{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T13:12:50Z","timestamp":1770988370101,"version":"3.50.1"},"reference-count":104,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,6,1]],"date-time":"2020-06-01T00:00:00Z","timestamp":1590969600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["IOS-1456868"],"award-info":[{"award-number":["IOS-1456868"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["IOS-2016049"],"award-info":[{"award-number":["IOS-2016049"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000888","name":"W. M. Keck Foundation","doi-asserted-by":"publisher","award":["Medical Research Grant"],"award-info":[{"award-number":["Medical Research Grant"]}],"id":[{"id":"10.13039\/100000888","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008883","name":"Northern Arizona University","doi-asserted-by":"publisher","award":["Technology Research Initiative Fund"],"award-info":[{"award-number":["Technology Research Initiative Fund"]}],"id":[{"id":"10.13039\/100008883","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Since its belated discovery, our understanding of the giant protein titin has grown exponentially from its humble beginning as a sarcomeric scaffold to recent recognition of its critical mechanical and signaling functions in active muscle. One uniquely useful model to unravel titin\u2019s functions, muscular dystrophy with myositis (mdm), arose spontaneously in mice as a transposon-like LINE repeat insertion that results in a small deletion in the N2A region of titin. This small deletion profoundly affects hypertrophic signaling and muscle mechanics, thereby providing insights into the function of this specific region and the consequences of its dysfunction. The impact of this mutation is profound, affecting diverse aspects of the phenotype including muscle mechanics, developmental hypertrophy, and thermoregulation. In this review, we explore accumulating evidence that points to the N2A region of titin as a dynamic \u201cswitch\u201d that is critical for both mechanical and signaling functions in skeletal muscle. Calcium-dependent binding of N2A titin to actin filaments triggers a cascade of changes in titin that affect mechanical properties such as elastic energy storage and return, as well as hypertrophic signaling. The mdm phenotype also points to the existence of as yet unidentified signaling pathways for muscle hypertrophy and thermoregulation, likely involving titin\u2019s PEVK region as well as the N2A signalosome.<\/jats:p>","DOI":"10.3390\/ijms21113974","type":"journal-article","created":{"date-parts":[[2020,6,2]],"date-time":"2020-06-02T04:09:03Z","timestamp":1591070943000},"page":"3974","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["N2A Titin: Signaling Hub and Mechanical Switch in Skeletal Muscle"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8252-0285","authenticated-orcid":false,"given":"Kiisa","family":"Nishikawa","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ 86011-5640, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stan L.","family":"Lindstedt","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ 86011-5640, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Hessel","sequence":"additional","affiliation":[{"name":"Institute of Physiology II, University of M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dhruv","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Northern Arizona University, Flagstaff, AZ 86011-5640, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1086\/342380","article-title":"Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin","volume":"71","author":"Hackman","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1161\/hh2301.100981","article-title":"The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system","volume":"89","author":"Bang","year":"2001","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3685","DOI":"10.1073\/pnas.81.12.3685","article-title":"Titin is an extraordinarily long, flexible, and slender myofibrillar protein","volume":"81","author":"Wang","year":"1984","journal-title":"Sci. Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/S0955-0674(99)80003-9","article-title":"Muscle assembly: A titanic achievement?","volume":"11","author":"Gregorio","year":"1999","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"8052","DOI":"10.1073\/pnas.95.14.8052","article-title":"Nature of PEVK-titin elasticity in skeletal muscle","volume":"95","author":"Linke","year":"1998","journal-title":"Sci. Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.1083\/jcb.105.5.2217","article-title":"The positional stability of thick filaments in activated skeletal muscle depends on sarcomere length: Evidence for the role of titin filaments","volume":"105","author":"Horowits","year":"1987","journal-title":"J. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1242\/jeb.124941","article-title":"The sarcomeric cytoskeleton: From molecules to motion","volume":"219","author":"Gautel","year":"2016","journal-title":"J. Exp. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1016\/j.cjca.2015.08.016","article-title":"The Rapidly Evolving Role of Titin in Cardiac Physiology and Cardiomyopathy","volume":"31","author":"Gerull","year":"2015","journal-title":"Can. J. Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1056\/NEJMoa1110186","article-title":"Truncations of titin causing dilated cardiomyopathy","volume":"366","author":"Herman","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"753675","DOI":"10.1155\/2010\/753675","article-title":"Titin diversity\u2014Alternative splicing gone wild","volume":"2010","author":"Guo","year":"2010","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"293","DOI":"10.3233\/JND-160158","article-title":"Increasing Role of Titin Mutations in Neuromuscular Disorders","volume":"3","author":"Savarese","year":"2016","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1002\/humu.22611","article-title":"A rising titan: TTN review and mutation update","volume":"35","author":"Chauveau","year":"2014","journal-title":"Hum. Mutat."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.1111\/febs.14854","article-title":"Posttranslational modifications of titin from cardiac muscle: How, where, and what for?","volume":"286","author":"Koser","year":"2019","journal-title":"FEBS J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1007\/s00424-019-02272-5","article-title":"Titin mutations and muscle disease","volume":"471","author":"Kellermayer","year":"2019","journal-title":"Pflugers Arch."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1006\/geno.2002.6685","article-title":"The muscular dystrophy with myositis (mdm) mouse mutation disrupts a skeletal muscle-specific domain of titin","volume":"79","author":"Garvey","year":"2002","journal-title":"Genomics"},{"key":"ref_16","first-page":"18","article-title":"Muscular dystrophy with myositis (mdm)","volume":"73","author":"Lane","year":"1985","journal-title":"Mouse News Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/ng815","article-title":"Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy","volume":"30","author":"Gerull","year":"2002","journal-title":"Nat. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1126\/science.270.5234.293","article-title":"Titins: Giant proteins in charge of muscle ultrastructure and elasticity","volume":"270","author":"Labeit","year":"1995","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1007\/s004410050554","article-title":"Overshooting production of satellite cells in murine skeletal muscle affected by the mutation \"muscular dystrophy with myositis\" (mdm, Chr 2)","volume":"283","author":"Heimann","year":"1996","journal-title":"Cell Tissue Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Brynnel, A., Hernandez, Y., Kiss, B., Lindqvist, J., Adler, M., Kolb, J., van der Pijl, R., Gohlke, J., Strom, J., and Smith, J. (2018). Downsizing the molecular spring of the giant protein titin reveals that skeletal muscle titin determines passive stiffness and drives longitudinal hypertrophy. eLife, 7.","DOI":"10.7554\/eLife.40532"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1242\/jeb.124057","article-title":"Eccentric contraction: Unraveling mechanisms of force enhancement and energy conservation","volume":"219","author":"Nishikawa","year":"2016","journal-title":"J. Exp. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/S0888-7543(05)80356-8","article-title":"Chromosomal localization of the mouse titin gene and its relation to \"muscular dystrophy with myositis\" and nebulin genes on chromosome 2","volume":"18","author":"Kaupmann","year":"1993","journal-title":"Genomics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1093\/icb\/icy023","article-title":"Muscle Function from Organisms to Molecules","volume":"58","author":"Nishikawa","year":"2018","journal-title":"Integr. Comp. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.jmb.2003.12.021","article-title":"Induction and myofibrillar targeting of CARP, and suppression of the Nkx2.5 pathway in the MDM mouse with impaired titin-based signaling","volume":"336","author":"Witt","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Powers, K., Nishikawa, K., Joumaa, V., and Herzog, W. (2016). Decreased force enhancement in skeletal muscle sarcomeRes. with a deletion in titin. J. Exp. Biol.","DOI":"10.1242\/jeb.132027"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Hessel, A.L., Joumaa, V., Eck, S., Herzog, W., and Nishikawa, K.C. (2019). Optimal length, calcium sensitivity and twitch characteristics of skeletal muscles from mdm mice with a deletion in N2A titin. J. Exp. Biol., 222.","DOI":"10.1242\/jeb.200840"},{"key":"ref_27","first-page":"3110","article-title":"Titin force enhancement following active stretch of skinned skeletal muscle fibres","volume":"220","author":"Powers","year":"2017","journal-title":"J. Exp. Biol."},{"key":"ref_28","first-page":"4177","article-title":"Effects of a titin mutation on negative work during stretch-shortening cycles in skeletal muscles","volume":"220","author":"Hessel","year":"2017","journal-title":"J. Exp. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2801","DOI":"10.1093\/hmg\/ddi313","article-title":"Mdm muscular dystrophy: Interactions with calpain 3 and a novel functional role for titin\u2019s N2A domain","volume":"14","author":"Huebsch","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s00359-016-1137-5","article-title":"The effects of a skeletal muscle titin mutation on walking in mice","volume":"203","author":"Pace","year":"2017","journal-title":"J. Comp. Physiol. A Neuroethol. Sens. Neural Behav. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1007\/s11914-018-0468-2","article-title":"Targeting the Muscle-Bone Unit: Filling Two Needs with One Deed in the Treatment of Duchenne Muscular Dystrophy","volume":"16","author":"Hamoudi","year":"2018","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1242\/jeb.111849","article-title":"Shiver me titin! Elucidating titin\u2019s role in shivering thermogenesis","volume":"218","author":"Monroy","year":"2015","journal-title":"J. Exp. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Miyano, C.A., Orezzoli, S.F., Buck, C.L., and Nishikawa, K.C. (2019). Severe thermoregulatory deficiencies in mice with a deletion in the titin gene TTN. J. Exp. Biol., 222.","DOI":"10.1242\/jeb.198564"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1152\/japplphysiol.00865.2018","article-title":"Titin as a force-generating muscle protein under regulatory control","volume":"126","author":"Freundt","year":"2019","journal-title":"J. Appl. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"76","DOI":"10.3389\/fphys.2016.00076","article-title":"Titin, a Central Mediator for Hypertrophic Signaling, Exercise-Induced Mechanosignaling and Skeletal Muscle Remodeling","volume":"7","author":"Kruger","year":"2016","journal-title":"Front. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1146\/annurev-physiol-021317-121234","article-title":"Titin Gene and Protein Functions in Passive and Active Muscle","volume":"80","author":"Linke","year":"2018","journal-title":"Rev. Ann. Rev. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1212\/WNL.56.7.869","article-title":"Secondary calpain3 deficiency in 2q-linked muscular dystrophy: Titin is the candidate gene","volume":"56","author":"Haravuori","year":"2001","journal-title":"Neurology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"18519","DOI":"10.1074\/jbc.M601029200","article-title":"Suppressed disassembly of autolyzing p94\/CAPN3 by N2A connectin\/titin in a genetic reporter system","volume":"281","author":"Ono","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1093\/hmg\/11.3.263","article-title":"A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice","volume":"11","author":"Porter","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s10048-006-0031-7","article-title":"Analysis of gene expression differences between utrophin\/dystrophin-deficient vs mdx skeletal muscles reveals a specific upregulation of slow muscle genes in limb muscles","volume":"7","author":"Baker","year":"2006","journal-title":"Neurogenetics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/j.jmb.2003.09.012","article-title":"The muscle ankyrin repeat proteins: CARP, ankrd2\/Arpp and DARP as a family of titin filament-based stress response molecules","volume":"333","author":"Miller","year":"2003","journal-title":"J. Mol. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1152\/physrev.00017.2009","article-title":"Muscle giants: Molecular scaffolds in sarcomerogenesis","volume":"89","author":"Ackermann","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"14801","DOI":"10.1074\/jbc.M708262200","article-title":"Multiple molecular interactions implicate the connectin\/titin N2A region as a modulating scaffold for p94\/calpain 3 activity in skeletal muscle","volume":"283","author":"Hayashi","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"31158","DOI":"10.1074\/jbc.270.52.31158","article-title":"Muscle-specific calpain, p94, responsible for limb girdle muscular dystrophy type 2A, associates with connectin through IS2, a p94-specific sequence","volume":"270","author":"Sorimachi","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.biochi.2015.09.010","article-title":"An eccentric calpain, CAPN3\/p94\/calpain-3","volume":"122","author":"Ono","year":"2016","journal-title":"Biochimie"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1023\/A:1005572125827","article-title":"Fibre type-specific expression of p94, a skeletal muscle-specific calpain","volume":"20","author":"Jones","year":"1999","journal-title":"J. Muscle Res. Cell Motil."