furthermore, dysferlin-deficiency attenuated muscle regeneration resulting in the presence of an increased number of immature fibers and suggesting that regenerative process is delayed or incomplete in dysferlinopathy [67]. Normal muscle regeneration process requires temporally acute and transient immune response for well-timed removal of necrotic fibers [68], however, the extended inflammatory response in a mouse model of dysferlinopathy is probably due to the defect in stimulated cytokine release by myoblasts [67].
In summary, dysferlin could have additional functions in vesicular trafficking of growth factors receptors, secreted pro-inflammatory molecules and even fusogenic proteins that promote muscle growth and regeneration. We hypothesize that dysferlin-dependent trafficking of such signaling molecules can modulate gene expression and the function of the adult muscle stem (or satellite) cells responsible for the skeletal muscle growth and regeneration in mature individuals.

4. Functions of Myoferlin and Fer1L5

Like dysferlin, myoferlin and Fer1L5 are important for skeletal muscle growth [69][70][71]. Myoferlin can localize to the PM and intracellular vesicles in myoblasts and to the sarcolemma of mature muscle fibers [15][72][69]. However, in contrast to dysferlin, myoferlin was not found associated with T-tubules and does not induce tubular structures in cells upon heterologous expression [1][51]. Myoferlin also can localize to the nuclear envelope and translocates to the nucleus together with the transcription factor STAT3 upon activation [72][73]. Other myoferlin interacting proteins include dysferlin, AHNAK, ADAM12 (A Disintegrin and Metalloproteinase 12) and EHD1 and 2 (Eps15 homology-domain containing proteins 1 and 2 regulating endocytic recycling) [74][27][29][75].
The first function described for myoferlin was its role in skeletal muscle growth and regeneration [69]. Interestingly, myoferlin knock-out mice have lower body mass with decreased diameters of skeletal muscle fibers. These mice show delayed muscle regeneration upon cardiotoxin injection, but no myopathy [69]. In contrast, dysferlin-deficient mice grow normally up to a certain age and later develop muscular dystrophy [74], emphasizing functional differences between myo- and dysferlin in mice. In humans for a long time no pathogenic mutations in MYOF was reported. However, recently the first case of limb-girdle type muscular dystrophy and associated cardiomyopathy linked to MYOF mutation was described [7].
Known Fer1L5-binding proteins are EHD1, EHD2 and GRAF1 (Rho-GAP GTPase regulator associated with focal adhesion kinase-1) [74][76][77]. EHD proteins are dynamin-related ATPases capable of vesicle scission, while GRAF1 regulates the actin cytoskeleton and sculptures membranes [77][78]. It was suggested that myoferlin and Fer1L5 mediate intracellular trafficking events essential for efficient myoblast to myotube fusion, and that knock-down of EHD2 or GRAF1 interferes with trafficking of these ferlins to a cell periphery [74][76][77]. Indeed, together with EHD proteins myoferlin and Fer1L5 could participate in recycling of IGF1R and the glucose transporter GLUT4, which both are required for muscle growth [70][71][75]. It would be important to determine whether myoferlin, like dysferlin, could play a role in trafficking of the myoblast fusion proteins minion/myomerger and myomaker.
Myoferlin is also involved in membrane repair in muscle fibers and during accelerated proliferation of tumor cells [24][79] as well as in the maintenance of T-tubules stability and function in striated muscle [51]. Thus, myoferlin, similar to dysferlin, may be required for multiple trafficking events in the secretory and endocytic pathways and the functions of the muscle-expressed ferlins, dysferlin, myoferlin and Fer1L5, could overlap to a significant degree.

5. Ferlins in Human Diseases: Dysferlinopathies and Their Pathomechanisms

Dysferlinopathies are diseases caused by mutations in DYSF, affecting mainly skeletal muscles [80]. There are two common dysferlinopathy phenotypes—limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM)—along with several more rare conditions: distal myopathy with anterior tibialis onset (distal anterior compartment myopathy), congenital muscular dystrophy and isolated hyperCKemia, an elevated concentration of serum creatine kinase (CK) [80]. Onset and progression of the disease as well as distribution of muscle weakness and wasting may vary significantly between individuals affected by dysferlinopathies. Several different clinical phenotypes can occur even within families carrying the same pathogenic variants of DYSF [5][81][82][83]. These observations emphasize the importance of investigating potential modifier genes [5][81].
Dysferlinopathies are characterized by late onset and slow progression. In carriers of pathogenic gene variants disease usually manifests in the second or third decade of life. The first symptoms are lower limb weakness accompanied by an increase in serum CK levels. The patients with the most severe phenotype of LGMD2B can become confined to wheelchair after two or three decades of disease progression, while most MM patients preserve ambulation [84]. Histological signs of the diseases are degeneration and regeneration of skeletal muscle [85] and in the more severe cases, fibrotic and adipogenic replacement of myofibers. On the protein level, dysferlinopathies are diagnosed by a complete loss or severe reduction of dysferlin in muscle biopsies or peripheral blood monocytes [86].
Mouse models lacking dysferlin develop muscular dystrophy, however, with an apparently less severe phenotype than humans and do not lose ambulation with age [87][88]. In dysferlin-deficient mice, the earliest symptoms are centrally nucleated fibers and marked differences in the myofiber diameter as well as 4- to 6-fold elevated CK levels at four weeks of age [89].
Latent cardiac dysfunction has been reported in dysferlinophathies, but patients do not primarily suffer from cardiomyopathies [90][91]. In a retrospective analysis, cardiac and respiratory functions were studied in dysferlinopathy patients [91]. Thus, a cardiovascular magnetic resonance analysis of LGMD2B patients showed indications of mild structural and functional cardiomyopathy [92]. One fifth of the patients developed respiratory problems and 9% required non-invasive ventilation. Accordingly, heart function in dysferlinopathy mouse models is either not or mildly affected [87][90][93][94][95]. However, also membrane repair in cardiomyocytes is dependent on dysferlin [96] and in a model of ischemia/reperfusion injury, dysferlin was shown to be cardioprotective [96][97]. Furthermore, physical stress exercise, or β-adrenergic activation provoke various symptoms of cardiac dysfunction in dysferlinopathy mice [90][94][96][97][98][99]. Mice with dysferlin inactivation show increased susceptibility to coxsackie virus infection and virus-induced myocardial damage [100], suggesting that pathways of viral infection and muscle repair may overlap.
