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Ankrd2 in Mechanotransduction and Oxidative Stress Response in Skeletal Muscle: New Cues for the Pathogenesis of Muscular Laminopathies

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Ankrd2 in Mechanotransduction and Oxidative Stress Response in Skeletal Muscle: New Cues for the Pathogenesis of Muscular Laminopathies Hindawi Oxidative Medicine and Cellular Longevity Volume 2019, Article ID 7318796, 15 pages https://doi.org/10.1155/2019/7318796 Review Article Ankrd2 in Mechanotransduction and Oxidative Stress Response in Skeletal Muscle: New Cues for the Pathogenesis of Muscular Laminopathies Vittoria Cenni ,1,2 Snezana Kojic,3 Cristina Capanni,1,2 Georgine Faulkner,4 and Giovanna Lattanzi 1,2 1CNR National Research Council of Italy, Institute of Molecular Genetics, Unit of Bologna, 40126 Bologna, Italy 2IRCCS Istituto Ortopedico Rizzoli, 40126 Bologna, Italy 3Institute of Molecular Genetics and Genetic Engineering University of Belgrade, 11010 Belgrade, Serbia 4Department of Biology, University of Padua, 35121 Padua, Italy Correspondence should be addressed to Vittoria Cenni; [email protected] and Giovanna Lattanzi; [email protected] Received 4 March 2019; Revised 2 May 2019; Accepted 19 May 2019; Published 24 July 2019 Guest Editor: Andrey J. Serra Copyright © 2019 Vittoria Cenni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ankrd2 (ankyrin repeats containing domain 2) or Arpp (ankyrin repeat, PEST sequence, and proline-rich region) is a member of the muscle ankyrin repeat protein family. Ankrd2 is mostly expressed in skeletal muscle, where it plays an intriguing role in the transcriptional response to stress induced by mechanical stimulation as well as by cellular reactive oxygen species. Our studies in myoblasts from Emery-Dreifuss muscular dystrophy 2, a LMNA-linked disease affecting skeletal and cardiac muscles, demonstrated that Ankrd2 is a lamin A-binding protein and that mutated lamins found in Emery-Dreifuss muscular dystrophy change the dynamics of Ankrd2 nuclear import, thus affecting oxidative stress response. In this review, besides describing the latest advances related to Ankrd2 studies, including novel discoveries on Ankrd2 isoform-specific functions, we report the main findings on the relationship of Ankrd2 with A-type lamins and discuss known and potential mechanisms involving defective Ankrd2-lamin A interplay in the pathogenesis of muscular laminopathies. 1. Introduction anomalous expression level of Ankrd2, as well as defective nuclear recruitment of the protein, might contribute to a Ankrd2 (ankyrin repeats containing domain 2) or Arpp muscular phenotype. Very recently, we found that Ankrd2 (ankyrin repeat, PEST sequence, and proline-rich region) is is a novel interactor of A-type lamins, which are produced a member of the MARP (muscle ankyrin repeat protein) by the LMNA gene and are the major constituents of the family of proteins that also includes Ankrd1, or Carp nuclear lamina. Mutations of LMNA gene are the cause of a (Cardiac Ankyrin Repeat Protein), and Ankrd23, or DARP substantial number of pathologies, some of which affecting (Diabetes-related Ankyrin Repeat Protein) [1]. As we will skeletal and cardiac muscles. Moreover, altered expression describe in detail in this review, Ankrd2 is principally of Ankrd2 was detected in myopathies [2], cardiomyopathies expressed in skeletal muscle, where it plays an intriguing role [3], and some tumors [4]. In this review, apart from describ- in the transcriptional response to stress induced by mechan- ing the latest advances related to Ankrd2, including an ever- ical stimulation, as well as by cellular ROS (reactive oxygen growing interest for Ankrd2 isoform-specific functions, we species). In particular, although the Ankrd2 knockout mouse will report the main findings on Ankrd2 and its relation to model has revealed that Ankrd2 is not necessary for life nor lamins and discuss known and potential mechanisms, the direct cause of any muscular disorder, multiple evidence through which defective Ankrd2-lamin A interplay might obtained from muscular cell lines or primary cultures from have a role in the pathogenesis of LMNA-related muscular patients affected by muscular diseases suggest that an disorders. 2 Oxidative Medicine and Cellular Longevity 2. Ankrd2 in Striated Muscles of slow muscle fibers [17]), corroborating Ankrd2 prefer- ential expression in slow fibers [6]. Ankrd2, together with other proteins of the MARP family, is Although the existence of Ankrd2 isoforms was reported considered as STRaND (shuttling transcriptional regulators in 2003 by Miller et al. [7], their specific expression and local- and non-DNA-binding protein), having signature features: ization in human skeletal and cardiac muscles, as well as in shuttling from the cytoplasm to the nucleus, absence of primary human myoblasts and myotubes, have been recently DNA binding, and regulation of transcription via interaction determined by studies in which their discrimination was with transcription factors [5]. Recently, data from Wette enabled by specific antibodies [6, 18]. fi et al., obtained on single muscle bers, have shown that The most important Ankrd2 