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.1172\/JCI40658","article-title":"Dynamic distribution of muscle-specific calpain in mice has a key role in physical-stress adaptation and is impaired in muscular dystrophy","volume":"120","author":"Ojima","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0092-8674(95)90368-2","article-title":"Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A","volume":"81","author":"Richard","year":"1995","journal-title":"Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1083\/jcb.151.7.1583","article-title":"Loss of calpain 3 proteolytic activity leads to muscular dystrophy and to apoptosis-associated IkappaBalpha\/nuclear factor kappaB pathway perturbation in mice","volume":"151","author":"Richard","year":"2000","journal-title":"J. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1093\/hmg\/9.9.1393","article-title":"Myopathy phenotype of transgenic mice expressing active site-mutated inactive p94 skeletal muscle-specific calpain, the gene product responsible for limb girdle muscular dystrophy type 2A","volume":"9","author":"Tagawa","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"C355","DOI":"10.1152\/ajpcell.00211.2003","article-title":"Rapid muscle-specific gene expression changes after a single bout of eccentric contractions in the mouse","volume":"286","author":"Barash","year":"2004","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1002\/ar.22968","article-title":"Probing muscle ankyrin-repeat protein (MARP) structure and function","volume":"297","author":"Lun","year":"2014","journal-title":"Anat. Rec."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1002\/jcsm.12319","article-title":"Titin-based mechanosensing modulates muscle hypertrophy","volume":"9","author":"Strom","year":"2018","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"12120","DOI":"10.1038\/ncomms12120","article-title":"MLP and CARP are linked to chronic PKCalpha signalling in dilated cardiomyopathy","volume":"7","author":"Lange","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1016\/S0002-9440(10)61123-6","article-title":"Carp, a cardiac ankyrin-repeated protein, and its new homologue, Arpp, are differentially expressed in heart, skeletal muscle, and rhabdomyosarcomas","volume":"160","author":"Ishiguro","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"C218","DOI":"10.1152\/ajpcell.00055.2007","article-title":"Structural and regulatory roles of muscle ankyrin repeat protein family in skeletal muscle","volume":"293","author":"Barash","year":"2007","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1002\/1873-3468.12362","article-title":"CARP interacts with titin at a unique helical N2A sequence and at the domain Ig81 to form a structured complex","volume":"590","author":"Zhou","year":"2016","journal-title":"FEBS Lett."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"173","DOI":"10.3389\/fphys.2020.00173","article-title":"Single-Molecule Force Spectroscopy on the N2A Element of Titin: Effects of Phosphorylation and CARP","volume":"11","author":"Lanzicher","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2102","DOI":"10.1529\/biophysj.107.106153","article-title":"Interaction forces between F-actin and titin PEVK domain measured with optical tweezers","volume":"93","author":"Bianco","year":"2007","journal-title":"Biophys. J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1016\/S0006-3495(98)77706-9","article-title":"A spring tale: New facts on titin elasticity","volume":"75","author":"Linke","year":"1998","journal-title":"Biophys. J."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1006\/jsbi.1998.3984","article-title":"PEVK extension of human soleus muscle titin revealed by immunolabeling with the anti-titin antibody 9D10","volume":"122","author":"Trombitas","year":"1998","journal-title":"J. Struct. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"13716","DOI":"10.1073\/pnas.2235652100","article-title":"Calcium-dependent molecular spring elements in the giant protein titin","volume":"100","author":"Labeit","year":"2003","journal-title":"Sci. Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"C19","DOI":"10.1152\/ajpcell.00156.2015","article-title":"The increase in non-cross-bridge forces after stretch of activated striated muscle is related to titin isoforms","volume":"310","author":"Cornachione","year":"2016","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"H2528","DOI":"10.1152\/ajpheart.00553.2004","article-title":"Titin isoform-dependent effect of calcium on passive myocardial tension","volume":"287","author":"Fujita","year":"2004","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1152\/physiol.00036.2019","article-title":"Titin: A Tunable Spring in Active Muscle","volume":"35","author":"Nishikawa","year":"2020","journal-title":"Physiology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"70","DOI":"10.3389\/fphys.2017.00070","article-title":"Physiological Mechanisms of Eccentric Contraction and Its Applications: A Role for the Giant Titin Protein","volume":"8","author":"Hessel","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1146\/annurev-physiol-022516-034152","article-title":"Huxleys\u2019 missing filament: Form and function of titin in vertebrate skelletal muscle","volume":"79","author":"Lindstedt","year":"2017","journal-title":"Ann. Rev. Physiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s10974-019-09540-y","article-title":"Calcium-dependent titin-thin filament interactions in muscle: Observations and theory","volume":"41","author":"Nishikawa","year":"2020","journal-title":"J. Muscle Res. Cell Motil."