It is generally assumed that disease causing mutations are more or less uniformly distributed along the dysferlin-coding sequence [101] (Table 1). Two pathogenic missense mutations in human dysferlin FerA do destabilize the domain in differential scanning calorimetry (DSC) experiments [18] and a similar prediction was made for the three most frequent out of 15 missense mutations in the inner DysF domain [102]. These and other mutations may result in the poor dysferlin folding and degradation of the protein via different pathways. For example, missense mutation L1341P in C2E domain causes dysferlin aggregation in the ER and degradation by the additional autophagy/lysosome ER-associated degradation system [103]. Dysferlin lacking C2C domain or carrying patient mutation L344P within FerI domain demonstrate accelerated endocytosis, protein lability and endosomal proteolysis [104].
At present it is not clear how exactly loss-of-function mutations of DYSF and a decrease of the corresponding protein expression level lead to the development of dysferlinopathies. The following mechanisms may contribute to the development of the disease: (a) a defect in sarcolemma repair; (b) changes in Ca2+-homeostasis; (c) impaired muscle growth and regeneration and (d) inflammatory processes. Below, we discussed these factors in turn. To which degree, however, these mechanisms contribute to the development of the disease is still not known. The situation becomes even more complex when considering the existence of the various clinical manifestations of dysferlinopathies.

5.1. Defective Repair of Myofiber Sarcolemma and, Possibly, T-Tubules

The pathomechanism could be the following: dysferlin deficiency decreases the efficiency of sarcolemma and, probably, T-tubule system repair [48][19][105]. This increases (i) influx of Ca2+ into injured muscle fibers, (ii) leakage of the muscle fiber contents such as muscle enzymes, e.g., CK, and (iii) the probability of death of damaged myofibers [5][19]. The latter promotes cycles of muscle degeneration and regeneration. In parallel, inefficient sarcolemma repair changes the properties of the regenerative niche by enhanced accumulation of dysferlin partner protein annexin A2 in the myofiber matrix [24][106]. The formation of a regenerative niche requires the absence of annexin A2 in the myofiber matrix, and if it is progressively accumulating, fibro/adipogenic precursors are escaping apoptotic signal. This leads to their differentiation into adipocytes and the substitution of muscle fibers in dysferlinopathy [106].

5.2. Changes in Muscle Fibers Ca2+ Homeostasis

Overloading of the cells with Ca2+ or abnormal intracellular distribution of these ions can lead to autophagic, necrotic or apoptotic cell death [107]. In muscles of dysferlinopathy patients, altered Ca2+ homeostasis and Ca2+-mediated cytotoxicity can result from (i) impaired sarcolemma and T-tubule system repair contributing to the leakage of extracellular Ca2+ into the sarcoplasm through a lesion and DHPRs as well as sarcoplasmic reticulum-stored Ca2+ through RyRs, (ii) abnormalities in the biogenesis of the T-tubule system and triads as well as a decrease in their plasticity in response to stress and (iii) enhanced X-ROS (NADPH oxidase 2-dependent reactive oxygen species, ROS) signaling activating mechano-sensitive Ca2+ channels in the T-tubule system, coupling mechanical stress to changes in the intracellular Ca2+ concentration [108].
Under normal physiological conditions, ROS production is linked to both signaling and metabolism (as a side product of the latter) [109]. In the mouse model of dysferlinopathy (A/J strain), X-ROS signaling is amplified and contributes to the development of myopathy in aged animals (> 6 month). Thus, in the stretched dysferlin-deficient muscle fibers of A/J mice, intracellular ROS and Ca2+ concentrations increased in comparison to wild-type controls [108], implying that X-ROS signaling could be enhanced as a result of dysferlin dysfunction.
Altered Ca2+ homeostasis in dysferlinopathy can lead to myofibers death and cycles of regeneration via (i) activation of endonucleases, phospholipases and proteases like calpains leading to unwanted cleavage of cellular components; (ii) triggering multiple signaling cascades affecting gene expression or cell survival [107].

5.3. Impaired Muscle Growth and Regeneration

The potential effect of dysferlin deficiency on muscle growth and regeneration was discussed above in Section 6.3. Additionally, dysferlin functions in these processes could be linked to T-tubule development in regenerating muscle, abnormalities in Ca2+-homeostasis and inflammatory processes (Figure 4). Formation of an irregular T-tubule network upon myofiber regeneration may disturb Ca2+-homeostasis. The impaired Ca2+-compartmentalization and signaling may lead to myofiber death, promote cycles of muscle regeneration and reduce secretion of cytokines by surviving myoblasts or myofibers [67][107][110]. The defects in secretion of chemotactic molecules leads to a decrease in the number of recruited neutrophils, delayed removal of necrotic fibers, prolonged inflammatory responses, incomplete regeneration cycles and development of muscular dystrophy [67].
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Figure 4. The network of dysferlin functions. Malfunctioning of one or several aspects contributes to the pathology of dysferlinopathies (red arrows). (1) Impaired sarcolemma repair leads to changes in Ca2+ homeostasis and in turn could be affected by intracellular Ca2+ compartmentalization and signaling. (2) The T-tubule system is necessary to maintain Ca2+ homeostasis and in turn could be affected by abnormalities in Ca2+ signaling. (3) Deficits in sarcolemma and T-tubule system repair may cause death of damaged myofibers and promote cycles of the muscle regeneration. Leakage of the muscle fibers contents may change properties of the regenerative niche. (4) Changes in Ca2+ compartmentalization and signaling in myofibers can result in dysregulation of, e.g., cytokines secretion and prolonged inflammatory responses. (5) Dysregulation of Ca2+ homeostasis may lead to myofibers death, which promotes cycles of muscle regeneration. (6) Sarcolemma repair may depend on the function of T-tubule system as a membrane reservoir and affect T-tubule system function via changes in Ca2+ homeostasis. (7) T-tubule system function may be affected by abnormalities in its structure arising during dysferlin-deficient muscle regeneration. (8) Malfunctioning of sarcolemma repair enhances leakage of damage-associated molecules, e.g., annexin A2, promoting inflammation. (9) Prolonged inflammation may result in incomplete cycles of regeneration and pro-inflammatory signaling may inhibit myogenesis.

5.4. Inflammatory Processes

Dysferlinopathies are often accompanied by muscle inflammation and dysferlinopathy patients can be misdiagnosed as having polymyositis [111][112][113]. The role of dysferlin in the inflammatory response was reviewed by several authors [114][115]. Inflammation could originate from:
  • Leakage of damage-associated molecules such as annexin A2 from dysferlin-deficient myofibers [116] through sarcolemma lesions [115],
  • Intrinsic pro-inflammatory signaling of dysferlin-deficient muscle fibers [62][117],
  • Deregulation of cytokine secretion [67], and/or,
  • Activation of dysferlin-deficient monocytes or macrophages [111].
However, there is also evidence that inflammation in dysferlinopathies originates autonomously within the skeletal muscle and not due to dysferlin function in other cell types. For example, it was shown by means of bone marrow transplantation that inflammation in SJL/J mice does not depend on the genotype of the leukocytes [118]. Along the same lines, transgenic mice generated from the A/J mouse model of dysferlinopathy, expressing dysferlin under a skeletal muscle-specific promoter are indistinguishable from dysferlin-sufficient mice [119]. Lastly, it was shown that macrophage infiltration is a consequence of myofiber damage and not vice versa [120].
In summary, reduced efficiency of sarcolemma and, likely, T-tubule system repair can lead to changes in Ca2+ homeostasis, myofiber necrosis, inflammation and cycles of regeneration followed by fibro-adipogenic substitution of the muscles, resulting in their weakness (Figure 4) [121]. However, pathomechanisms leading to the development of dysferlinopathies are, likely, not restricted to the defects in sarcolemma repair, since rescue of PM repair malfunctioning by myoferlin overexpression does not improve muscle histology [122]. This means that dysferlin functions other than sarcolemma repair are also indispensable for skeletal muscle health.

References

  1. Hofhuis, J.; Bersch, K.; Büssenschütt, R.; Drzymalski, M.; Liebetanz, D.; Nikolaev, V.O.; Wagner, S.; Maier, L.S.; Gärtner, J.; Klinge, L.; et al. Dysferlin mediates membrane tubulation and links T-tubule biogenesis to muscular dystrophy. J. Cell. Sci. 2017, 130, 841–852.
  2. Johnson, C.P. Emerging Functional Differences between the Synaptotagmin and Ferlin Calcium Sensor Families. Biochemistry 2017, 56, 6413–6417.
  3. Pangrsic, T.; Vogl, C. Balancing presynaptic release and endocytic membrane retrieval at hair cell ribbon synapses. FEBS Lett. 2018, 592, 3633–3650.
  4. Bashir, R.; Britton, S.; Strachan, T.; Keers, S.; Vafiadaki, E.; Lako, M.; Richard, I.; Marchand, S.; Bourg, N.; Argov, Z.; et al. A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nat. Genet. 1998, 20, 37–42.
  5. Liu, J.; Aoki, M.; Illa, I.; Wu, C.; Fardeau, M.; Angelini, C.; Serrano, C.; Urtizberea, J.A.; Hentati, F.; Hamida, M.B.; et al. Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat. Genet. 1998, 20, 31–36.
  6. Yasunaga, S.; Grati, M.; Cohen-Salmon, M.; El-Amraoui, A.; Mustapha, M.; Salem, N.; El-Zir, E.; Loiselet, J.; Petit, C. A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness. Nat. Genet. 1999, 21, 363–369.
  7. Kiselev, A.; Vaz, R.; Knyazeva, A.; Sergushichev, A.; Dmitrieva, R.; Khudiakov, A.; Jorholt, J.; Smolina, N.; Sukhareva, K.; Fomicheva, Y.; et al. Truncating Variant in Myof Gene Is Associated With Limb-Girdle Type Muscular Dystrophy and Cardiomyopathy. Front. Genet. 2019, 10, 608.
  8. Peulen, O.; Rademaker, G.; Anania, S.; Turtoi, A.; Bellahcène, A.; Castronovo, V. Ferlin Overview: From Membrane to Cancer Biology. Cells 2019, 8, E954.
  9. Cunningham, F.; Achuthan, P.; Akanni, W.; Allen, J.; Amode, M.R.; Armean, I.M.; Bennett, R.; Bhai, J.; Billis, K.; Boddu, S.; et al. Ensembl 2019. Nucleic Acids Res. 2019, 47, D745–D751.
  10. El-Gebali, S.; Mistry, J.; Bateman, A.; Eddy, S.R.; Luciani, A.; Potter, S.C.; Qureshi, M.; Richardson, L.J.; Salazar, G.A.; Smart, A.; et al. The Pfam protein families database in 2019. Nucleic Acids Res. 2019, 47, D427–D432.
  11. Letunic, I.; Bork, P. 20 years of the SMART protein domain annotation resource. Nucleic Acids Res. 2018, 46, D493–D496.
  12. Madeira, F.; Park, Y.M.; Lee, J.; Buso, N.; Gur, T.; Madhusoodanan, N.; Basutkar, P.; Tivey, A.R.N.; Potter, S.C.; Finn, R.D.; et al. The EMBL-EBI search and sequence analysis tools APIs in 2019. Nucleic Acids Res. 2019, 47, W636–W641.
  13. Lek, A.; Lek, M.; North, K.N.; Cooper, S.T. Phylogenetic analysis of ferlin genes reveals ancient eukaryotic origins. BMC Evol. Biol. 2010, 10, 231.
  14. Song, H.; Sun, W.; Ye, G.; Ding, X.; Liu, Z.; Zhang, S.; Xia, T.; Xiao, B.; Xi, Y.; Guo, J. Long non-coding RNA expression profile in human gastric cancer and its clinical significances. J. Transl. Med. 2013, 11, 225.
  15. Redpath, G.M.I.; Sophocleous, R.A.; Turnbull, L.; Whitchurch, C.B.; Cooper, S.T. Ferlins Show Tissue-Specific Expression and Segregate as Plasma Membrane/Late Endosomal or Trans-Golgi/Recycling Ferlins. Traffic 2016, 17, 245–266.
  16. Chatterjee, P.; Padmanarayana, M.; Abdullah, N.; Holman, C.L.; LaDu, J.; Tanguay, R.L.; Johnson, C.P. Otoferlin deficiency in zebrafish results in defects in balance and hearing: Rescue of the balance and hearing phenotype with full-length and truncated forms of mouse otoferlin. Mol. Cell. Biol. 2015, 35, 1043–1054.
  17. Bonventre, J.A.; Holman, C.; Manchanda, A.; Codding, S.J.; Chau, T.; Huegel, J.; Barton, C.; Tanguay, R.; Johnson, C.P. Fer1l6 is essential for the development of vertebrate muscle tissue in zebrafish. Mol. Biol. Cell 2019, 30, 293–301.
  18. Harsini, F.M.; Chebrolu, S.; Fuson, K.L.; White, M.A.; Rice, A.M.; Sutton, R.B. FerA is a Membrane-Associating Four-Helix Bundle Domain in the Ferlin Family of Membrane-Fusion Proteins. Sci. Rep. 2018, 8, 10949.
  19. Bansal, D.; Miyake, K.; Vogel, S.S.; Groh, S.; Chen, C.-C.; Williamson, R.; McNeil, P.L.; Campbell, K.P. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 2003, 423, 168–172.
  20. Barthélémy, F.; Defour, A.; Lévy, N.; Krahn, M.; Bartoli, M. Muscle Cells Fix Breaches by Orchestrating a Membrane Repair Ballet. J. Neuromuscul. Dis. 2018, 5, 21–28.
  21. Abdullah, N.; Padmanarayana, M.; Marty, N.J.; Johnson, C.P. Quantitation of the calcium and membrane binding properties of the C2 domains of dysferlin. Biophys. J. 2014, 106, 382–389.
  22. Therrien, C.; Di Fulvio, S.; Pickles, S.; Sinnreich, M. Characterization of lipid binding specificities of dysferlin C2 domains reveals novel interactions with phosphoinositides. Biochemistry 2009, 48, 2377–2384.
  23. Lennon, N.J.; Kho, A.; Bacskai, B.J.; Perlmutter, S.L.; Hyman, B.T.; Brown, R.H. Dysferlin interacts with annexins A1 and A2 and mediates sarcolemmal wound-healing. J. Biol. Chem. 2003, 278, 50466–50473.
  24. Demonbreun, A.R.; Quattrocelli, M.; Barefield, D.Y.; Allen, M.V.; Swanson, K.E.; McNally, E.M. An actin-dependent annexin complex mediates plasma membrane repair in muscle. J. Cell Biol. 2016, 213, 705–718.
  25. Hernández-Deviez, D.J.; Howes, M.T.; Laval, S.H.; Bushby, K.; Hancock, J.F.; Parton, R.G. Caveolin regulates endocytosis of the muscle repair protein, dysferlin. J. Biol. Chem. 2008, 283, 6476–6488.
  26. Cai, C.; Weisleder, N.; Ko, J.-K.; Komazaki, S.; Sunada, Y.; Nishi, M.; Takeshima, H.; Ma, J. Membrane repair defects in muscular dystrophy are linked to altered interaction between MG53, caveolin-3, and dysferlin. J. Biol. Chem. 2009, 284, 15894–15902.
  27. Huang, Y.; Laval, S.H.; van Remoortere, A.; Baudier, J.; Benaud, C.; Anderson, L.V.B.; Straub, V.; Deelder, A.; Frants, R.R.; den Dunnen, J.T.; et al. AHNAK, a novel component of the dysferlin protein complex, redistributes to the cytoplasm with dysferlin during skeletal muscle regeneration. FASEB J. 2007, 21, 732–742.
  28. Park, J.W.; Kim, I.Y.; Choi, J.W.; Lim, H.J.; Shin, J.H.; Kim, Y.N.; Lee, S.H.; Son, Y.; Sohn, M.; Woo, J.K.; et al. AHNAK Loss in Mice Promotes Type II Pneumocyte Hyperplasia and Lung Tumor Development. Mol. Cancer Res. 2018, 16, 1287–1298.
  29. de Morrée, A.; Hensbergen, P.J.; van Haagen, H.H.H.B.M.; Dragan, I.; Deelder, A.M.; ’t Hoen, P.A.C.; Frants, R.R.; van der Maarel, S.M. Proteomic analysis of the dysferlin protein complex unveils its importance for sarcolemmal maintenance and integrity. PLoS ONE 2010, 5, e13854.
  30. Matsuda, C.; Kameyama, K.; Tagawa, K.; Ogawa, M.; Suzuki, A.; Yamaji, S.; Okamoto, H.; Nishino, I.; Hayashi, Y.K. Dysferlin interacts with affixin (beta-parvin) at the sarcolemma. J. Neuropathol. Exp. Neurol. 2005, 64, 334–340.
  31. Flix, B.; de la Torre, C.; Castillo, J.; Casal, C.; Illa, I.; Gallardo, E. Dysferlin interacts with calsequestrin-1, myomesin-2 and dynein in human skeletal muscle. Int. J. Biochem. Cell Biol. 2013, 45, 1927–1938.
  32. Defour, A.; Van der Meulen, J.H.; Bhat, R.; Bigot, A.; Bashir, R.; Nagaraju, K.; Jaiswal, J.K. Dysferlin regulates cell membrane repair by facilitating injury-triggered acid sphingomyelinase secretion. Cell Death Dis. 2014, 5, e1306.
  33. McDade, J.R.; Archambeau, A.; Michele, D.E. Rapid actin-cytoskeleton-dependent recruitment of plasma membrane-derived dysferlin at wounds is critical for muscle membrane repair. FASEB J. 2014, 28, 3660–3670.
  34. Middel, V.; Zhou, L.; Takamiya, M.; Beil, T.; Shahid, M.; Roostalu, U.; Grabher, C.; Rastegar, S.; Reischl, M.; Nienhaus, G.U.; et al. Dysferlin-mediated phosphatidylserine sorting engages macrophages in sarcolemma repair. Nat Commun 2016, 7, 12875.
  35. Moe, A.M.; Golding, A.E.; Bement, W.M. Cell healing: Calcium, repair and regeneration. Semin. Cell Dev. Biol. 2015, 45, 18–23.
  36. Roostalu, U.; Strähle, U. In vivo imaging of molecular interactions at damaged sarcolemma. Dev. Cell 2012, 22, 515–529.
  37. Piccolo, F.; Moore, S.A.; Ford, G.C.; Campbell, K.P. Intracellular accumulation and reduced sarcolemmal expression of dysferlin in limb--girdle muscular dystrophies. Ann. Neurol. 2000, 48, 902–912.
  38. Selcen, D.; Stilling, G.; Engel, A.G. The earliest pathologic alterations in dysferlinopathy. Neurology 2001, 56, 1472–1481.
  39. McDade, J.R.; Michele, D.E. Membrane damage-induced vesicle-vesicle fusion of dysferlin-containing vesicles in muscle cells requires microtubules and kinesin. Hum. Mol. Genet. 2014, 23, 1677–1686.
  40. Tam, C.; Idone, V.; Devlin, C.; Fernandes, M.C.; Flannery, A.; He, X.; Schuchman, E.; Tabas, I.; Andrews, N.W. Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. J. Cell Biol. 2010, 189, 1027–1038.
  41. Corrotte, M.; Almeida, P.E.; Tam, C.; Castro-Gomes, T.; Fernandes, M.C.; Millis, B.A.; Cortez, M.; Miller, H.; Song, W.; Maugel, T.K.; et al. Caveolae internalization repairs wounded cells and muscle fibers. Elife 2013, 2, e00926.
