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La maladie de Huntington (HD) est une pathologie génétique multisystémique neurodégénérative rare caractérisée par des atteintes motrices, cognitives et psychiatriques. Elle est due à une augmentation de la répétition de triplet CAG dans l'exon 1 du gène HTT, dont la taille normale est de 6 à 35 répétitions. Cette expansion de triplets conduit à la présence d'une répétition de glutamine de taille anormale dans l'extrémité N-terminale de la protéine huntingtine (HTT). Les conséquences de la mutation sont d’une part la diminution de l’expression de la protéine non mutée et d’autre part l’expression d’une protéine mutée. L’une des fonctions de la HTT est le transport intracellulaire de vésicules le long des microtubules dans les neurones. Par ailleurs, une phénocopie : Huntington disease like 2 maladie ayant un phénotype similaire, est due à une perte de fonction de la junctophilin-3 ayant pour rôle l’établissement de points de contact entre la membrane plasmique et le reticulum endoplasmique au niveau neuronal. Les présents travaux visent à découvrir les mécanismes au sein desquels la HTT est impliquée dans un modèle différent de la cellule neuronale : la cellule musculaire. En effet, les points de contact nommées triades sont le cœur du couplage excitation-contraction. Les travaux ont permis de montrer, après avoir créé des modèles cellulaires et in vivo avec baisse d’expression de la protéine, un défaut de la fonction musculaire au niveau cellulaire comme au niveau physiologique. Les relâchements calciques sont altérés. La force est diminuée. De plus, ces altérations de fonctionnement sont corrélées à une baisse d’expression des principaux récepteurs de la triade. Enfin, une fraction exogène de la partie N-terminale de la protéine non mutée restaure les défauts calciques observés. La huntingtine a donc un rôle prépondérant dans la fonction princeps du muscle : la contraction. / Huntington Disease (HD) is a rare multisystemic neurodegenerative genetic disorder, which combines psychiatric, cognitive and motor alterations. It is caused by an increase in CAG repeats in the huntingtin gene, resulting in an expansion of polyglutamine stretch in the protein. This induced a loss of the huntingtin protein (HTT) normal function associated with production of a mutant protein. HTT is an ubiquitous microtubules associated protein, with numerous functions among which vesicles and organelles traffic along microtubules. Along this line, one of its functions could be the traffic of reticulum vesicles to form contact point with the plasma membrane in neurons. Moreover, a phenocopy named Huntington’s disease like 2 is due to junctophilin-3 loss of function. Junctophilin 3 is involved in contact points between endoplasmic reticulum and plasma membrane in neurons. These studies are dedicated to the validation of the hypothesis of the role of HTT in contact points between endoplasmic reticulum and plasma membrane in another model, in which contacts between reticulum and plasma membrane are of major importance: the skeletal muscle cell. Indeed, the contact points between sarcoplasmic reticulum and plasma membrane (T-Tubule), called the triads, are the basis of excitation-contraction coupling in muscle. In these studies, we develop cellular and animals models with a loss of expression of HTT in skeletal muscle specifically. Theses studies show that calcium release is altered at the cellular level and muscle force is altered at animal model level. Theses alterations are correlated with loss of expression of the main receptors of the triad. Finally, fragment of the normal protein can restore calcium defects. Theses studies put forward the role of huntingtine in skeletal muscle.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.

Graduation date: 1994

Thesis (Ph. D. in Cell and Developmental Biology)--Vanderbilt University, May 2007. / Title from title screen. Includes bibliographical references.

An acute bout of resistance exercise (RE) and dietary protein consumption stimulate muscle protein synthesis (MPS). This anabolic effect is believed to be attenuated with resistance exercise training (RET), however, the mechanism for this plateau" is unknown. In addition, the ideal timing for protein consumption to optimize MPS is not well characterized. The central hypothesis of this research is that RE stimulates cumulative (measured over 24-36 h) MPS in rats and humans. Study one determined whether an acute bout of RE in rats enhances MPS when assessed with the traditional flooding dose (~ 25 min) and 2H2O (4 and 24 h measurements); thus a comparison of the two methodologies was made. An acute session of RE did not result in an elevation in MPS when quantified by either the flooding dose or 2H2O over 4 and 24 h (methods compared qualitatively). Therefore, an acute bout of RE in rats does not appear to be anabolic and adaptation resulting from multiple bouts is likely necessary. Study two determined if RET in rats results in attenuation in MPS (plateau effect) 16 h following the final RE session (peak anabolic window) and if it is due to an increase in 4E-BP1 (a key regulator of mRNA translation initiation) activity; or if the timing in anabolism changes, which could be detected with a cumulative assessment (2H2O). MPS at 16 h was unchanged following RE training. Consistent with this finding, there were no differences in 4E-BP1 activity. Conversely, cumulative MPS was significantly increased with RET, suggesting a temporal shift in anabolism. Study three determined if dietary protein consumed immediately following RE augments cumulative (24 h) MPS in young adult human males when energy and macronutrients are controlled. RE and post-RE protein had no effect on mixed MPS; however, myofibrillar MPS was significantly increased with RE suggesting specific changes within a heterogeneous protein pool. Collectively, these are the first studies to assess changes in cumulative MPS with RE in rats and humans. The long term goals of this research are to understand muscle protein anabolism in "free-living" mammals and the mechanisms that regulate this process.

An acute bout of resistance exercise (RE) and dietary protein consumption stimulate muscle protein synthesis (MPS). This anabolic effect is believed to be attenuated with resistance exercise training (RET), however, the mechanism for this plateau" is unknown. In addition, the ideal timing for protein consumption to optimize MPS is not well characterized. The central hypothesis of this research is that RE stimulates cumulative (measured over 24-36 h) MPS in rats and humans. Study one determined whether an acute bout of RE in rats enhances MPS when assessed with the traditional flooding dose (~ 25 min) and 2H2O (4 and 24 h measurements); thus a comparison of the two methodologies was made. An acute session of RE did not result in an elevation in MPS when quantified by either the flooding dose or 2H2O over 4 and 24 h (methods compared qualitatively). Therefore, an acute bout of RE in rats does not appear to be anabolic and adaptation resulting from multiple bouts is likely necessary. Study two determined if RET in rats results in attenuation in MPS (plateau effect) 16 h following the final RE session (peak anabolic window) and if it is due to an increase in 4E-BP1 (a key regulator of mRNA translation initiation) activity; or if the timing in anabolism changes, which could be detected with a cumulative assessment (2H2O). MPS at 16 h was unchanged following RE training. Consistent with this finding, there were no differences in 4E-BP1 activity. Conversely, cumulative MPS was significantly increased with RET, suggesting a temporal shift in anabolism. Study three determined if dietary protein consumed immediately following RE augments cumulative (24 h) MPS in young adult human males when energy and macronutrients are controlled. RE and post-RE protein had no effect on mixed MPS; however, myofibrillar MPS was significantly increased with RE suggesting specific changes within a heterogeneous protein pool. Collectively, these are the first studies to assess changes in cumulative MPS with RE in rats and humans. The long term goals of this research are to understand muscle protein anabolism in "free-living" mammals and the mechanisms that regulate this process.

Thesis (Ph. D.)--University of Missouri--Columbia, 2003. / "December 2003." Typescript. Vita. Includes bibliographical references (leaves 63-74). Also issued on the Internet.

Thesis (Ph.D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Mechanical Engineering. Title from title-page of electronic thesis. Bibliography: leaves 98-106.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences