The proteasome inhibitor MG132 reduces immobilization-induced skeletal muscle atrophy in miceReportar como inadecuado

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BMC Musculoskeletal Disorders

, 12:185

Pathophysiology of musculoskeletal disorders


BackgroundSkeletal muscle atrophy is a serious concern for the rehabilitation of patients afflicted by prolonged limb restriction. This debilitating condition is associated with a marked activation of NFκB activity. The ubiquitin-proteasome pathway degrades the NFκB inhibitor IκBα, enabling NFκB to translocate to the nucleus and bind to the target genes that promote muscle atrophy. Although several studies showed that proteasome inhibitors are efficient to reduce atrophy, no studies have demonstrated the ability of these inhibitors to preserve muscle function under catabolic condition.

MethodsWe recently developed a new hindlimb immobilization procedure that induces significant skeletal muscle atrophy and used it to show that an inflammatory process characterized by the up-regulation of TNFα, a known activator of the canonical NFκB pathway, is associated with the atrophy. Here, we used this model to investigate the effect of in vivo proteasome inhibition on the muscle integrity by histological approach. TNFα, IL-1, IL-6, MuRF-1 and Atrogin-MAFbx mRNA level were determined by qPCR. Also, a functional measurement of locomotors activity was performed to determine if the treatment can shorten the rehabilitation period following immobilization.

ResultsIn the present study, we showed that the proteasome inhibitor MG132 significantly inhibited IκBα degradation thus preventing NFκB activation in vitro. MG132 preserved muscle and myofiber cross-sectional area by downregulating the muscle-specific ubiquitin ligases atrogin-1-MAFbx and MuRF-1 mRNA in vivo. This effect resulted in a diminished rehabilitation period.

ConclusionThese finding demonstrate that proteasome inhibitors show potential for the development of pharmacological therapies to prevent muscle atrophy and thus favor muscle rehabilitation.

List of abbreviationsCSAcross sectional area

DMSOdimethyl suloxide

TAtibialis anterior

Tnfαtumor necrosis factor alpha.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2474-12-185 contains supplementary material, which is available to authorized users.

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Autor: Annabelle Z Caron - Sonia Haroun - Élisabeth Leblanc - Frédéric Trensz - Chantal Guindi - Aziz Amrani - Guillaume Greni


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