  42. Draeger, A.; Babiychuk, E.B. Ceramide in plasma membrane repair. Handb. Exp. Pharmacol. 2013, 216, 341–353.
  43. Borgonovo, B.; Cocucci, E.; Racchetti, G.; Podini, P.; Bachi, A.; Meldolesi, J. Regulated exocytosis: A novel, widely expressed system. Nat. Cell Biol. 2002, 4, 955–962.
  44. Klinge, L.; Laval, S.; Keers, S.; Haldane, F.; Straub, V.; Barresi, R.; Bushby, K. From T-tubule to sarcolemma: Damage-induced dysferlin translocation in early myogenesis. FASEB J. 2007, 21, 1768–1776.
  45. Lek, A.; Evesson, F.J.; Lemckert, F.A.; Redpath, G.M.I.; Lueders, A.-K.; Turnbull, L.; Whitchurch, C.B.; North, K.N.; Cooper, S.T. Calpains, cleaved mini-dysferlinC72, and L-type channels underpin calcium-dependent muscle membrane repair. J. Neurosci. 2013, 33, 5085–5094.
  46. Lin, P.; Zhu, H.; Cai, C.; Wang, X.; Cao, C.; Xiao, R.; Pan, Z.; Weisleder, N.; Takeshima, H.; Ma, J. Nonmuscle myosin IIA facilitates vesicle trafficking for MG53-mediated cell membrane repair. FASEB J. 2012, 26, 1875–1883.
  47. Boye, T.L.; Maeda, K.; Pezeshkian, W.; Sønder, S.L.; Haeger, S.C.; Gerke, V.; Simonsen, A.C.; Nylandsted, J. Annexin A4 and A6 induce membrane curvature and constriction during cell membrane repair. Nat. Commun. 2017, 8, 1623.
  48. Waddell, L.B.; Lemckert, F.A.; Zheng, X.F.; Tran, J.; Evesson, F.J.; Hawkes, J.M.; Lek, A.; Street, N.E.; Lin, P.; Clarke, N.F.; et al. Dysferlin, annexin A1, and mitsugumin 53 are upregulated in muscular dystrophy and localize to longitudinal tubules of the T-system with stretch. J. Neuropathol. Exp. Neurol. 2011, 70, 302–313.
  49. Klinge, L.; Harris, J.; Sewry, C.; Charlton, R.; Anderson, L.; Laval, S.; Chiu, Y.-H.; Hornsey, M.; Straub, V.; Barresi, R.; et al. Dysferlin associates with the developing T-tubule system in rodent and human skeletal muscle. Muscle Nerve 2010, 41, 166–173.
  50. Kerr, J.P.; Ziman, A.P.; Mueller, A.L.; Muriel, J.M.; Kleinhans-Welte, E.; Gumerson, J.D.; Vogel, S.S.; Ward, C.W.; Roche, J.A.; Bloch, R.J. Dysferlin stabilizes stress-induced Ca2+ signaling in the transverse tubule membrane. Proc. Natl. Acad. Sci. USA 2013, 110, 20831–20836.
  51. Demonbreun, A.R.; Rossi, A.E.; Alvarez, M.G.; Swanson, K.E.; Deveaux, H.K.; Earley, J.U.; Hadhazy, M.; Vohra, R.; Walter, G.A.; Pytel, P.; et al. Dysferlin and myoferlin regulate transverse tubule formation and glycerol sensitivity. Am. J. Pathol. 2014, 184, 248–259.
  52. Lukyanenko, V.; Muriel, J.M.; Bloch, R.J. Coupling of excitation to Ca2+ release is modulated by dysferlin. J. Physiol. (Lond.) 2017, 595, 5191–5207.
  53. Ampong, B.N.; Imamura, M.; Matsumiya, T.; Yoshida, M.; Takeda, S. Intracellular localization of dysferlin and its association with the dihydropyridine receptor. Acta Myol. 2005, 24, 134–144.
  54. Galbiati, F.; Engelman, J.A.; Volonte, D.; Zhang, X.L.; Minetti, C.; Li, M.; Hou, H.; Kneitz, B.; Edelmann, W.; Lisanti, M.P. Caveolin-3 null mice show a loss of caveolae, changes in the microdomain distribution of the dystrophin-glycoprotein complex, and t-tubule abnormalities. J. Biol. Chem. 2001, 276, 21425–21433.
  55. Lee, E.; Marcucci, M.; Daniell, L.; Pypaert, M.; Weisz, O.A.; Ochoa, G.-C.; Farsad, K.; Wenk, M.R.; De Camilli, P. Amphiphysin 2 (Bin1) and T-tubule biogenesis in muscle. Science 2002, 297, 1193–1196.
  56. Humphrey, G.W.; Mekhedov, E.; Blank, P.S.; de Morree, A.; Pekkurnaz, G.; Nagaraju, K.; Zimmerberg, J. GREG cells, a dysferlin-deficient myogenic mouse cell line. Exp. Cell Res. 2012, 318, 127–135.
  57. Philippi, S.; Bigot, A.; Marg, A.; Mouly, V.; Spuler, S.; Zacharias, U. Dysferlin-deficient immortalized human myoblasts and myotubes as a useful tool to study dysferlinopathy. PLoS Curr. 2012, 4, RRN1298.
  58. Mitchell, C.A.; McGeachie, J.K.; Grounds, M.D. Cellular differences in the regeneration of murine skeletal muscle: A quantitative histological study in SJL/J and BALB/c mice. Cell Tissue Res. 1992, 269, 159–166.
  59. Maley, M.A.; Fan, Y.; Beilharz, M.W.; Grounds, M.D. Intrinsic differences in MyoD and myogenin expression between primary cultures of SJL/J and BALB/C skeletal muscle. Exp. Cell Res. 1994, 211, 99–107.
  60. Ishiba, R.; Santos, A.L.F.; Almeida, C.F.; Caires, L.C.; Ribeiro, A.F.; Ayub-Guerrieri, D.; Fernandes, S.A.; Souza, L.S.; Vainzof, M. Faster regeneration associated to high expression of Fam65b and Hdac6 in dysferlin-deficient mouse. J. Mol. Histol. 2019, 50, 375–387.
  61. de Luna, N.; Gallardo, E.; Soriano, M.; Dominguez-Perles, R.; de la Torre, C.; Rojas-García, R.; García-Verdugo, J.M.; Illa, I. Absence of dysferlin alters myogenin expression and delays human muscle differentiation “in vitro”. J. Biol. Chem. 2006, 281, 17092–17098.
