Diss. (sammanfattning) Linköping : Univ., 2006. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Missouri--Columbia, 2004. / "May 2004." Typescript. Vita. Includes bibliographical references (leaves 166-179). Also issued on the Internet.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2004. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Missouri--Columbia, 2002. / "May 2002." Typescript. Vita. Includes bibliographical references (leaves 110-136). Also available online.

Thesis (Ph. D.)--University of Missouri--Columbia, 2002. / Typescript. Vita. Includes bibliographical references (leaves 110-136). Also available online. Also available on the Internet.

Thesis (Ph. D.)--University of Missouri--Columbia, 2004. / Typescript. Vita. Includes bibliographical references (leaves 166-179). Also issued on the Internet.

Smooth muscle is a primary determinant of physiology as its ability to contract affords dynamic control of diameter of the hollow organs it encircles including the airways. Mature airway smooth muscle (ASM) cells are phenotypically plastic, enabling them to subserve contractile, proliferative, migratory and secretory roles that relates to its function in health and disease. ASM cells can control airway diameter both acutely, via reversible contraction, and chronically, by driving fixed changes in structure and function properties of the airway wall. However, the scope of research on ASM biology and function has broadened greatly in the past two decades, embracing the now recognized dynamic and multifunctional behavior, but there is always a need to investigate the role of new proteins regulating ASM phenotype in vitro and lung function in vivo. The multimeric dystrophin-glycoprotein complex (DGC) links the extracellular matrix (ECM) and actin cytoskeleton while caveolae form membrane arrays on ASM cells. Using ASM cells and tissues from human and canine and intact mouse for lung physiology, we investigated the role of DGC in phenotype maturation. We also investigated the mechanism for the organization of DGC with caveolae and further tested whether this is functionally important in mobilizing intracellular calcium in ASM cells, contraction of ASM tissue and finally its role in airway physiology. Our data demonstrate that the expression of DGC is an integral feature and a key determinant for phenotype maturation of human ASM cells. Our new data reveals an interaction between caveolin-1 and DGC and indicate that this association, in concert with anchoring to the actin cytoskeleton, underpins the spatial organization of caveolae on the membrane and has a functional role in receptor-mediated calcium release in ASM in vitro, ASM contraction ex vivo and lung function in vivo. Collectively our study indicates that the organization of caveolae and DGC, and its link from ECM to the actin cytoskeleton with in caveolae are a determinant of phenotype and functional properties of ASM, which underpins its role in physiology and pathophysiology of chronic airway diseases such as asthma.

Smooth muscle is a primary determinant of physiology as its ability to contract affords dynamic control of diameter of the hollow organs it encircles including the airways. Mature airway smooth muscle (ASM) cells are phenotypically plastic, enabling them to subserve contractile, proliferative, migratory and secretory roles that relates to its function in health and disease. ASM cells can control airway diameter both acutely, via reversible contraction, and chronically, by driving fixed changes in structure and function properties of the airway wall. However, the scope of research on ASM biology and function has broadened greatly in the past two decades, embracing the now recognized dynamic and multifunctional behavior, but there is always a need to investigate the role of new proteins regulating ASM phenotype in vitro and lung function in vivo. The multimeric dystrophin-glycoprotein complex (DGC) links the extracellular matrix (ECM) and actin cytoskeleton while caveolae form membrane arrays on ASM cells. Using ASM cells and tissues from human and canine and intact mouse for lung physiology, we investigated the role of DGC in phenotype maturation. We also investigated the mechanism for the organization of DGC with caveolae and further tested whether this is functionally important in mobilizing intracellular calcium in ASM cells, contraction of ASM tissue and finally its role in airway physiology. Our data demonstrate that the expression of DGC is an integral feature and a key determinant for phenotype maturation of human ASM cells. Our new data reveals an interaction between caveolin-1 and DGC and indicate that this association, in concert with anchoring to the actin cytoskeleton, underpins the spatial organization of caveolae on the membrane and has a functional role in receptor-mediated calcium release in ASM in vitro, ASM contraction ex vivo and lung function in vivo. Collectively our study indicates that the organization of caveolae and DGC, and its link from ECM to the actin cytoskeleton with in caveolae are a determinant of phenotype and functional properties of ASM, which underpins its role in physiology and pathophysiology of chronic airway diseases such as asthma.

La sarcopénie est une maladie dégénérative liée à l’âge qui se caractérise par une perte progressive et involontaire de la masse et de la force musculaire. Elle s’accompagne d’une atteinte de la régénération musculaire et d’une accumulation des espèces réactives de l’oxygène. Les cavéoles sont des invaginations de la membrane plasmique. Dans le muscle, elles jouent un rôle dans la différenciation des cellules satellites et dans le maintien de l’unité contractile dans le muscle différencié. Certaines formes de myopathies sont consécutives à l’absence de cavéoles dans le muscle. Elles sont également impliquées dans la médiation de signaux liés à la régulation du stress oxydant. Afin de mieux comprendre les mécanismes régulant la mise en place de la sarcopénie, nous avons étudié ici les relations existant entre le stress oxydant et les cavéoles. Des cellules musculaires de souris ont été traitées par l’H2O2 et une diminution du taux des cavéolines-1et -3 a été mise en évidence dans des myoblastes et les myotubes, respectivement. Il apparaît donc que les protéines constitutives des cavéoles sont effectivement sensibles au stress oxydant dans les cellules musculaires. En présence d’H2O2, la fonction des cavéoles (endocytose et résistance au stress mécanique) était également significativement altérée dans des myoblastes. L’ensemble des résultats obtenus suggère que le stress oxydant aurait un effet sur les cavéoles, ce qui pourrait entraîner des conséquences sur la régénération et le maintien de l’intégrité musculaire au cours du vieillissement. / Sarcopenia is an age-related degenerative disease which is characterized by a progressive and involuntary loss of muscle mass and strength. It is accompanied by an impairment of muscle regeneration and accumulation of reactive oxygen species. Caveolae are invaginations of the plasma membrane. In muscle, they play a role in the differentiation of satellite cells and in maintaining the contractile unit of the differentiated skeletal muscle. Some myopathies are resulting from the absence of caveolae in muscle. Caveolae are also involved in mediating signals related to the regulation of oxidative stress. To better understand the mechanisms involved in the development of sarcopenia, we investigated here the relationship between oxidative stress and caveolae. Mouse muscle cells were treated with H2O2 and decreased levels of caveolin-1 and -3 were demonstrated in myoblasts and myotubes, respectively. It therefore appears that caveolae constituent proteins are actually sensitive to oxidative stress in muscle cells. In the presence of H2O2, caveolae functions (endocytosis and resistance to mechanical stress) were also significantly degraded in myoblasts. Altogether, these data suggest that oxidative stress would affect caveolae, which could have consequences on regeneration and maintenance of muscle integrity during aging.