[HTML][HTML] The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors

TN Stitt, D Drujan, BA Clarke, F Panaro, Y Timofeyva… - Molecular cell, 2004 - cell.com
TN Stitt, D Drujan, BA Clarke, F Panaro, Y Timofeyva, WO Kline, M Gonzalez
Molecular cell, 2004cell.com
Skeletal muscle size depends upon a dynamic balance between anabolic (or hypertrophic)
and catabolic (or atrophic) processes. Previously, no link between the molecular mediators
of atrophy and hypertrophy had been reported. We demonstrate a hierarchy between the
signals which mediate hypertrophy and those which mediate atrophy: the IGF-1/PI3K/Akt
pathway, which has been shown to induce hypertrophy, prevents induction of requisite
atrophy mediators, namely the muscle-specific ubiquitin ligases MAFbx and MuRF1 …
Abstract
Skeletal muscle size depends upon a dynamic balance between anabolic (or hypertrophic) and catabolic (or atrophic) processes. Previously, no link between the molecular mediators of atrophy and hypertrophy had been reported. We demonstrate a hierarchy between the signals which mediate hypertrophy and those which mediate atrophy: the IGF-1/PI3K/Akt pathway, which has been shown to induce hypertrophy, prevents induction of requisite atrophy mediators, namely the muscle-specific ubiquitin ligases MAFbx and MuRF1. Moreover, the mechanism for this inhibition involves Akt-mediated inhibition of the FoxO family of transcription factors; a mutant form of FOXO1, which prevents Akt phosphorylation, thereby prevents Akt-mediated inhibition of MuRF1 and MAFbx upregulation. Our study thus defines a previously uncharacterized function for Akt, which has important therapeutic relevance: Akt is not only capable of activating prosynthetic pathways, as previously demonstrated, but is simultaneously and dominantly able to suppress catabolic pathways, allowing it to prevent glucocorticoid and denervation-induced muscle atrophy.
cell.com