  62. Cohen, T.V.; Cohen, J.E.; Partridge, T.A. Myogenesis in dysferlin-deficient myoblasts is inhibited by an intrinsic inflammatory response. Neuromuscul. Disord. 2012, 22, 648–658.
  63. Belanto, J.J.; Diaz-Perez, S.V.; Magyar, C.E.; Maxwell, M.M.; Yilmaz, Y.; Topp, K.; Boso, G.; Jamieson, C.H.; Cacalano, N.A.; Jamieson, C.A.M. Dexamethasone induces dysferlin in myoblasts and enhances their myogenic differentiation. Neuromuscul. Disord. 2010, 20, 111–121.
  64. Zhang, Q.; Vashisht, A.A.; O’Rourke, J.; Corbel, S.Y.; Moran, R.; Romero, A.; Miraglia, L.; Zhang, J.; Durrant, E.; Schmedt, C.; et al. The microprotein Minion controls cell fusion and muscle formation. Nat. Commun. 2017, 8, 15664.
  65. Demonbreun, A.R.; Fahrenbach, J.P.; Deveaux, K.; Earley, J.U.; Pytel, P.; McNally, E.M. Impaired muscle growth and response to insulin-like growth factor 1 in dysferlin-mediated muscular dystrophy. Hum. Mol. Genet. 2011, 20, 779–789.
  66. Zanou, N.; Gailly, P. Skeletal muscle hypertrophy and regeneration: Interplay between the myogenic regulatory factors (MRFs) and insulin-like growth factors (IGFs) pathways. Cell. Mol. Life Sci. 2013, 70, 4117–4130.
  67. Chiu, Y.-H.; Hornsey, M.A.; Klinge, L.; Jørgensen, L.H.; Laval, S.H.; Charlton, R.; Barresi, R.; Straub, V.; Lochmüller, H.; Bushby, K. Attenuated muscle regeneration is a key factor in dysferlin-deficient muscular dystrophy. Hum. Mol. Genet. 2009, 18, 1976–1989.
  68. Blau, H.M.; Cosgrove, B.D.; Ho, A.T.V. The central role of muscle stem cells in regenerative failure with aging. Nat. Med. 2015, 21, 854–862.
  69. Doherty, K.R.; Cave, A.; Davis, D.B.; Delmonte, A.J.; Posey, A.; Earley, J.U.; Hadhazy, M.; McNally, E.M. Normal myoblast fusion requires myoferlin. Development 2005, 132, 5565–5575.
  70. Demonbreun, A.R.; Posey, A.D.; Heretis, K.; Swaggart, K.A.; Earley, J.U.; Pytel, P.; McNally, E.M. Myoferlin is required for insulin-like growth factor response and muscle growth. FASEB J. 2010, 24, 1284–1295.
  71. Posey, A.D.; Swanson, K.E.; Alvarez, M.G.; Krishnan, S.; Earley, J.U.; Band, H.; Pytel, P.; McNally, E.M.; Demonbreun, A.R. EHD1 mediates vesicle trafficking required for normal muscle growth and transverse tubule development. Dev. Biol. 2014, 387, 179–190.
  72. Davis, D.B.; Delmonte, A.J.; Ly, C.T.; McNally, E.M. Myoferlin, a candidate gene and potential modifier of muscular dystrophy. Hum. Mol. Genet. 2000, 9, 217–226.
  73. Yadav, A.; Kumar, B.; Lang, J.C.; Teknos, T.N.; Kumar, P. A muscle-specific protein “myoferlin” modulates IL-6/STAT3 signaling by chaperoning activated STAT3 to nucleus. Oncogene 2017, 36, 6374–6382.
  74. Posey, A.D.; Pytel, P.; Gardikiotes, K.; Demonbreun, A.R.; Rainey, M.; George, M.; Band, H.; McNally, E.M. Endocytic recycling proteins EHD1 and EHD2 interact with fer-1-like-5 (Fer1L5) and mediate myoblast fusion. J. Biol. Chem. 2011, 286, 7379–7388.
  75. Doherty, K.R.; Demonbreun, A.R.; Wallace, G.Q.; Cave, A.; Posey, A.D.; Heretis, K.; Pytel, P.; McNally, E.M. The endocytic recycling protein EHD2 interacts with myoferlin to regulate myoblast fusion. J. Biol. Chem. 2008, 283, 20252–20260.
  76. Lenhart, K.C.; O’Neill, T.J.; Cheng, Z.; Dee, R.; Demonbreun, A.R.; Li, J.; Xiao, X.; McNally, E.M.; Mack, C.P.; Taylor, J.M. GRAF1 deficiency blunts sarcolemmal injury repair and exacerbates cardiac and skeletal muscle pathology in dystrophin-deficient mice. Skelet Muscle 2015, 5, 27.
  77. Lenhart, K.C.; Becherer, A.L.; Li, J.; Xiao, X.; McNally, E.M.; Mack, C.P.; Taylor, J.M. GRAF1 promotes ferlin-dependent myoblast fusion. Dev. Biol. 2014, 393, 298–311.
  78. Melo, A.A.; Hegde, B.G.; Shah, C.; Larsson, E.; Isas, J.M.; Kunz, S.; Lundmark, R.; Langen, R.; Daumke, O. Structural insights into the activation mechanism of dynamin-like EHD ATPases. Proc. Natl. Acad. Sci. USA 2017, 114, 5629–5634.
  79. Leung, C.; Yu, C.; Lin, M.I.; Tognon, C.; Bernatchez, P. Expression of myoferlin in human and murine carcinoma tumors: Role in membrane repair, cell proliferation, and tumorigenesis. Am. J. Pathol. 2013, 182, 1900–1909.
  80. Aoki, M. Dysferlinopathy. In GeneReviews®; Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J., Stephens, K., Amemiya, A., Eds.; University of Washington, Seattle: Seattle, WA, USA, 2015.
  81. Weiler, T.; Bashir, R.; Anderson, L.V.; Davison, K.; Moss, J.A.; Britton, S.; Nylen, E.; Keers, S.; Vafiadaki, E.; Greenberg, C.R.; et al. Identical mutation in patients with limb girdle muscular dystrophy type 2B or Miyoshi myopathy suggests a role for modifier gene(s). Hum. Mol. Genet. 1999, 8, 871–877.
  82. Illarioshkin, S.N.; Ivanova-Smolenskaya, I.A.; Greenberg, C.R.; Nylen, E.; Sukhorukov, V.S.; Poleshchuk, V.V.; Markova, E.D.; Wrogemann, K. Identical dysferlin mutation in limb-girdle muscular dystrophy type 2B and distal myopathy. Neurology 2000, 55, 1931–1933.
