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Muscular atrophy.

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A healthy skeletal musculature is necessary for a good quality of life and is important in sports. The loss of skeletal muscle mass leads to severe clinical complications and alters daily functioning. The aim of this book is to give an overview of skeletal muscle atrophy including pathomechanism, clinical characters, and the tools for prevention and treatment. Skeletal muscle atrophy can develop due to neurogenic or myogenic reasons, and frequently appears as an age-dependent disorder (sarcopenia). The studies of theoretical background give promising perspectives to prevent and treat muscle atrophy. The book is recommended to scientists, practitioners, students, sportsmen, and everybody who is interested in the normal and impaired function of the skeletal muscle.

Muscular atrophy.

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A healthy skeletal musculature is necessary for a good quality of life and is important in sports. The loss of skeletal muscle mass leads to severe clinical complications and alters daily functioning. The aim of this book is to give an overview of skeletal muscle atrophy including pathomechanism, clinical characters, and the tools for prevention and treatment. Skeletal muscle atrophy can develop due to neurogenic or myogenic reasons, and frequently appears as an age-dependent disorder (sarcopenia). The studies of theoretical background give promising perspectives to prevent and treat muscle atrophy. The book is recommended to scientists, practitioners, students, sportsmen, and everybody who is interested in the normal and impaired function of the skeletal muscle.

Muscular atrophy.

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Spinal muscular atrophy --- Spinal muscular atrophy --- Children

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During hypercatabolitic states, activation of the ubiquin-proteasome system is the principal cause of muscular mass loss. Two ubiquin ligases, Mafbx/Astrogin-1 and MuRF1, have been recently reported to play a crucial role in the process Nevertheless, the regulation of these ubiquitin ligases remains unknown.
Endotoxin (LPS) Injection, a classical model of experimental sepsis, induces an outburst of these ubiquitine ligases. In contrast, the induction of two other components of this proteolytic system, the conjugating enzyme E214Da and the ubiquitin remains modest.
The ubiquitin-proteasome system response can be regulated by glucocorticoids, pro-inflammatory cytokines and IGF-I. Their action on these ubiquitin ligases remains unknown. In opposition to diabetes and fasting, the administration of IGF-I in septic rats, does not prevent the induction of these enzymes. This observation indicates that the reduction of IGF-I induced by LPS is not responsible for the induction of these ubiquitin ligases. Moreover, induction of the two ligases is not prevented by inhibition of the TNF-α production by the pentoxyfilline. Therefore, elevation of circulating TNF-α caused by LPS does not probably play a major role in the stimulation of these ubiquitin ligases during the sepsis.
In a, second step, we have extended our in vivo observations by the study of the regulation of Mafbx/Astrogin-1 by the glucocorticoids, TNF-α and IGF-I in muscular cell culture. We observed that IGF-I at physiological concentrations inhibits the Mafbx/Astrogin-1 expression. In contrast, this ligase is induced by glucocorticoids, at pharmacological concentrations. TNF-α does not induce the expression of this gene. Moreover, the action of IGF-I on the Mafbx/Astrogin-1 is not inhibited by TNF-α or glucocorticoids.
In conclusion, this study indicates that the induction of the Mafbx/Astrogin-1 during the sepsis is probably caused by glucocorticoids and not by the induction of TNF-α or the reduction of IGF-I La perte de masse musculaire Durant les états hypercataboliques est principalement causée par l’activation du système protéique ubiquitine-protéasome. Deux ubiquitine ligases, Mafbx/Atrogine-1 et MuRF1, susceptibles de jouer un rôle crucial dans la perte de mase musculaire au cours des états hypercataboliques viennent d’être décrites. La régulation de ces ubiquitine ligases dans le sepsis est mal connue. Mon travail a montré que l’injection d’endotoxine (LPS), un modèle de sepsis, induit l’expression de ces deux ubiquitine ligases de manière fulgurante dans le muscle squelettique. L’induction de deux autres composants du système ubiquitine-protéasome, l’enzyme de conjugaison E214Da et l’ubiquitine elle-même, est par contre modeste.
Plusieurs facteurs régulent le système ubiquitine-protéasome, parmi lesquels les glucocorticoïdes, les cytokines et l’IGF-I. Leur rôle dans la régulation de ces ubiquitine ligases au cours du sepsis est inconnu. Mon travail a montré que l’administration d’IGF-I à des rats septiques ne prévient pas l’induction des enzymes. Cette observation indique donc la diminution d’IGF-I induite par le LPS n’est pas responsable de l’induction de ces ubiquitine ligases. Nous avons également montré que l’inhibition de la production du TNF-α par la pentoxyfilline ne prévient pas non plus l’induction de ces ubiquitine ligases. Ces données indiquent que l’élévation des taux circulants de TNF-α causée par le LPS ne joue probablement pas de rôle dans la stimulation de ces ubiquitine ligases au cours du sepsis.
Ces travaux chez l’animal ont été prolongés par l’étude de la régulation de Mafbx/Atrogine-1 par l’IGF-I, le TNF-α et les glucocorticoïdes dans un modèle de cellules musculaires en culture. Dans ce modèle, nous avons observé que l’IGF-I, à des concentrations physiologiques, inhibe l’expression de Mafbx/Atrogine-1. Par contre, les glucocorticoïdes, mais à des concentrations pharmacologiques, stimulent l’expression de cette ubiquitine. Le TNF-α, lui, n’a aucun effet sur l’expression de ce gène. Ni le TNF-α ni les glucocorticoïdes ne bloquent cependant l’action inhibitrice de l’IGF-I sur Mafbx/Atrogine-1.
Mon travail suggère donc que l’induction de Mafbx/Atrogine-1 au cours du sepsis est causée par les glucocorticoïdes et non par l’induction du TNF-α ou le déclin de l’IGF-I

Sepsis --- Ubiquitin --- Muscular Atrophy