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.jshs.2018.06.002","article-title":"Basic science and clinical use of eccentric contractions: History and uncertainties","volume":"7","author":"Nishikawa","year":"2018","journal-title":"J. Sport Health Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"7101","DOI":"10.1073\/pnas.88.16.7101","article-title":"Regulation of skeletal muscle stiffness and elasticity by titin isoforms: A test of the segmental extension model of resting tension","volume":"88","author":"Wang","year":"1991","journal-title":"Sci. Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/978-1-4419-9029-7_46","article-title":"Adaptations in titin\u2019s spring elements in normal and cardiomyopathic hearts","volume":"538","author":"Granzier","year":"2003","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/0014-5793(96)00338-9","article-title":"A molecular map of titin\/connectin elasticity reveals two different mechanisms acting in series","volume":"385","author":"Gautel","year":"1996","journal-title":"FEBS Lett."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1006\/jmbi.1996.0441","article-title":"Towards a molecular understanding of the elasticity of titin","volume":"261","author":"Linke","year":"1996","journal-title":"J. Mol. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1126\/science.4071053","article-title":"Myofibrils bear most of the resting tension in frog skeletal muscle","volume":"230","author":"Magid","year":"1985","journal-title":"Science"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"12688","DOI":"10.1073\/pnas.2133733100","article-title":"Damped elastic recoil of the titin spring in myofibrils of human myocardium","volume":"100","author":"Opitz","year":"2003","journal-title":"Sci. Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1023\/A:1026053530766","article-title":"Gigantic variety: Expression patterns of titin isoforms in striated muscles and consequences for myofibrillar passive stiffness","volume":"24","author":"Neagoe","year":"2003","journal-title":"J. Muscle Res. Cell Motil."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1085\/jgp.200509364","article-title":"Isoform diversity of giant proteins in relation to passive and active contractile properties of rabbit skeletal muscles","volume":"126","author":"Prado","year":"2005","journal-title":"J. Gen. Physiol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"C1092","DOI":"10.1152\/ajpcell.16.2008","article-title":"Early mechanical dysfunction of the diaphragm in the muscular dystrophy with myositis (Ttnmdm) model","volume":"295","author":"Lopez","year":"2008","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_79","first-page":"828","article-title":"Effects of activation on the elastic properties of intact soleus muscles with a deletion in titin","volume":"220","author":"Monroy","year":"2017","journal-title":"J. Exp. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Tahir, U., Monroy, J.A., Rice, N.A., and Nishikawa, K.C. (2020). Effects of a titin mutation on force enhancement and force depression in mouse soleus muscles. J. Exp. Biol., 223.","DOI":"10.1242\/jeb.197038"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"14575","DOI":"10.1038\/s41598-018-32952-8","article-title":"Calcium increases titin N2A binding to F-actin and regulated thin filaments","volume":"8","author":"Dutta","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1113\/jphysiol.2002.032185","article-title":"Energy storage during stretch of active single fibRes. from frog skeletal muscle","volume":"548","author":"Linari","year":"2003","journal-title":"J. Physiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1113\/jphysiol.1979.sp012895","article-title":"The effect on tension of non-uniform distribution of length changes applied to frog muscle fibres","volume":"293","author":"Julian","year":"1979","journal-title":"J. Physiol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1242\/jcs.111.11.1567","article-title":"Characterizing titin\u2019s I-band Ig domain region as an entropic spring","volume":"111 Pt 11","author":"Linke","year":"1998","journal-title":"J. Cell Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"3118","DOI":"10.1016\/S0006-3495(02)75653-1","article-title":"A non-cross-bridge stiffness in activated frog muscle fibers","volume":"82","author":"Bagni","year":"2002","journal-title":"Biophys. J."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1113\/jphysiol.1994.sp020437","article-title":"Development of stiffness precedes cross-bridge attachment during the early tension rise in single frog muscle fibres","volume":"481 Pt 2","author":"Bagni","year":"1994","journal-title":"J. Physiol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"C1353","DOI":"10.1152\/ajpcell.00493.2003","article-title":"Non-cross-bridge calcium-dependent stiffness in frog muscle fibers","volume":"286","author":"Bagni","year":"2004","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"C1123","DOI":"10.1152\/ajpcell.00290.2014","article-title":"Force enhancement after stretch in mammalian muscle fiber: No evidence of cross-bridge involvement","volume":"307","author":"Nocella","year":"2014","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"C566","DOI":"10.1152\/ajpcell.00355.2011","article-title":"A non-cross-bridge, static tension is present in permeabilized skeletal muscle fibers after active force inhibition or actin extraction","volume":"302","author":"Cornachione","year":"2012","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1242\/jeb.205.9.1275","article-title":"Force enhancement following stretching of skeletal muscle: A new mechanism","volume":"205","author":"Herzog","year":"2002","journal-title":"J. Exp. Biol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s00424-007-0287-2","article-title":"Passive force enhancement in single myofibrils","volume":"455","author":"Joumaa","year":"2007","journal-title":"Pflugers Arch."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"C74","DOI":"10.1152\/ajpcell.00218.2007","article-title":"The origin of passive force enhancement in skeletal muscle","volume":"294","author":"Joumaa","year":"2008","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"269","DOI":"10.6061\/clinics\/2013(02)R01","article-title":"Muscle residual force enhancement: A brief review","volume":"68","author":"Minozzo","year":"2013","journal-title":"Clinics"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1113\/JP272983","article-title":"Residual force enhancement is regulated by titin in skeletal and cardiac myofibrils","volume":"595","author":"Shalabi","year":"2017","journal-title":"J. Physiol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"C14","DOI":"10.1152\/ajpcell.00049.2010","article-title":"Regulation of muscle force in the absence of actin-myosin-based cross-bridge interaction","volume":"299","author":"Leonard","year":"2010","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_96","first-page":"981","article-title":"Is titin a \u2018winding filament\u2019? A new twist on muscle contraction","volume":"279","author":"Nishikawa","year":"2012","journal-title":"Proc. Biol. Sci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1242\/jeb.02276","article-title":"Storage and recovery of elastic potential energy powers ballistic prey capture in toads","volume":"209","author":"Lappin","year":"2006","journal-title":"J. Exp. Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/978-1-4615-4267-4_22","article-title":"Possible contribution of titin filaments to the compliant series elastic component in horseshoe crab skeletal muscle fibers","volume":"481","author":"Sugi","year":"2000","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_99","first-page":"3629","article-title":"Titin force is enhanced in actively stretched skeletal muscle","volume":"217","author":"Powers","year":"2014","journal-title":"J. Exp. Biol."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Schappacher-Tilp, G., Leonard, T., Desch, G., and Herzog, W. (2015). A novel three-filament model of force generation in eccentric contraction of skeletal muscles. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117634"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1002\/jcsm.12486","article-title":"Myopalladin promotes muscle growth through modulation of the serum response factor pathway","volume":"11","author":"Filomena","year":"2020","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"7442","DOI":"10.1074\/jbc.M008851200","article-title":"Modular motif, structural folds and affinity profiles of the PEVK segment of human fetal skeletal muscle titin","volume":"276","author":"Wang","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/S0014-5793(02)03655-4","article-title":"Interaction of nebulin SH3 domain with titin PEVK and myopalladin: Implications for the signaling and assembly role of titin and nebulin","volume":"532","author":"Ma","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"27539","DOI":"10.1074\/jbc.M604525200","article-title":"Titin as a giant scaffold for integrating stress and Src homology domain 3-mediated signaling pathways: The clustering of novel overlap ligand motifs in the elastic PEVK segment","volume":"281","author":"Ma","year":"2006","journal-title":"J. Biol. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/11\/3974\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:34:38Z","timestamp":1760175278000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/11\/3974"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,1]]},"references-count":104,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["ijms21113974"],"URL":"https:\/\/doi.org\/10.3390\/ijms21113974","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,1]]}}}