  83. Nakagawa, M.; Matsuzaki, T.; Suehara, M.; Kanzato, N.; Takashima, H.; Higuchi, I.; Matsumura, T.; Goto, K.; Arahata, K.; Osame, M. Phenotypic variation in a large Japanese family with Miyoshi myopathy with nonsense mutation in exon 19 of dysferlin gene. J. Neurol. Sci. 2001, 184, 15–19.
  84. Urtizberea, J.A.; Bassez, G.; Leturcq, F.; Nguyen, K.; Krahn, M.; Levy, N. Dysferlinopathies. Neurol. India 2008, 56, 289–297.
  85. Magri, F.; Nigro, V.; Angelini, C.; Mongini, T.; Mora, M.; Moroni, I.; Toscano, A.; D’angelo, M.G.; Tomelleri, G.; Siciliano, G.; et al. The italian limb girdle muscular dystrophy registry: Relative frequency, clinical features, and differential diagnosis. Muscle Nerve 2017, 55, 55–68.
  86. Fanin, M.; Angelini, C. Progress and challenges in diagnosis of dysferlinopathy. Muscle Nerve 2016, 54, 821–835.
  87. Hornsey, M.A.; Laval, S.H.; Barresi, R.; Lochmüller, H.; Bushby, K. Muscular dystrophy in dysferlin-deficient mouse models. Neuromuscul. Disord. 2013, 23, 377–387.
  88. Sellers, S.L.; Milad, N.; White, Z.; Pascoe, C.; Chan, R.; Payne, G.W.; Seow, C.; Rossi, F.; Seidman, M.A.; Bernatchez, P. Increased nonHDL cholesterol levels cause muscle wasting and ambulatory dysfunction in the mouse model of LGMD2B. J. Lipid Res. 2018, 59, 261–272.
  89. Ho, M.; Post, C.M.; Donahue, L.R.; Lidov, H.G.W.; Bronson, R.T.; Goolsby, H.; Watkins, S.C.; Cox, G.A.; Brown, R.H. Disruption of muscle membrane and phenotype divergence in two novel mouse models of dysferlin deficiency. Hum. Mol. Genet. 2004, 13, 1999–2010.
  90. Wenzel, K.; Geier, C.; Qadri, F.; Hubner, N.; Schulz, H.; Erdmann, B.; Gross, V.; Bauer, D.; Dechend, R.; Dietz, R.; et al. Dysfunction of dysferlin-deficient hearts. J. Mol. Med. 2007, 85, 1203–1214.
  91. Nishikawa, A.; Mori-Yoshimura, M.; Segawa, K.; Hayashi, Y.K.; Takahashi, T.; Saito, Y.; Nonaka, I.; Krahn, M.; Levy, N.; Shimizu, J.; et al. Respiratory and cardiac function in japanese patients with dysferlinopathy. Muscle Nerve 2016, 53, 394–401.
  92. Rosales, X.Q.; Moser, S.J.; Tran, T.; McCarthy, B.; Dunn, N.; Habib, P.; Simonetti, O.P.; Mendell, J.R.; Raman, S.V. Cardiovascular magnetic resonance of cardiomyopathy in limb girdle muscular dystrophy 2B and 2I. J. Cardiovasc. Magn. Reson. Off. J. Soc. Cardiovasc. Magn. Reson. 2011, 13, 39.
  93. Rubi, L.; Gawali, V.S.; Kubista, H.; Todt, H.; Hilber, K.; Koenig, X. Proper Voltage-Dependent Ion Channel Function in Dysferlin-Deficient Cardiomyocytes. Cell Physiol. Biochem. 2015, 36, 1049–1058.
  94. Chase, T.H.; Cox, G.A.; Burzenski, L.; Foreman, O.; Shultz, L.D. Dysferlin deficiency and the development of cardiomyopathy in a mouse model of limb-girdle muscular dystrophy 2B. Am. J. Pathol. 2009, 175, 2299–2308.
  95. Kitmitto, A.; Baudoin, F.; Cartwright, E.J. Cardiomyocyte damage control in heart failure and the role of the sarcolemma. J. Muscle Res. Cell. Motil. 2019, 40, 319–333.
  96. Han, R.; Bansal, D.; Miyake, K.; Muniz, V.P.; Weiss, R.M.; McNeil, P.L.; Campbell, K.P. Dysferlin-mediated membrane repair protects the heart from stress-induced left ventricular injury. J. Clin. Invest. 2007, 117, 1805–1813.
  97. Tzeng, H.-P.; Evans, S.; Gao, F.; Chambers, K.; Topkara, V.K.; Sivasubramanian, N.; Barger, P.M.; Mann, D.L. Dysferlin mediates the cytoprotective effects of TRAF2 following myocardial ischemia reperfusion injury. J. Am. Heart Assoc. 2014, 3, e000662.
  98. Wei, B.; Wei, H.; Jin, J.-P. Dysferlin deficiency blunts β-adrenergic-dependent lusitropic function of mouse heart. J. Physiol. 2015, 593, 5127–5144.
  99. Lemckert, F.A.; Bournazos, A.; Eckert, D.M.; Kenzler, M.; Hawkes, J.M.; Butler, T.L.; Ceely, B.; North, K.N.; Winlaw, D.S.; Egan, J.R.; et al. Lack of MG53 in human heart precludes utility as a biomarker of myocardial injury or endogenous cardioprotective factor. Cardiovasc. Res. 2016, 110, 178–187.
  100. Wang, C.; Wong, J.; Fung, G.; Shi, J.; Deng, H.; Zhang, J.; Bernatchez, P.; Luo, H. Dysferlin deficiency confers increased susceptibility to coxsackievirus-induced cardiomyopathy. Cell. Microbiol. 2015, 17, 1423–1430.
  101. Shin, H.Y.; Jang, H.; Han, J.H.; Park, H.J.; Lee, J.H.; Kim, S.W.; Kim, S.M.; Park, Y.-E.; Kim, D.-S.; Bang, D.; et al. Targeted next-generation sequencing for the genetic diagnosis of dysferlinopathy. Neuromuscul. Disord. 2015, 25, 502–510.
  102. Sula, A.; Cole, A.R.; Yeats, C.; Orengo, C.; Keep, N.H. Crystal structures of the human Dysferlin inner DysF domain. BMC Struct. Biol. 2014, 14, 3.
