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Focal Adhesion Kinase Coordinates Costamere-Related JNK Signaling with Muscle Fiber Transformation After Achilles Tenotomy and Tendon Reconstruction

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Focal Adhesion Kinase Coordinates Costamere-Related JNK Signaling with Muscle Fiber Transformation After Achilles Tenotomy and Tendon Reconstruction Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2019 Focal adhesion kinase coordinates costamere-related JNK signaling with muscle fiber transformation after Achilles tenotomy and tendon reconstruction Ferrié, Céline ; Kasper, Stephanie ; Wanivenhaus, Florian ; Flück, Martin Abstract: Achilles tendon rupture necessitates rapid tendon reattachment to reinstate plantar flexion before affected muscles deteriorate through muscle fiber atrophy and transformation. The implicated process may involve alterations in sarcolemmal sites of myofibril attachment (costameres), which control myofibrillogenesis via a mechano-regulated mechanism through integrin-associated focal adhesion kinase (FAK). We assessed the contribution of FAK to alterations in fiber type composition and expression of costamere-associated structural proteins, the phosphorylation status of Y397-FAK and downstream mTOR/JNK-P70S6K hypertrophy signaling in rat soleus muscle after Achilles tenotomy and tendon repair. Achilles tenotomy induced a profound deterioration of muscle composition 14 days, but not 4 days, following tendon release, comprising specifically increased area percentages of fast type fibers, fibers with internal nuclei, and connective tissue. Concomitantly, expression of costameric proteins FAK and meta-vinculin, and phosphorylation of T421/S424-P70S6K and T183/Y185-JNK was elevated, all of which was mitigated by tendon reattachment immediately after release. Overexpression of FAK in soleus muscle fibers and reattachment corrected the expression of meta- and gamma-vinculin isoforms tothe lower levels in mock controls while further enhancing T183/Y185-JNK phosphorylation and levels of FAK C-terminus-related inhibitory proteins. Co-overexpression of the FAK inhibitor, FRNK, lowered FAK- overexpression driven Y397-FAK phosphorylation and T183/Y185-JNK phosphorylation. FAK levels correlated to molecular and cellular hallmarks of fiber degeneration. The findings demarcate the window between 4 and 14 days after tenotomy as costamere-dependent muscle transformation process, and expose that FAK overexpression prevents molecular aspects of the pathology which within the study limitations does not result in the mitigation of muscle fiber degeneration.250 words. DOI: https://doi.org/10.1016/j.yexmp.2019.03.006 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-170096 Journal Article Published Version The following work is licensed under a Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License. Originally published at: Ferrié, Céline; Kasper, Stephanie; Wanivenhaus, Florian; Flück, Martin (2019). Focal adhesion kinase coordinates costamere-related JNK signaling with muscle fiber transformation after Achilles tenotomy and tendon reconstruction. Experimental and Molecular Pathology, 108:42-56. DOI: https://doi.org/10.1016/j.yexmp.2019.03.006 2 Experimental and Molecular Pathology 108 (2019) 42–56 Contents lists available at ScienceDirect Experimental and Molecular Pathology journal homepage: www.elsevier.com/locate/yexmp Focal adhesion kinase coordinates costamere-related JNK signaling with muscle fiber transformation after Achilles tenotomy and tendon T reconstruction ⁎ Céline Ferriéa, Stephanie Kaspera, Florian Wanivenhausb, Martin Flücka, a Laboratory for Muscle Plasticity, Department of Orthopedics, University of Zurich, Balgrist Campus, Zurich, Switzerland b Department of Orthopedic Surgery, Balgrist University Hospital, Zurich, Switzerland ARTICLE INFO ABSTRACT Keywords: Achilles tendon rupture necessitates rapid tendon reattachment to reinstate plantar flexion before affected Tenotomy muscles deteriorate through muscle fiber atrophy and transformation. The implicated process may involve al- Gene therapy terations in sarcolemmal sites of myofibril attachment (costameres), which control myofibrillogenesis via a Costamere mechano-regulated mechanism through integrin-associated focal adhesion kinase (FAK). FAK We assessed the contribution of FAK to alterations in fiber type composition and expression of costamere- Vinculin associated structural proteins, the phosphorylation status of Y397-FAK and downstream mTOR/JNK-P70S6K mTOR/P70S6K pathway hypertrophy signaling in rat soleus muscle after Achilles tenotomy and tendon repair. Achilles tenotomy induced a profound deterioration of muscle composition 14 days, but not 4 days, following tendon release, comprising specifically increased area percentages of fast type fibers, fibers with internal