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Sustained activation of mTORC1 in skeletal muscle inhibits constitutive and starvation-induced autophagy and causes a severe, late-onset myopathy.

Abstract：

:Autophagy is a catabolic process that ensures homeostatic cell clearance and is deregulated in a growing number of myopathological conditions. Although FoxO3 was shown to promote the expression of autophagy-related genes in skeletal muscle, the mechanisms triggering autophagy are unclear. We show that TSC1-deficient mice (TSCmKO), characterized by sustained activation of mTORC1, develop a late-onset myopathy related to impaired autophagy. In young TSCmKO mice, constitutive and starvation-induced autophagy is blocked at the induction steps via mTORC1-mediated inhibition of Ulk1, despite FoxO3 activation. Rapamycin is sufficient to restore autophagy in TSCmKO mice and improves the muscle phenotype of old mutant mice. Inversely, abrogation of mTORC1 signaling by depletion of raptor induces autophagy regardless of FoxO inhibition. Thus, mTORC1 is the dominant regulator of autophagy induction in skeletal muscle and ensures a tight coordination of metabolic pathways. These findings may open interesting avenues for therapeutic strategies directed toward autophagy-related muscle diseases.

journal_name

Cell Metab

journal_title

Cell metabolism

authors

Castets P,Lin S,Rion N,Di Fulvio S,Romanino K,Guridi M,Frank S,Tintignac LA,Sinnreich M,Rüegg MA

doi

10.1016/j.cmet.2013.03.015

subject

Has Abstract

pub_date

2013-05-07 00:00:00

pages

731-44

issue

5

eissn

1550-4131

issn

1932-7420

pii

S1550-4131(13)00119-8

journal_volume

17

pub_type

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