  103. Fujita, E.; Kouroku, Y.; Isoai, A.; Kumagai, H.; Misutani, A.; Matsuda, C.; Hayashi, Y.K.; Momoi, T. Two endoplasmic reticulum-associated degradation (ERAD) systems for the novel variant of the mutant dysferlin: Ubiquitin/proteasome ERAD(I) and autophagy/lysosome ERAD(II). Hum. Mol. Genet. 2007, 16, 618–629.
  104. Evesson, F.J.; Peat, R.A.; Lek, A.; Brilot, F.; Lo, H.P.; Dale, R.C.; Parton, R.G.; North, K.N.; Cooper, S.T. Reduced plasma membrane expression of dysferlin mutants is attributed to accelerated endocytosis via a syntaxin-4-associated pathway. J. Biol. Chem. 2010, 285, 28529–28539.
  105. Voigt, T.; Sebald, H.-J.; Schoenauer, R.; Levano, S.; Girard, T.; Hoppeler, H.H.; Babiychuk, E.B.; Draeger, A. Annexin A1 is a biomarker of T-tubular repair in skeletal muscle of nonmyopathic patients undergoing statin therapy. FASEB J. 2013, 27, 2156–2164.
  106. Hogarth, M.W.; Defour, A.; Lazarski, C.; Gallardo, E.; Diaz Manera, J.; Partridge, T.A.; Nagaraju, K.; Jaiswal, J.K. Fibroadipogenic progenitors are responsible for muscle loss in limb girdle muscular dystrophy 2B. Nat. Commun. 2019, 10, 2430.
  107. Zhivotovsky, B.; Orrenius, S. Calcium and cell death mechanisms: A perspective from the cell death community. Cell Calcium. 2011, 50, 211–221.
  108. Prosser, B.L.; Khairallah, R.J.; Ziman, A.P.; Ward, C.W.; Lederer, W.J. X-ROS signaling in the heart and skeletal muscle: Stretch-dependent local ROS regulates [Ca2+]i. J. Mol. Cell. Cardiol. 2013, 58, 172–181.
  109. Kombairaju, P.; Kerr, J.P.; Roche, J.A.; Pratt, S.J.P.; Lovering, R.M.; Sussan, T.E.; Kim, J.-H.; Shi, G.; Biswal, S.; Ward, C.W. Genetic silencing of Nrf2 enhances X-ROS in dysferlin-deficient muscle. Front. Physiol. 2014, 5, 57.
  110. Beringer, A.; Gouriou, Y.; Lavocat, F.; Ovize, M.; Miossec, P. Blockade of Store-Operated Calcium Entry Reduces IL-17/TNF Cytokine-Induced Inflammatory Response in Human Myoblasts. Front. Immunol. 2018, 9, 3170.
  111. Nagaraju, K.; Rawat, R.; Veszelovszky, E.; Thapliyal, R.; Kesari, A.; Sparks, S.; Raben, N.; Plotz, P.; Hoffman, E.P. Dysferlin deficiency enhances monocyte phagocytosis: A model for the inflammatory onset of limb-girdle muscular dystrophy 2B. Am. J. Pathol. 2008, 172, 774–785.
  112. McNally, E.M.; Ly, C.T.; Rosenmann, H.; Mitrani Rosenbaum, S.; Jiang, W.; Anderson, L.V.; Soffer, D.; Argov, Z. Splicing mutation in dysferlin produces limb-girdle muscular dystrophy with inflammation. Am. J. Med. Genet. 2000, 91, 305–312.
  113. Yin, X.; Wang, Q.; Chen, T.; Niu, J.; Ban, R.; Liu, J.; Mao, Y.; Pu, C. CD4+ cells, macrophages, MHC-I and C5b-9 involve the pathogenesis of dysferlinopathy. Int. J. Clin. Exp. Pathol. 2015, 8, 3069–3075.
  114. Cárdenas, A.M.; González-Jamett, A.M.; Cea, L.A.; Bevilacqua, J.A.; Caviedes, P. Dysferlin function in skeletal muscle: Possible pathological mechanisms and therapeutical targets in dysferlinopathies. Exp. Neurol. 2016, 283, 246–254.
  115. Mariano, A.; Henning, A.; Han, R. Dysferlin-deficient muscular dystrophy and innate immune activation. FEBS J. 2013, 280, 4165–4176.
  116. Defour, A.; Medikayala, S.; Van der Meulen, J.H.; Hogarth, M.W.; Holdreith, N.; Malatras, A.; Duddy, W.; Boehler, J.; Nagaraju, K.; Jaiswal, J.K. Annexin A2 links poor myofiber repair with inflammation and adipogenic replacement of the injured muscle. Hum. Mol. Genet. 2017, 26, 1979–1991.
  117. Wenzel, K.; Zabojszcza, J.; Carl, M.; Taubert, S.; Lass, A.; Harris, C.L.; Ho, M.; Schulz, H.; Hummel, O.; Hubner, N.; et al. Increased susceptibility to complement attack due to down-regulation of decay-accelerating factor/CD55 in dysferlin-deficient muscular dystrophy. J. Immunol. (Baltim. Md. 1950) 2005, 175, 6219–6225.
  118. Mitchell, C.A.; Grounds, M.D.; Papadimitriou, J.M. The genotype of bone marrow-derived inflammatory cells does not account for differences in skeletal muscle regeneration between SJL/J and BALB/c mice. Cell Tissue Res. 1995, 280, 407–413.
  119. Millay, D.P.; Maillet, M.; Roche, J.A.; Sargent, M.A.; McNally, E.M.; Bloch, R.J.; Molkentin, J.D. Genetic manipulation of dysferlin expression in skeletal muscle: Novel insights into muscular dystrophy. Am. J. Pathol. 2009, 175, 1817–1823.
  120. Roche, J.A.; Tulapurkar, M.E.; Mueller, A.L.; van Rooijen, N.; Hasday, J.D.; Lovering, R.M.; Bloch, R.J. Myofiber damage precedes macrophage infiltration after in vivo injury in dysferlin-deficient A/J mouse skeletal muscle. Am. J. Pathol. 2015, 185, 1686–1698.
  121. McElhanon, K.E.; Bhattacharya, S. Altered membrane integrity in the progression of muscle diseases. Life Sci. 2018, 192, 166–172.
  122. Lostal, W.; Bartoli, M.; Roudaut, C.; Bourg, N.; Krahn, M.; Pryadkina, M.; Borel, P.; Suel, L.; Roche, J.A.; Stockholm, D.; et al. Lack of correlation between outcomes of membrane repair assay and correction of dystrophic changes in experimental therapeutic strategy in dysferlinopathy. PLoS ONE 2012, 7, e38036.
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