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Quarta, Marco (2008) Calcium signals in myogenics cells and muscle fibers: an integrated study. [Tesi di dottorato]

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Abstract (inglese)

Calcium release during skeletal muscle excitation-contraction (EC) coupling occurs at the junctions between the sarcoplasmic reticulum (SR) and either the plasma membrane or T-Tubule. These Ca2+ release units are characterized by a specific molecular composition and their specific structural organization, both of which are important for the tissue-specific mode of skeletal muscle EC coupling. Though EC coupling has been known for over half a century, it is still an active area of biomedical research. The general scheme is that an action potential arrives to depolarise the cell membrane. By mechanisms specific to the muscle type, this depolarisation results in an increase in cytosolic calcium that is called calcium transient. This increase in calcium activates calcium-sensitive myofibrillar proteins that then trigger ATP hydrolysis by myosin causing cell shortening. However, the exact mechanism if EC coupling and the role of related Ca2+ singnaling in regulating intracellular skeletal muscle ptthways is far to be clear. To higlight some of these unclear and dark points, we realized two null-mice for SR proteins. The first lacks of a sarcoplasmic reticulum Ca2+-binding protein, termed Calsequestrin (Csq), which plays an important role in buffering [Ca2+]SR and modulating Ca2+ release and reuptake during EC coupling. Our findings reveal the essential role of Csq1 in reorganizing stores and an impaired calcium handling in mice lacking Csq1.
an essential role of Cs as presented in chapter 1. Our data suggest that Csq1 deficency may result in a myopathy similar to that caused by mutations of RyR1 in skeletal muscle, leading to fulminant malignant hyperthermia (MH) episodes, as presented in chapter 2.
To investigate the structural role of SR we realized a second model, Ank1.5-null mice. The highly regulated nature of the arrangement of the SR around myofibrils is such that specific domains of the SR involved in the mechanisms of Ca2+ release and uptake (i.e., terminal cisternae and longitudinal tubules, respectively) are positioned at regular intervals in correspondence of specific regions of the sarcomere. However, the molecular mechanisms responsible of the interactions between these two cellular structures are not known. The small Ankirin 1.5 locates at SR level and participate in positioning SR and myofibrils. In chapter 3 we present evidence of contractile response impairment in skeletal muscles and altered animal performances of Ank1.5 deficient mices, without structural and ultrastructural morphological changes. The Ank1.5 could play a specific role not restricted to a correct positioning of the SR at specific sarcomere regions and its deficency may contribute to the generation of myopathies, and EC coupling dysfunctions.
To perform a deeper study of the development of the skeletal muscle cells, and in particular to better explore calcium signals in the context of EC coupling, we developed a muscle-cell / semiconductor chip device to induce EC coupling with non invasive long termed electric capacitive stimulation. We present in chapter 4 for the first time a new technique to study live EC coupling and Calcium signals in long term experiments and with high resolution, down to single cells, to induce muscle plasticity and synaptogenesis effects. The same approach is used for muscle fibers dissociated from mouse FDB muscle. To conclude, our hybrid device put an innovative base for new approaches aimed to better understand the muscle development and regeneration in normal and pathogenic conditions.

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Tipo di EPrint:Tesi di dottorato
Relatore:Reggiani, Carlo
Dottorato (corsi e scuole):Ciclo 20 > Scuole per il 20simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > NEUROSCIENZE
Data di deposito della tesi:2008
Anno di Pubblicazione:2008
Parole chiave (italiano / inglese):EC coupling, calsequestrin, malignant hyperthermia syndrome, ankyrin, skeletal muscle, semiconductor silicon chip, myoelectronics
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/09 Fisiologia
Struttura di riferimento:Dipartimenti > Dipartimento di Anatomia e Fisiologia Umana
Codice ID:640
Depositato il:13 Nov 2008
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