isoforms, namely, S-Ankrd2 > Ankrd2 is mostly found ( 70% of total Ankrd2) in the (333 aa) and M-Ankrd2 (360 aa), are identical, except for cytosol [6]. The remaining amount is distributed between 27 aa extension at the N-terminus of M-Ankrd2. Accord- intracellular structures, including the sarcomere and the ing to qPCR results, the expression of Ankrd2 isoforms is fl nucleus, with proportions that re ect the physiology, such regulated at the transcriptional level [18]. S-Ankrd2 is as the type (slow/fast) or the condition (forming/mature/ expressed in both heart and skeletal muscles [18] where fi regenerating/injured), of the ber considered. In healthy it is the predominant form [6, 18]. The well-known chess- striated muscle, Ankrd2 is found at the sarcomeric I-band board pattern of Ankrd2 expression observed in transver- [7, 8] where it contributes to the formation and function of sal sections of skeletal muscle may be attributed almost the I-band mechanosensory complex, probably via interac- exclusively to S-Ankrd2 [6, 18], which has been therefore tion with calpain 3 and the elastic portion of titin (N2A proposed as the canonical Ankrd2 isoform. Although still region) [7, 9]. As extensively described in the next sections, a matter of debate, in mature muscle fibers, the small Ankrd2 also interacts with nuclear proteins with both struc- amount of M-Ankrd2 has been identified in nuclei [18]. tural and enzymatic roles [1] and is accumulated in nuclei of In human myoblasts, S-Ankrd2 is expressed mainly in injured muscle [10]. An overview of the main structural and nuclei at a low level, while in myotubes, it is upregulated functional features of Ankrd2, including protein domains, and localized in the cytoplasm. M-Ankrd2 is also upregu- fi fi posttranslational modi cations, expression pro le, proposed lated upon differentiation of myoblasts to myotubes; ff functions, interacting proteins, and pathways a ected by however, it maintains its nuclear localization. Striking dif- ANKRD2 silencing in human myoblasts, is given in Table 1. ferences in expression and localization of Ankrd2 isoforms In the nucleus, Ankrd2 participates in the regulation of genes may mirror their different functions which however need fl involved in the cell cycle, myogenesis, and in ammatory to be further explored [18]. For example, M-Ankrd2 might – response [11 15]. Of note, in mature muscle cells, the have a more regulatory role, being predominantly nuclear, evidence reporting that the majority of Ankrd2 is freely while sarcomeric and cytosolic S-Ankrd2 may have a ff fi di usible in the cytosol [6] has for the rst time pointed to structural and downstream signaling role, respectively. the open question if Ankrd2, besides being involved in Domain organization, alignment, and updated database sarcomeric activity, might also participate in cellular func- entries for all five Ankrd2 isoforms are shown in tions in other subcellular districts, thus suggesting a role as Figures 1(a)–1(c), respectively. a downstream signal transducer in mechanosignaling path- ways. It is important to note that despite accumulated 2.2. Ankrd2 Expression in Cardiac Muscle. Ankrd2 is fi ndings from cell culture experiments, direct evidence of expressed in the human heart, including ventricles, the inter- Ankrd2 function in mature healthy and diseased striated ventricular septum, and the apex of the heart [4, 19], at a muscles is still missing. lower level compared to skeletal muscle. Ankrd2 expression in the heart is potentially regulated by cardiac-specific tran- 2.1. Ankrd2 Expression in Skeletal Muscle. Ankrd2 was scription factors Nkx2.5, Hand2, and Ankrd1 as demon- reported for the first time in a study performed in 2000 by strated by their interaction with the ANKRD2 promoter or Kemp and colleagues as a protein upregulated in murine by dual luciferase assay [20, 21]. Transcriptome profiling muscle exposed to prolonged passive stretch (7 days) [16]. confirmed a lower level of Ankrd2 in the ventricles of Preferential expression in skeletal muscle, more specifically human adult heart, compared to Ankrd1 [22]. Both S- and in slow (type I) muscle fibers, and responsiveness to mechan- M-Ankrd2 isoforms are expressed in cardiac muscle; they ical stress are signature features of this protein. Recently, have sarcomeric localization and are almost absent from Ankrd2 was confirmed to be the most abundant MARP nuclei [18]. The latter finding and the known interaction protein in human skeletal muscle, being ~30-fold more between Ankrd2 and the gap junction protein ZO-1 [20], expressed than DARP and ~150-fold more than Ankrd1 enriched in ICDs, suggest a role for Ankrd2 in intercellular [6]. In this study, performed on a group of four subjects, communication, which merits further investigation. In the absolute amount of Ankrd2 was subject-specific, ranging neonatal rat cardiomyocytes (NRCM), both sarcomeric and from 1.6 to 4.3 μmol/kg net weight, and proportional to the nuclear localizations of Ankrd2 were investigated during content of myosin heavy chain I (MHCI) protein, which is cellular differentiation and not shown to be affected by the a marker of slow (type I) muscle fibers [6].
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