nuclei, and connective tissue. Concomitantly, expression of costameric proteins FAK and meta-vinculin, and phos- phorylation of T421/S424-P70S6K and T183/Y185-JNK was elevated, all of which was mitigated by tendon reattachment immediately after release. Overexpression of FAK in soleus muscle fibers and reattachment cor- rected the expression of meta- and gamma-vinculin isoforms to the lower levels in mock controls while further enhancing T183/Y185-JNK phosphorylation and levels of FAK C-terminus-related inhibitory proteins. Co- overexpression of the FAK inhibitor, FRNK, lowered FAK-overexpression driven Y397-FAK phosphorylation and T183/Y185-JNK phosphorylation. FAK levels correlated to molecular and cellular hallmarks of fiber degen- eration. The findings demarcate the window between 4 and 14 days after tenotomy as costamere-dependent muscle transformation process, and expose that FAK overexpression prevents molecular aspects of the pathology which within the study limitations does not result in the mitigation of muscle fiber degeneration.250 words. 1. Introduction are reattached early after tenotomy although the connectivity of the severed tendon stump to the calcaneus bone recovers spontaneously Release of the Achilles tendon (tenotomy) is a relatively frequent (Jakubiec-Puka et al., 1992; Abrams et al., 2000). Incomplete func- clinical situation occurring in consequence of a traumatic incidence or tional restoration of plantar flexion, as assessed through passive and therapeutic intervention to correct an equinus deformity (Egger and active tension, appears to be related, although not being explained by Berkowitz, 2017; Ramanujam and Zgonis, 2017). Achilles tenotomy the weakening and shortening of the involved plantar flexor/ankle produces considerable pain and renders motor tasks involving the extensor muscle-tendon composite through degenerative alterations of plantar flexor muscles, M. plantaris, gastrocnemius and soleus, hard to the injured tendon and muscle fiber (Abrams et al., 2000; Jamali et al., impossible. Recovery of severed (Achilles) tendons is best when tendons 2000). Abbreviations: AP-1, Activator protein 1 (heterodimer of jun/fos transcription factors); c-JUN, Transcription factor (seventeenths clone of the cellular isoform of the avian sarcoma virus); FAK, Focal adhesion kinase; FRNK, FAK-related non-kinase; JNK, c-JUN N-terminal kinase; mTOR, Mammalian target of rapamycin; P70S6K, Phosphoprotein 70 ribosomal protein S6; p65FAK, FAK C-terminus related protein at 65 kDa; p55FAK, FAK C-terminus related protein at 55 kDa; pS63-cJUN, Serine 63 phosphorylated c-JUN; pS2448-mTOR, Serine 2448 phosphorylated mTOR; pT421/S424-P70S6K, Threonine 421 and serine 424 phosphorylated P70S6K; pT183/ Y185-JNK, Threonine 183 and tyrosine 185 phosphorylated JNK; FAK, Focal adhesion kinase; Y397-FAK, Tyrosine 397 of FAK ⁎ Corresponding author. E-mail address: mfl[email protected] (M. Flück). https://doi.org/10.1016/j.yexmp.2019.03.006 Received 25 June 2018; Received in revised form 29 January 2019; Accepted 12 March 2019 Available online 15 March 2019 0014-4800/ © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). C. Ferrié, et al. Experimental and Molecular Pathology 108 (2019) 42–56 The cellular processes underlying extensor muscle degeneration Andreucci et al., 2002). after tenotomy, and Achilles tenotomy in particular, involve a loss in Y397 phosphorylation and localisation of FAK to focal adhesions is contractile material (i.e. sarcomeres), reducing the length and mean further inhibited by an endogenous process which involves protein cross sectional area of muscle fibers, a slow-to-fast transformation of products that stem from its C-terminus (Zak et al., 2017). For instance, the muscle phenotype, and a concomitant increase in connective tissue FRNK, which corresponds to the C-terminal focal adhesion targeting per muscle tissue (Sunderland and Lavarack, 1959; Baker and Hall- domain of FAK is expressed in a muscle fiber type-related way and Craggs, 1980; Jakubiec-Puka et al., 1992; Jamali et al., 2000). Both the interferes with Y397 phosphorylation of FAK and load-regulated and removal of sarcomeres during the atrophic process, and the exchange of costamere-related expression of the slow oxidative gene program in slow with fast type sarcomeres during muscle fiber transformation, soleus muscle (Fluck et al., 2002; Durieux et al., 2009; Klossner et al., involve modifications in focal sites of adhesion in the sarcolemma (so 2013; Zak et al., 2017). As well, in numerous cell types, catabolic si- called costameres), which hold sarcomeres in register (Goll et al., 2008; tuations which lead to cell death, have similarly as seen for the costa- Klossner et al., 2013; Li et al., 2013; Jaka et al., 2015). Costameres meric proteins vinculin and talin (Goll et
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