A Proposed Mechanism for Enhanced Titin-Based Force during Ca2+-activation

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atmire.migration.oldid5503
dc.contributor.advisorHerzog, Walter
dc.contributor.authorPowers, Krysta
dc.contributor.committeememberPollack, Gerald
dc.contributor.committeememberSchmidt, Tannin
dc.contributor.committeememberSyme, Douglas
dc.contributor.committeememberNishikawa, Kiisa
dc.contributor.committeememberShemanko, Carrie
dc.contributor.committeememberFederico, Salvatore
dc.date.accessioned2017-04-27T19:01:17Z
dc.date.available2017-04-27T19:01:17Z
dc.date.issued2017
dc.date.submitted2017en
dc.description.abstractWhen an active skeletal muscle sarcomere is stretched, it generates more force after the stretch is completed when compared to a contraction at the same corresponding length. This mechanical property of skeletal muscle defies explanation by any conventional mechanism of contraction. Surmounting evidence indicates that the explanation for enhanced force following active stretch may be provided by the titin protein in the sarcomere, which becomes stiffer during Ca2+-activation. This thesis explores the mechanisms by which titin force is enhanced in actively stretched sarcomeres. Known to stiffen in the presence of Ca2+, the first study quantifies the contribution of Ca2+ to enhanced titin force, showing that an alternative mechanism accounts for the majority of titin force enhancement. The mechanism is further investigated using chemical inhibition of cross-bridges which shows that titin force enhancement is initiated with the development of contractile force. The next set of studies increase support for an interdependence of titin force enhancement and contractile force, showing that titin force enhancement is essentially eliminated and contractile force is decreased in sarcomeres with muscular dystrophy with myositis (mdm), a genetic mutation affecting the titin protein. The final study seeks to determine whether mechanical deficiencies in titin force enhancement are observed in a less reduced, single fiber preparation. Mutant fibers generated comparable contractile force and total force following active stretch beyond filament overlap as control fibers. Titin force enhancement was abolished in some mutant fibers and measured in other mutant fibers suggesting that the mdm mutation differentially affects fibers (and titin) in skeletal muscle. Passive force was increased in mutant fibers, showing that alternative structural components in a fiber can re-establish enhanced active stiffness in the absence of titin force enhancement. Collectively, the findings from this thesis show that titin-based force enhancement is an inherent property of skeletal muscle. The mechanism of titin force enhancement is crucial to sarcomere mechanics; as in its absence, sarcomeres generate less force and alternative structures to titin establish a comparable increase in active stiffness.en_US
dc.identifier.citationPowers, K. (2017). A Proposed Mechanism for Enhanced Titin-Based Force during Ca2+-activation (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/24984en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/24984
dc.identifier.urihttp://hdl.handle.net/11023/3753
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectPhysiology
dc.subjectEngineering--Biomedical
dc.titleA Proposed Mechanism for Enhanced Titin-Based Force during Ca2+-activation
dc.typedoctoral thesis
thesis.degree.disciplineBiomedical Engineering
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
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